Chapter 5 Nutrition
In developing countries, lack of food and poor usage of the available food can result in protein-energy malnutrition (PEM); 50 million pre-school African children have PEM. In developed countries, excess food is available and the most common nutritional problem is obesity.
Diet and disease are interrelated in many ways:
Excess energy intake contributes to a number of diseases, including ischaemic heart disease and diabetes, particularly when high in animal (saturated) fat content.
There is a relationship between food intake and cancer, as found in many epidemiological studies. An excess of energy-rich foods (i.e. fat and sugar containing), often with physical inactivity, plays a role in the development of certain cancers, while diets high in vegetables and fruits reduce the risk of most epithelial cancers. Numerous carcinogens, intentional additions (e.g. nitrates for preserving foods) or accidental contaminants (e.g. moulds producing aflatoxin and fungi) may also be involved in the development of cancer.
The proportion of processed foods eaten may affect the development of disease. Some processed convenience foods have a high sugar and fat content and therefore predispose to dental caries and obesity, respectively. They also have a low fibre content, and dietary fibre can help in the prevention of a number of diseases (see p. 199).
Long-term undernutrition is implicated in disease by some epidemiological studies, for example low growth rates in utero are associated with high death rates from cardiovascular disease in adult life.
In the UK, dietary reference values for food and energy and nutrients are stated as reference nutrient intakes (RNIs), on the basis of data from the Food and Agriculture Organization (FAO-WHO), United Nations University (UNU) expert committee, and elsewhere. The RNI is sufficient or more than sufficient to meet the nutritional needs of 97.5% of healthy people in a population. Most people’s daily requirements are less than this, and so an estimated average requirement (EAR) is also given, which will certainly be adequate for most. A lower reference nutrient intake (LRNI) which fails to meet the requirements of 97.5% of the population is also given. The RNI figures quoted in this chapter are for the age group 19–50 years. These represent values for healthy subjects and are not always appropriate for patients with disease.
Water and electrolyte balance
Water and electrolyte balance is dealt with fully in Chapter 13. About 1 L of water is required in the daily diet to balance insensible losses, but much more is usually drunk, the kidneys being able to excrete large quantities. The daily RNI for sodium is 70 mmol (1.6 g) but daily sodium intake varies in the range 90–440 mmol (2–10 g). These are needlessly high intakes of sodium which are thought by some to play a role in causing hypertension (see p. 778).
Food is necessary to provide the body with energy (Fig. 5.1). The SI unit of energy is the joule (J), and 1 kJ = 0.239 kcal. The conversion factor of 4.2 kJ, equivalent to 1.00 kcal, is used in clinical nutrition.
Figure 5.1 The production of energy from the main constituents of food. Alcohol produces up to 5% of total calories, but the variation between individuals is wide. 1 mol of glucose produces 36 mol of ATP. NEFA, non-esterified fatty acids; ATP, adenosine triphosphate; TCA, tricarboxylic acid.
Energy balance is the difference between energy intake and energy expenditure. Weight gain or loss is a simple, but accurate, way of indicating differences in energy balance.
There are two approaches to assessing energy requirements for subjects who are weight stable and close to energy balance:
This can be estimated from dietary surveys and in the past this has been used to decide daily energy requirements. However, measurement of energy expenditure gives a more accurate assessment of requirements.
Daily energy expenditure (Fig. 5.2) is the sum of:
The basal metabolic rate (BMR)
The thermic effect of food eaten
Figure 5.2 Daily energy expenditure in an active and a sedentary 70 kg adult. BMR, basal metabolic rate; DIT, dietary induced thermogenesis; PAR, physical activity ratio.
Total energy expenditure can be measured using a double-labelled water technique. Water containing the stable isotopes 2H and 18O is given orally. As energy is expended carbon dioxide and water are produced. The difference between the rates of loss of the two isotopes is used to calculate the carbon dioxide production, which is then used to calculate energy expenditure. This can be done on urine samples over a 2–3-week period with the subject ambulatory. The technique is accurate, but it is expensive and requires the availability of a mass spectrometer. An alternative tracer technique for measuring total energy expenditure is to estimate CO2 production by isotopic dilution. A subcutaneous infusion of labelled bicarbonate is administered continuously by a minipump, and urine is collected to measure isotopic dilution by urea, which is formed from CO2. Other methods for estimating energy expenditure, such as heart rate monitors or activity monitors, are also available but are less accurate.
Basal metabolic rate. The BMR can be calculated by measuring oxygen consumption and CO2 production, but it is more usually taken from standardized tables (Table 5.1) that only require knowledge of the subject’s age, weight and sex.
|Age range (years)||Equation for predicting BMRa||95% confidence limits|
0.0740 × (wt) + 2.754
0.0630 × (wt) + 2.896
0.0480 × (wt) + 3.653
0.0499 × (wt) + 2.930
0.0350 × (wt) + 3.434
0.0560 × (wt) + 2.898
0.0620 × (wt) + 2.036
0.0340 × (wt) + 3.538
0.0386 × (wt) + 2.875
0.0410 × (wt) + 2.610
Data from Department of Health, 1991. BMR, basal metabolic rate. aBodyweight (wt) in kg.
Physical activity. The physical activity ratio (PAR) is expressed as multiples of the BMR for both occupational and non-occupational activities of varying intensities (Table 5.2).
Domestic helper/sales person
Total daily energy expenditure = BMR × [Time in bed + (Time at work × PAR) + (Non-occupational time × PAR)].
Thus, for example, to determine the daily energy expenditure of a 69-year-old, 50 kg female doctor, with a BMR of 4805 kJ/day spending one-third of a day sleeping, working and engaged in non-occupational activities, the latter at a PAR of 2.1, the following calculation ensues:
In the UK, the estimated ‘average’ daily energy requirement is:
This is at present made up of about 50% carbohydrate, 35% fat, 15% protein ± 5% alcohol. In developing countries, however, carbohydrate may be >75% of the total energy input, and fat <15% of the total energy input.
Energy requirements increase during the growing period, with pregnancy and lactation, and sometimes following infection or trauma. In general, the increased BMR associated with inflammatory or traumatic conditions is counteracted or more than counteracted by a decrease in physical activity, so that total energy requirements are not increased.
In the basal state, energy demands for resting muscle are 20% of the total energy required, abdominal viscera 35–40%, brain 20% and heart 10%. There can be more than a 50-fold increase in muscle energy demands during exercise.
Although virtually all body fat and glycogen are available for oxidation, less than half the protein is available for oxidation. Figure 5.3 shows that fat accounts for the largest reserves of energy in both lean and obese subjects. The size of the stores determines survival during starvation.
Bodyweight depends on energy balance. Intake depends not only on food availability but also on a number of complex interrelationships that include the stimulus of good food, the role of hunger, metabolic changes (e.g. hypoglycaemia), and the pleasure and habit of eating. Some people are able to keep their bodyweight constant within a few kilograms for many years, but most gradually increase their weight owing to a small but continuous increase of intake over expenditure. A gain or loss of energy of 25–29 MJ (6000–7000 kcal) would respectively increase or decrease bodyweight by approximately 1 kg.
In the UK, the adult daily RNI for protein is 0.75 g/kg, with protein representing at least 10% of the total energy intake. Most affluent people eat more than this, consuming 80–100 g of protein per day.
The total amount of nitrogen excreted in the urine represents the balance between protein breakdown and synthesis. In order to maintain nitrogen balance, at least 40–50 g of protein are needed. The amount of protein oxidized can be calculated from the amount of nitrogen excreted in the urine over 24 h using the following equation:
Grams of protein required = Urinary nitrogen × 6.25 (most proteins contain about 16% of nitrogen).
In practice, urinary urea is more easily measured and forms 80–90% of the total urinary nitrogen (N). In healthy individuals urinary nitrogen excretion reflects protein intake. However, excretion does not match intake in catabolic conditions (negative N balance) or during growth or repletion following an illness (positive N balance).
Protein contains many amino acids:
Indispensable (essential): there are nine amino acids that cannot be synthesized and must be provided in the diet: tryptophan, histidine, methionine, threonine, isoleucine, valine, phenylalanine, lysine, leucine.
Dispensable (non-essential): amino acids that can be synthesized in the body (some may still be needed in the diet unless adequate amounts of their precursors are available).
Animal proteins (e.g. in milk, meat, eggs) contain a good balance of all indispensable amino acids, but many proteins from vegetables are deficient in at least one indispensable amino acid. In developing countries, protein intake derives mainly from vegetable proteins. By combining foodstuffs with different low concentrations of indispensable amino acids (e.g. maize with legumes), protein intake can be adequate provided enough vegetables are available.
Loss of protein from the body (negative N balance) occurs not only because of inadequate protein intake, but also because of inadequate energy intake. When there is loss of energy from the body, more protein is directed towards oxidative pathways and eventually gluconeogenesis for energy.
Role of amino acids
Glutamine is quantitatively the most significant in the circulation and in inter-organ exchange.
Alanine is released from muscle; it is deaminated and converted into pyruvic acid before entering the citric acid cycle.
Homocysteine is a sulphur-containing amino acid which is derived from methionine in the diet. A raised plasma concentration is an independent risk factor for vascular disease (see p. 728).
Amino acids are utilized to synthesize products other than protein or urea. For example:
Dietary fat is chiefly in the form of triglycerides, which are esters of glycerol and free fatty acids. Fatty acids vary in chain length and in saturation (Table 5.3). The hydrogen molecules related to the double bonds can be in the cis or the trans position; most natural fatty acids in food are in the cis position (Box 5.1).
|Fatty acid||No. of carbon atoms : No. of double bonds||Position of double bondsa|
a Positions of the double bonds (designated either n as here or ω) are shown counted from the methyl end of the molecule. All double bonds are in the cis position except that marked trans.
Dietary sources of fatty acids
|Type of acid||Sources|
Saturated fatty acids
Mainly animal fat
n-6 fatty acids
Vegetable oils and other plant foods
n-3 fatty acids
Vegetable foods, rapeseed oil, fish oils
trans fatty acids
Hydrogenated fat or oils, e.g. in margarine, cakes, biscuits
The essential fatty acids (EFAs) are linoleic and α-linolenic acid, both of which are precursors of prostaglandins. Eicosapentaenoic and docosahexaenoic acid are also necessary, but can be made to a limited extent in the tissues from linoleic and linolenic acid, and thus a dietary supply is not essential.
Synthesis of triglycerides, sterols and phospholipids is very efficient. Even with low-fat diets subcutaneous fat stores can be normal.
Dietary fat provides 37 kJ (9 kcal) of energy per gram. A high-fat intake has been implicated in the causation of:
The data on causation are largely epidemiological and disputed by many. Nevertheless, it is often suggested that the consumption of saturated fatty acids should be reduced, accompanied by an increase in monounsaturated fatty acids (the ‘Mediterranean diet’) or polyunsaturated fatty acids. Any increase in polyunsaturated fats should not, however, exceed 10% of the total food energy, particularly as this requires a big dietary change.
Trans fats (partly hydrogenated fatty acids)
Increased consumption of hydrogenated vegetable and fish oils in margarines has led to increased trans fatty acid consumption. Trans fatty acids (also called trans fats) behave as if they were saturated fatty acids, increasing circulating LDL and decreasing HDL cholesterol concentrations, which in turn increase the risk of cardiovascular disease. In most countries, nutrition labels for all conventional foods and supplements must indicate the trans fatty acid content. The usage of trans fatty acids from partially hydrogenated oils has now been banned in many countries.
Polyunsaturated fatty acids
The n-6 polyunsaturated fatty acids (PUFA) are components of membrane phospholipids, influencing membrane fluidity and ion transport. They also have antiarrhythmic, antithrombotic and anti-inflammatory properties, all of which are potentially helpful in preventing cardiovascular disease.
The n-3 PUFA increase circulating high-density lipoprotein (HDL) cholesterol and lower triglycerides, both of which might reduce cardiovascular risk. Some of the actions of n-3 PUFA are mediated by a range of leukotrienes and eicosanoids, which differ in pattern and functions from those produced from n-6 PUFA.
Epidemiological studies and clinical intervention studies suggest that n-3 PUFA may have effects in the secondary prevention of cardiovascular disease and ‘all-cause mortality’ (e.g. 20–30% reduction in mortality from cardiovascular disease according to some studies). The benefits, which have been noted as early as 4 months after intervention, have been largely attributed to the antiarrhythmic effects of n-3 PUFA, but some work suggests that n-3 PUFA, administered as capsules, can be rapidly incorporated into atheromatous plaques, stabilizing them and preventing rupture. Whether these effects are due directly to n-3 PUFA or other changes in the diet is still debated.
The GISSI Prevention Trial, which followed over 11 000 patients for 3.5 years after a myocardial infarction, administered fish oils (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA) in the form of capsules and demonstrated a striking benefit in reducing mortality. The effects of vitamin E (300 mg α-tocopherol/day) were also studied, but no benefit was found.
Recommendations for fat intake
The British Nutrition Foundation and the American Heart Association presently recommend a two-fold increase of the current intake of total n-3 PUFA (several fold increase in the intake of fish oils, and a 50% increase in the intake of α-linolenic acid). Implementing this recommendation will mean either a major change in the dietary habits of populations that eat little fish, or ingestion of capsules containing fish oils. Some government agencies have warned of the hazards of eating certain types of fish, which increase the risk of mercury poisoning and possibly other toxicities.
The current recommendations for fat intake for the UK are shown in Box 5.2.
Recommended healthy dietary intake
|Dietary component||Approximate amounts given as % of total energy unless otherwise stated||General hints|
Increase fruit, vegetables, beans, pasta, bread
Decrease sugary drinks
Decrease red meat (see fat below)
Increase vegetable (including olive oil) and fish oil and decrease animal fat
Saturated fatty acids
Cis-mono unsaturated fatty acids
Mainly oleic acid (n-6)
Cis-polyunsaturated fatty acids
Both n-6 and n-3 PUFA
<300 (<300) mg/day
Decrease meat and eggs
<6 (<5) g/day
Decrease prepared meats and do not add extra salt to food
Total dietary fibre
30 (>25) g/day
Increase fruit and vegetables and wholegrain foods
Values in parentheses are goals for the intake of populations, as given by the WHO (including populations who are already on low-fat diets). Some of the extreme ranges are not realistic short-term goals for developed countries, e.g. 75% of total energy from carbohydrate and 15% fat. When total energy intake is 2500 kcal (10 500 kJ) per day, 55% of intake comes from carbohydrate (344 g, i.e. 1376 kcal (5579 kJ)) and 30% from fat (83 g, i.e. 747 kcal (3137 kJ)).
Cholesterol is found in all animal products. Eggs are particularly rich in cholesterol, which is virtually absent from plants. The average daily intake in the UK is 300–500 mg. Cholesterol is also synthesized (see p. 306) and only very high or low dietary intakes will significantly affect blood levels.
Essential fatty acid deficiency
Essential fatty acid deficiency may accompany protein-energy malnutrition (PEM), but it has been clearly defined as a clinical entity only in patients on long-term parenteral nutrition given glucose, protein and no fat. Alopecia, thrombocytopenia, anaemia and dermatitis occur within weeks with an increased ratio of triene (n-9) to tetraene (n-6) in plasma fatty acids.
Carbohydrates are readily available in the diet, providing 17 kJ (4 kcal) per gram of energy (15.7 kJ (3.75 kcal) per gram monosaccharide equivalent). Carbohydrate intake comprises:
Carbohydrate is cheap compared with other foodstuffs; a great deal is therefore eaten, usually more than required.
Dietary fibre, which is largely non-starch polysaccharide (NSP) (entirely NSP according to some authorities), is often removed in the processing of food. This leaves highly refined carbohydrates such as sucrose which contribute to the development of dental caries and obesity. Lignin is included in dietary fibre in some classification systems, but it is not a polysaccharide. It is only a minor component of the human diet.
The principal classes of NSP are:
None of these are digested by gut enzymes. However, NSP is partly broken down in the gastrointestinal tract, mainly by colonic bacteria, producing gas and volatile fatty acids, e.g. butyrate.
All plant food, when unprocessed, contains NSP, so that all unprocessed food eaten will increase the NSP content of the diet. Bran, the fibre from wheat, provides an easy way of adding additional fibre to the diet: it increases faecal bulk and is helpful in the treatment of constipation.
The average daily intake of NSP in the diet is approximately 16 g. NSP deficiency is accepted as an entity by many authorities and it is suggested that the total NSP be increased to up to 30 g daily. This could be achieved by increased consumption of bread, potatoes, fruit and vegetables, with a reduction in sugar intake in order not to increase total calories. Each extra gram of fibre daily adds approximately 3–5 g to the daily stool weight. Pectins and gums have also been added to food to slow down monosaccharide absorption, particularly useful in type 2 diabetes.
Eating a diet rich in plant foods (fruits, vegetables, cereals and whole grain – the main sources of dietary fibre) is generally recommended for general health promotion, including protection against ischaemic heart disease, stroke and certain types of cancers. This has been attributed to a lipid lowering effect, the presence of protective substances, such as vitamin and non-vitamin antioxidants and other vitamins such as folic acid, which is linked to homocysteine metabolism, a risk factor for cardiovascular disease. Fermentation of fibre in the colon may protect against development of colonic cancer. However, associated lifestyle factors such as low physical activity may also help explain some of those associations.
Many chronic diseases – particularly obesity, diabetes mellitus and cardiovascular disease – cause premature mortality and morbidity and are potentially preventable by dietary change. This is a global problem, e.g. obesity affects one in nine adults in the world with the BMI being now similar in high- and middle-income groups. Reduction in salt and fat intake, combined with exercise and stopping smoking, would have a major effect on the health of the population.
Box 5.2 suggests the composition of the ‘ideal healthy diet’. The values given are based on the principle of:
reducing total fat in the diet, particularly saturated fat
increasing consumption of fish which contain n-3 (or ω-3) polyunsaturated fatty acids
increasing intake of whole-grain cereals, green and orange vegetables and fruits, leading to an increase in fibre and antioxidants.
Reductions in dietary sodium and cholesterol have also been suggested. There would be no disadvantage in this, and most studies have suggested some benefit.
Fortification of foods
Fortification of foods with specific nutrients is common. In the UK, margarine and milk are fortified with vitamins A and D, flour with calcium, iron, thiamin and niacin and breakfast cereals with several vitamins and iron. Not all substances used in fortification have nutritive value. For example, Olestra is a polymer of sucrose and six or more triglycerides which has been introduced to combat obesity. It is not absorbed and is therefore used particularly in savoury snack foods (where it has FDA approval) as a ‘fake fat’. Therefore, it results in a reduction in total calories. It has side-effects, e.g. loose stools, abdominal cramps, and its use is being carefully monitored.
Nutrient goals and dietary guidelines
The interests of the individual are often different from those associated with government policy. A distinction needs to be made between nutrient goals and dietary guidelines:
Nutrient goals refer to the national intakes of nutrients that are considered appropriate for optimal health in the population.
Dietary guidelines refer to the dietary methods used to achieve these goals.
Since dietary habits in different countries vary, dietary guidelines may also differ, even when the nutrient goals are the same. Nutrient goals are based on scientific information that links nutrient intake to disease. Although the information is incomplete, it includes evidence from a wide range of sources, including experimental animal studies, clinical studies and both short-term and long-term epidemiological studies.
Beaglehole R, Horton R. Chronic diseases: global action must match global evidence. Lancet 2010; 376:1619–1621.
Elia M, Cummings, JH. Physiological aspects of energy metabolism and gastrointestinal effects of carbohydrates. Eur J Clin Nutr 2007; (Suppl 1):SO40–SO74.
Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, protein, and amino acids. Washington, DC: The National Academies Press; 2005.
World Health Organization. Protein and amino acid requirements in human nutrition WHO Technical Report Series 935. Report of a Joint WHO/FAO/UNU Expert Consultation United Nations. Geneva: WHO; 2007.
WHO/FAO Expert Consultation. Diet, nutrition and the prevention of chronic diseases. Geneva: WHO; 2003.
Zampelas A. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis 2010; 212:34–35.
Protein-energy malnutrition (PEM)
Starvation uncomplicated by disease is relatively uncommon in developed countries, although some degree of undernourishment is seen in very poor areas. Most nutritional problems occurring in the population at large are due to eating wrong combinations of foodstuffs, such as an excess of refined carbohydrate or a diet low in fresh vegetables. Undernourishment associated with disease is common in hospitals and nursing homes, and Table 5.4 gives a list of conditions in which malnutrition is often seen. Surgical complications, with sepsis, are a common cause. Many patients are admitted to hospital undernourished, and a variety of chronic conditions predispose to this state (Table 5.5).
Surgery, particularly of GI tract with complications
Any very ill patient
GI disease, particularly involving the small bowel
Severe chronic inflammatory diseases
Psychosocial: poverty, social isolation, anorexia nervosa, depression
The majority of the weight loss, leading to malnutrition, is due to poor intake secondary to the anorexia associated with the underlying condition. Disease may also contribute by causing malabsorption and increased catabolism, which is mediated by complex changes in cytokines, hormones, side-effects of drugs, and immobility. The elderly are particularly at risk of malnutrition because they often suffer from diseases and psychosocial problems such as social isolation or bereavement (Table 5.5).
Pathophysiology of starvation (Fig. 5.4)
In the first 24 h following low dietary intake, the body relies for energy on the breakdown of hepatic glycogen to glucose. Hepatic glycogen stores are small and therefore gluconeogenesis is soon necessary to maintain glucose levels. Gluconeogenesis takes place mainly from pyruvate, lactate, glycerol and amino acids, especially alanine and glutamine. The majority of protein breakdown takes place in muscle, with eventual loss of muscle bulk.
Lipolysis, the breakdown of the body’s fat stores, also occurs. It is inhibited by insulin, but the level of this hormone falls off as starvation continues. The stored triglyceride is hydrolysed by lipase to glycerol, which is used for gluconeogenesis, and also to non-esterified fatty acids that can be used directly as a fuel or oxidized in the liver to ketone bodies.
Adaptive processes take place as starvation continues, to prevent the body’s available protein being completely utilized. There is a decrease in metabolic rate and total body energy expenditure. Central nervous metabolism changes from glucose as a substrate to ketone bodies. Gluconeogenesis in the liver decreases as does protein breakdown in muscle, both of these processes being inhibited directly by ketone bodies. Most of the energy at this stage comes from adipose tissue, with some gluconeogenesis from amino acids, particularly from alanine in the liver, and glutamine in the kidney.
The metabolic response to prolonged starvation differs between lean and obese individuals. One of the major differences concerns the proportion of energy derived from protein oxidation, which determines the proportion of weight loss from lean tissues. This proportion may be up to three times smaller in obese subjects than lean subjects. It can be regarded as an adaptation which depends on the composition of the initial reserves (Fig. 5.3). This means that deterioration in body function is more rapid in lean subjects. Furthermore, survival time is much less in lean subjects (~2 months), compared to the obese (can be at least several months).
Following trauma or shock, some of the adaptive changes do not take place. Glucocorticoids and cytokines (see below) stimulate the ubiquitin-proteasome pathway in muscle, which is responsible for accelerated proteolysis in muscle in many catabolic illnesses. In starvation, there is a decrease in BMR, while in inflammatory and traumatic disease the BMR is often increased. These changes all result in continuing gluconeogenesis with massive muscle breakdown, and further reduction in survival time.
Regulation of metabolism
Tissue metabolism is regulated by multiple coordinated processes. Some are rapid involving nerves, whilst others are slower involving circulating substrates and hormones. Factors include:
Circulating substrate concentrations. The uptake and metabolism of ketone bodies, which serve as the major fuel for the brain during prolonged starvation, is primarily determined by the circulatory concentration which can increase up to 5 mmol/L or more. The liver is responsible for producing ketone bodies, the production of which is in turn controlled by the availability of fatty acids derived from adipose tissue. Substrates may also compete with each other for metabolism, for example glucose competes with non-esterified fatty acids for uptake and metabolism in muscle and heart (the glucose-fatty acid cycle) and this is independent of hormones.
Blood flow. The delivery of substrates (and other signals) to tissues depends not only on their circulating concentration but also on the blood flow to tissues. In many tissues there is coupling between metabolic activity and blood flow, with arterioles regulating blood flow to the tissue according to demand, e.g. blood flow to muscle increases during exercise.
Signals. Hormones and other signals, such as cytokines (see below), regulate intracellular metabolism.
Insulin/glucagon ratios in the fed and fasted state
In the fed state, insulin/glucagon ratios are high. Insulin promotes synthesis of glycogen, protein and fat, and inhibits lipolysis and gluconeogenesis.
In the fasted state, insulin/glucagon ratios are low. Glucagon acts mainly on the liver and has no action on muscle. It increases glycogenolysis and gluconeogenesis, as well as increasing ketone body production from fatty acids. It also stimulates lipolysis in adipose tissue. Catecholamines have a similar action to glucagon but also affect muscle metabolism. These agents both act via cyclic adenosine monophosphate (cAMP) to stimulate lipolysis, producing free fatty acids that can then act as a major source of energy.
Proportion of lean to fat tissue
During weight loss uncomplicated by disease, the proportion of lean to fat tissue loss (or proportion of energy derived from protein metabolism) is greater in lean than overweight/obese individuals.
During acute disease, loss of lean tissue, which is associated with protein oxidation, can be particularly rapid. Hormones such as corticosteroids, proinflammatory cytokines and insulin resistance are all involved.
Role of cytokines
The metabolic response to trauma, injury and inflammation depends on the balance between proinflammatory (e.g. tumour necrosis factor, TNF; interleukin-2, IL-2) and anti-inflammatory cytokines (e.g. IL-10), and the production of many of these cytokines is influenced by genetic polymorphisms. Since many chronic diseases, including atherosclerosis, have an inflammatory component, these changes have wide-reaching metabolic implications.
Cytokines such as IL-1, IL-6 and TNF play a significant role in regulating metabolism. In acute diseases they contribute to the catabolic process, glycogenolysis, and acute-phase protein synthesis. TNF, which inhibits lipoprotein lipase, is one of a number of ‘cachexia factors’ in patients with cancer.
It is unclear how these cytokines interact with central feeding pathways to cause anorexia. However, in animal models of both cancer and inflammatory bowel disease, many peripheral and central mediators of appetite are involved. For example, neuropeptide Y levels in the hypothalamus are often inappropriately low, so there is a reduced drive to feeding.
Patients are sometimes seen with loss of weight or malnutrition as the primary symptom (failure to thrive in children). Mostly, however, malnourishment is only seen as an accompaniment of some other disease process, such as malignancy. Severe malnutrition is seen mainly with advanced organic disease or after surgical procedures followed by complications. Three key features which help in the detection of chronic protein-energy malnutrition (PEM) in adults are listed in Box 5.3.
Key features in detection of chronic protein-energy malnutrition (PEM) in developed countries
In patients with oedema or dehydration the BMI may be somewhat misleading.
2. Weight loss in previous 3–6 months: >10%, high risk; 5–10%, possible risk; <5% low/no risk of developing PEM.
3. Acute disease effect: diseases that have resulted or are likely to result in no dietary intake for >5 days are associated with a high risk of malnutrition (e.g. prolonged unconsciousness, persistent swallowing problems after a stroke, or prolonged ileus after abdominal surgery).
Other factors that may suggest PEM include:
History of decreased food intake/loss of appetite
Clothes becoming loosely fitting (weight loss) and a general appearance indicating obvious wasting
Physical and psychosocial disturbances likely to have contributed to the weight loss.
The factors listed in Box 5.3 act as a link between detection and management (Fig. 5.5, the ‘Malnutrition Universal Screening Tool’). If the underlying physical or psychosocial problems are not adequately addressed, treatment may not be successful.
Figure 5.5 ‘Malnutrition Universal Screening Tool’ (‘MUST’)
(with permission from the British Association for Parenteral and Enteral Nutrition (BAPEN), at: www.bapen.org.uk).
PEM leads to a depression of the immunological defence mechanism, resulting in a decreased resistance to infection. It also detrimentally affects muscle strength and fatigue, reproductive function (e.g. in anorexia nervosa, which is common in adolescent girls; p. 1188), wound healing, and psychological function (depression, anxiety, hypochondriasis, loss of libido).
In children, growth failure is a key element in the diagnosis of PEM. New WHO standards for optimal growth in children 0–4 years have been adopted by developing and developed countries. They aim to reflect optimal rather than prevailing growth in both developed and developing countries, since they involved a healthy pregnancy and children born to non-smoking, relatively affluent mothers who breast-fed their children exclusively or predominantly for the first 6 months of life. The general principles of management of severe PEM in children are similar in developed and developing countries but resources are required to manage the problems once identified (see p. 205).
When malnutrition is obvious and the underlying disease cannot be corrected at once, some form of nutritional support is necessary (see also pp. 221, 223). Nutrition should be given enterally if the gastrointestinal tract is functioning adequately. This can most easily be done by encouraging the patient to eat more often and by giving a high-calorie supplement. If this is not possible, a liquefied diet may be given intragastrically via a fine-bore tube or by a percutaneous endoscopic gastrostomy (PEG). If both of these measures fail, parenteral nutrition is given.
The International Union of Nutritional Sciences, with support from the International Pediatric Association, launched a global Malnutrition Task Force in 2005 to ensure that an integrated system of prevention and treatment of malnutrition is actively supported.
In many areas of the world, people are on the verge of malnutrition due to extreme poverty. In addition, if events such as drought, war or changes in political climate occur, millions suffer from starvation. Although the basic condition of PEM is the same in all parts of the world from whatever cause, malnutrition resulting from long periods of near-total starvation produces unique clinical appearances in children virtually never seen in high-income countries. The term ‘protein-energy malnutrition’ covers the spectrum of clinical conditions seen in adults and children. Children under 5 years may present with the following:
Kwashiorkor occurs typically in a young child displaced from breast-feeding by a new baby. It is often precipitated by infections such as measles, malaria and diarrhoeal illnesses. The child is apathetic and lethargic with severe anorexia. There is generalized oedema with skin pigmentation and thickening (Fig. 5.6b). The hair is dry, sparse and may become reddish or yellow in colour. The abdomen is distended owing to hepatomegaly and/or ascites. The serum albumin is always low. The exact cause is unknown, but theories related to diet (low in protein, and high in carbohydrate) and free radical damage in the presence of inadequate antioxidant defences have been proposed.
Marasmus is the childhood form of starvation, which is associated with obvious wasting. The child looks emaciated, there is obvious muscle wasting and loss of body fat. There is no oedema. The hair is thin and dry (Fig. 5.6a). The child is not so apathetic or anorexic as with kwashiorkor. Diarrhoea is frequently present and signs of infection must be looked for carefully.
A classification of severe malnutrition by the World Health Organization (WHO) (Table 5.6) makes no distinction between kwashiorkor and marasmus, because their approach to treatment is similar. The WHO classification of chronic undernutrition in children is based on standard deviation (SD) scores. Thus, children with an SD score between −2 and −3 (between 3 and 2 standard deviation scores below the median – corresponding to a value between 0.13 and 2.3 centile) can be regarded as being at moderate risk of undernutrition, and below an SD score of −3, of severe malnutrition. A low weight-for-height is a measure of thinness (wasting when pathological) and a low height-for-age is a measure of shortness (stunting when pathological). Those with oedema and clinical signs of severe malnutrition are classified as having oedematous malnutrition.
|Moderate malnutrition||Severe malnutritiona|
Yes: oedematous malnutritionb
Weight-for-height SD score
−3 to −2 (70–79%)c
Height-for-age SD score
−3 to −2 (85–89%)c
<−3 (<85%)c (severe stunting)
a The diagnoses are not mutually exclusive.
b Older classifications use the terms kwashiorkor and marasmic-kwashiorkor instead.
c Percentage of the median National Centre for Health Statistics/WHO reference.
d Called marasmus (without oedema) in the Wellcome classification and grade II in the Gomez classification.
Starvation in adults may lead to extreme loss of weight depending upon the severity and duration. They may crave for food, are apathetic and complain of cold and weakness with a loss of subcutaneous fat and muscle wasting. The WHO classification is based on body mass index (BMI), with a value <18.5 kg/m2 indicating malnutrition (severe malnutrition if <16.0 kg/m2).
Severely malnourished adults and children are very susceptible to respiratory and gastrointestinal infections, leading to an increased mortality in these groups.
These are not always practicable in certain settings in the developing world.
Stools should be examined for parasitic infestations.
Chest X-ray – tuberculosis is common and is easily missed if a chest X-ray is not performed.
Treatment must involve the provision of protein and energy supplements and the control of infection. The approach to treatment of children is described below. Adults do not usually suffer such severe malnutrition, but the same general principles of treatment should be followed.
Resuscitation and stabilization
The severely ill child will require:
Correction of fluid and electrolyte abnormalities, but intravenous therapy should be avoided if possible because of the danger of fluid overload
Treatment of shock with oxygen
Treatment of hypoglycaemia (blood glucose <3 mmol/L), hypothermia (reduce heat loss, and provide additional heat if necessary) and infection (antibiotics) – these often co-exist.
The standard WHO oral hydration solution has a high sodium and low potassium content and is not suitable for severely malnourished children. Instead, the rehydration solution for malnutrition (ReSoMal) is recommended. It is commercially available but can also be produced by modification of the standard WHO oral hydration solution.
Infection is common (Box 5.4). Diarrhoea is often due to bacterial or protozoal overgrowth; metronidazole is very effective and is often given routinely. Parasites are also common and, as facilities for stool examination are usually not available, mebendazole 100 mg twice daily should be given for 3 days. In high-risk areas, antimalarial therapy is given.
Infections seen in PEM in developing countries
Large doses of vitamin A are also given because deficiency of this vitamin is common. After the initial resuscitation, further stabilization over the next few days is undertaken, as indicated in Table 5.7.
This needs to be planned carefully. During the initial treatment of the acute situation, a balanced diet with sufficient protein and energy is given to maintain a steady state. Large increases in energy can lead to heart failure, circulatory collapse and death (re-feeding syndrome). Initial feeding involves administration of feeds of low osmolarity and low in lactose. WHO recommendations are 100 kcal/kg per day; 1.0–1.5 g protein/kg per day and 130 mL liquid/kg per day (100 mL/kg per day if the child has marked oedema). Attempts should be made to give the feeds slowly and frequently (e.g. 2-hourly during days 1–2; 3-hourly during days 3–5; and 4-hourly thereafter), although anorexia is often a problem and can be exacerbated by excessive feeding. If necessary, fluids and food should be given by nasogastric tube. The child is then gradually weaned to liquids and then solids by mouth. All severely malnourished children have vitamin and mineral deficiencies. Although anaemia is common, the WHO recommends giving iron only after the child develops a good appetite and starts gaining weight, because of concern about making the infection worse (iron is a pro-oxidant). The child should be given daily micronutrient supplements for at least 2 weeks. These should include a multivitamin supplement with folic acid, zinc and copper.
Gradually, as the child improves, more energy can be given, and during rehabilitation weight gain is achieved by providing extra energy and protein (‘catch-up weight gain’). Children who have been severely ill need constant attention right through the convalescent period, as often home conditions are poor and feeds are refused. Sensory stimulation and emotional support is a major component of management during both the stabilization and rehabilitation phases. The treatment of underlying chronic infective conditions such as HIV, malaria and tuberculosis is also necessary.
There are not enough hospitals or therapeutic feeding centres to cope with the malnutrition problem (even acute malnutrition problems), which emphasizes the need for outpatient and community based programmes, although these require investment and time to build to full capacity. These may involve the use of ready-to-use therapeutic foods, such as energy-dense pastes with minerals and vitamins, without the need to add water, which could potentially contaminate the food.
Children with extreme malnutrition have a mortality of over 50%. By careful management, this can be reduced significantly to less than 10%, depending on the availability of facilities and trained staff. Treatment of underlying disease is essential. Brain development takes place in the first years of life, a time when severe PEM frequently occurs. There is evidence that intellectual impairment and behavioural abnormalities occur in severely affected children. Physical growth is also impaired. Probably both of these effects can be alleviated if it is possible to maintain a high standard of living with a good diet and freedom from infection over a long period.
Prevention of PEM depends not only on adequate nutrients being available but also on education of both governments and individuals in the importance of good nutrition and immunization (Box 5.5). Short-term programmes are useful for acute shortages of food, but long-term programmes involving improved agriculture are equally necessary. Bad feeding practices and infections are more prevalent than actual shortage of food in many areas of the world. However, good surveillance is necessary to avoid periods of famine.
Prevention of protein-energy malnutrition – GOBIF (a WHO priority programme)
Food supplements (and additional vitamins) should be given to ‘at-risk’ groups by adding high-energy food (e.g. milk powder, meat concentrates) to the diet. Pregnancy and lactation are times of high energy requirement and supplements have been shown to be beneficial.
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Deficiencies due to inadequate intake associated with PEM (Table 5.8) are commonly seen in the developing countries. This is not, however, invariable. For example, vitamin A deficiency is not seen in Jamaica, but is common in PEM in Hyderabad, India. In the West, deficiency of vitamins is less common but prominent in the specific groups shown in Table 5.9. The widespread use of vitamins as ‘tonics’ is unnecessary and should be discouraged. Toxicity from excess fat-soluble vitamins is occasionally seen.
Vegans: vitamin D (if no exposure to sunlight) vitamin B12; elderly with poor diet: chiefly vitamin D (if no exposure to sunlight), folate
Vitamin A (retinol) is part of the family of retinoids which is present in food and the body as esters combined with long-chain fatty acids. The richest food source is liver, but it is also found in milk, butter, cheese, egg yolks and fish oils. Retinol or carotene is added to margarine in the UK and other countries.
Beta-carotene is the main carotenoid found in green vegetables, carrots and other yellow and red fruits. Other carotenoids, lycopene and lutein, are probably of little quantitative importance as dietary precursors of vitamin A.
Beta-carotene is cleaved in the intestinal mucosa by carotene dioxygenase, yielding retinaldehyde which can be reduced to retinol. Between a quarter and a third of dietary vitamin A in the UK is derived from retinoids. Nutritionally, 6 µg of β-carotene is equivalent to 1 µg of preformed retinol; vitamin A activity in the diet is given as retinol equivalents.
Retinol is stored in the liver and is transported in plasma bound to an α-globulin, retinol-binding protein (RBP). Vitamin A has several metabolic roles:
Retinaldehyde in its cis form is found in the opsin proteins in the rods (rhodopsin) and cones (iodopsin) of the retina (p. 1055). Light causes retinaldehyde to change to its trans isomer, and this leads to changes in membrane potentials that are transmitted to the brain.
Retinol and retinoic acid are involved in the control of cell proliferation and differentiation.
Retinyl phosphate is a cofactor in the synthesis of most glycoproteins containing mannose.
Vitamin A deficiency
Worldwide, vitamin A deficiency and xerophthalmia (see below) is the major cause of blindness in young children despite intensive preventative programmes.
Xerophthalmia has been classified by the WHO (Table 5.10). Impaired adaptation followed by night blindness is the first effect. There is dryness and thickening of the conjunctiva and the cornea (xerophthalmia occurs as a result of keratinization). Bitot’s spots – white plaques of keratinized epithelial cells – are found on the conjunctiva of young children with vitamin A deficiency. These spots can, however, be seen without vitamin A deficiency, possibly caused by exposure. Corneal softening, ulceration and dissolution (keratomalacia) eventually occur, superimposed infection is a frequent accompaniment and both lead to blindness. In PEM, retinol-binding protein along with other proteins is reduced. This suggests vitamin A deficiency, although body stores are not necessarily reduced.
Corneal ulceration/keratomalacia < corneal surface
Corneal ulceration/keratomalacia > corneal surface
From WHO/UNICEF/IVACG 1988. X, xerophthalmia.
Vitamin A deficiency. Blindness due to vitamin A deficiency and corneal scarring.
(Courtesy of Ehrnstrom P. In: Bolognia J, Jorrizzo J, Rapini R (eds). Dermatology, 2nd edn. St Louis: Mosby; 2008: Fig. 51.6.)