CHAPTER OUTLINE

The term ‘nutritional disorders’ covers a wide range of conditions. Some of these disorders are primarily nutritional and some are not, albeit that nutrition is still an important factor. This makes their classification somewhat arbitrary, but the following broad categories can be recognized:

‘Malnutrition’ is often taken to mean inadequate nutrition, but this definition also includes dietary excess, so the term ‘undernutrition’ is to be preferred. Undernutrition is a major public health problem in the developing world. Diets of affected populations tend to be deficient in both macronutrients and micronutrients. A high prevalence of bacterial and parasitic disease tends to contribute to undernutrition; in addition, an effect of undernutrition is to increase susceptibility to infection. In children, severe undernutrition is predominantly a state of protein energy malnutrition (PEM). In adults, in whom protein requirements are relatively lower (since growth has ceased), the term chronic energy deficiency (CED) is used. In the UK, severe undernutrition is most commonly seen in adults, usually in association with intercurrent illness and is discussed later in the chapter under nutrition support.

Worldwide, PEM remains the most common disorder of infancy and childhood: as many as 200 million children may be significantly affected at any one time and it accounts for over half the deaths in the under-five age group in developing countries. One way of assessing and categorizing undernutrition is by using a weight for height z score, which compares a child’s height to that of a healthy reference population of children of the same height or length. The z score is expressed in terms of standard deviations (SD) from the mean of the reference population. When height or length cannot be measured easily, upper arm circumference, which changes little in healthy children between the ages of six months and five years, can be used as a measure of lean body mass to identify undernutrition. Using these methods, acute undernutrition can be divided into moderate and severe. Moderate undernutrition is defined as a weight for height or length z score between − 2 and − 3SD. Severe undernutrition is defined by a z score of <−3SD, an arm circumference < 110 mm or the presence of nutritional oedema. Moderate or severe undernutrition without nutritional oedema is termed marasmus. Undernutrition with oedema is termed kwashiorkor.

Marasmus tends to occur in younger children who have the greatest energy requirements and susceptibility to infection. Affected children appear emaciated with loss of subcutaneous fat, muscle wasting and triangular facies due to loss of buccal fat pads. In addition to oedema, children with kwashiorkor have enlarged and fatty livers. They may also have dermatoses and depigmentation of hair, the latter being attributed to reduced availability of tyrosine, a precursor of melanin.

The classic explanation for the two different syndromes suggests that marasmus occurs on a diet poor in protein and energy and kwashiorkor on a diet poor in protein but with relatively more carbohydrate. In marasmus, insulin secretion would, therefore, be expected to be low, prompting breakdown of muscle protein and mobilization of amino acids for hepatic synthesis of protein, particularly albumin. In kwashiorkor, relatively higher carbohydrate intake would lead to maintenance of insulin secretion with relative sparing of muscle protein, therefore limiting amino acids available for synthesis of liver proteins. Reduced synthesis of albumin and apolipoproteins would lead to hypoalbuminaemia and oedema, and accumulation of lipids in the liver, respectively. However, recent studies have found marasmus and kwashiorkor to exist in populations where children are eating similar diets. It has been suggested that the clinical syndromes may in fact reflect differences in the metabolic response to starvation, for example varying rates of fatty acid oxidation, rather than the content of the diet.

The treatment of PEM is the provision of appropriate nutrition and treatment of associated infection. Treatment of moderate undernutrition involves the addition to the diet of suitable nutrient rich supplements containing significant energy and the recommended daily allowance of micronutrients; examples include cereal and legume blended flours and lipid rich fortified spreads.

Severe PEM is associated with atrophy of the small bowel mucosa, reducing its capacity for digestion and absorption, hence liquid, milk-based products, supplemented with potassium and phosphate, are favoured for treatment, initially administered as small boluses. Intravenous fluids should be avoided, except in children with profuse diarrhoea. Children with kwashiorkor have increased total body water with sodium retention. Those with marasmus have chronic hypovolaemia with secondary hyperaldosteronism, although tissue breakdown and urinary potassium loss tend to result in hypokalaemia. However, children with marasmus are particularly likely to have a degree of cardiac atrophy and reduced stroke volume, predisposing to cardiac failure if fluid overloaded. In addition, the reduction in subcutaneous fat renders these children susceptible to hypothermia and hypoglycaemia during the recovery process.

Studies of both medical and surgical inpatients in developed countries indicate that a significant proportion of patients have CED, although variation in the criteria used to define this means that the exact prevalence is uncertain. Caution is required in applying the marasmus/kwashiorkor distinction to such patients, since the presence of hypoalbuminaemia or oedema is more likely to be due to the underlying illness than malnutrition. Nonetheless, severe CED in such patients has important effects. Wasting of respiratory muscles increases the risk of chest infection and may delay weaning from a ventilator. Myocardial function may be impaired and skeletal muscle wasting delays mobilization, with a consequent increased risk of thromboembolism and bed sores. Chronic energy deficiency also results in impaired resistance to infection, and gut permeability may be increased, allowing entry of bacteria and toxins through the gut wall. Apathy and depression impair active efforts at recovery and may also impair appetite, worsening the situation further.

The recognition of undernutrition in adults and its treatment are considered later in this chapter in the section on nutritional support.

Obesity is an excess of body fat. For epidemiological studies and population surveys, as well as clinical assessment of individual patients, body mass index (BMI) is frequently used to define overweight (BMI ≥ 25 kg/m²) and obesity (BMI ≥ 30 kg/m²). Whilst it is a useful index, BMI is not without problems, but alternative methods are expensive and not readily available. In children, there are marked changes in BMI with age. It is recommended that obesity in children is defined with reference to BMI centiles, and charts are available for this purpose, but there is no universally accepted BMI classification system. In the UK, it is suggested that the 91st and 95th centiles should be used in children as indicators of overweight and obesity, respectively. Estimates of the prevalence of obesity are likely to be subject to variation because of differences in the definition, cut-offs and reference standards used.

The aetiology of obesity is complex and influences on body fat content include genetic, perinatal, behavioural and environmental factors. Epidemiological data indicate that the consumption of a diet that is high in fat and the frequent consumption of ‘fast food’ increase the risk of obesity. This is well demonstrated by the recent rise in obesity in developing countries, whose populations have replaced their indigenous diet with a more energy-dense Westernized alternative. There is also a close relationship between low levels of physical activity and weight gain and the duration of television viewing is a predictor of obesity risk in both adults and children.

Family studies have established that hereditary influences are important in determining body weight, although, to-date, genetic studies have concentrated on severe, early-onset forms of obesity, which are rare. Mutations resulting in leptin (see below) and leptin-receptor deficiencies have been described. Affected children are of normal birth weight, but exhibit extreme hyperphagia and gain weight rapidly. Children with congenital absence of pro-opiomelanocortin (POMC) gene products also become obese, despite glucocorticoid deficiency, an endocrine state normally associated with weight loss. These patients characteristically have pale skin and red hair, resulting from an absence of the action of POMC-derived peptides on melanocytes. A number of heterozygous point mutations in POMC have been found, which increase the risk of obesity, although are not invariably associated with it. Heterozygous mutations in the melanocortin receptor MC4R have been associated with dominantly inherited obesity and have been found in 1–2.5% of those with a BMI of > 30 kg/m².

Investigation of patients to exclude secondary causes of obesity is usually unrewarding, but remains important. Clinical features suggesting endocrine pathology should be pursued, but in-depth dynamic function testing to exclude rare disorders is not usually necessary. Hypothyroidism should be excluded by measuring serum thyroid stimulating hormone and free thyroxine concentrations. The investigation of possible Cushing syndrome may be more difficult, as false positive results have been described in pseudo-Cushing syndrome due to obesity. Growth hormone deficiency may also lead to weight gain, although morbid obesity is not usually present. Associations are also recognized between obesity and polycystic ovary syndrome, hypogonadism and insulinoma.

Some drugs are associated with weight gain. The effect is assumed to be due either to central effects on appetite (e.g. certain anticonvulsants and antipsychotics) or to peripheral metabolic effects (e.g. oral hypoglycaemic agents, protease inhibitors).

Energy homoeostasis is the result of a complex, integrated process involving neural, humoral and psychological factors that are integrated by the brain to ensure that nutrient supply remains at appropriate levels for different environmental conditions. In the past, there has not tended to be an evolutionary advantage in weight loss, hence the mechanisms underlying energy homoeostasis are tailored to ensure a powerful drive to eat, especially after weight loss.

The body’s appetite control centres are located in the hypothalamus. The ventromedial hypothalamus is thought to act as the satiety centre and the lateral hypothalamus as the feeding centre. Histochemical and molecular imaging techniques have shown that the hypothalamic nuclei involved in feeding regulation form interconnected circuits, utilizing neuropeptides as well as the classic amine neurotransmitters

The hypothalamus receives both neural and humoral input. At the base of the third ventricle, the arcuate nucleus (Arc; also known as the infundibular nucleus in humans) is able to receive signals from the circulation. The blood–brain barrier (BBB) surrounding the Arc is not complete and this allows hormones such as leptin, secreted by adipocytes, and insulin, from the pancreas, to gain access to the afferent signalling pathway that regulates appetite.

From the Arc, monosynaptic projections are made to many other brain regions, with the projections to the paraventricular nucleus (PVN) being of importance in the regulation of food intake. Integration of peripheral and central signals relating to energy homoeostasis takes place in the Arc. Two neuron populations play a role. The orexigenic (appetite-stimulating) peptides neuropeptide Y (NPY) and Agouti-related peptide (AgRP) are co-localized, while in another population of neurons, the anorectic (appetite-inhibiting) peptide cocaine- and amfetamine-regulated transcript (CART) and pro-opiomelanocortin (POMC, the precursor of α-melanocyte stimulating hormone (αMSH)) are also co-localized. The orexigenic NPY/AgRP neurons inhibit the anorexigenic POMC neurons through γ-aminobutyric acid (GABA)-ergic interneuronal connections. Fasting increases NPY and AgRP, while CART and POMC expression is reduced.

The vagus nerve and sympathetic fibres transmit satiety signals from the gut and liver to the nucleus of the tractus solitarius (NTS) in the brain stem. In areas such as the area postrema, which is in the brain stem adjacent to the NTS at the base of the fourth ventricle, the BBB is incomplete, also allowing circulating hormones access to the brain. The brain stem and hypothalamus are linked by projections from the NTS to the PVN and lateral hypothalamus, and from the raphe nuclei to the arcuate nucleus. Neurons such as those expressing glucagon-like peptide-1 (GLP-1) receive afferents from the vagal and glossopharyngeal nerves, integrating and relaying sensory information to hypothalamic and brain stem centres. Whilst the brain stem plays a role in regulating the size of individual meals, it is thought that the hypothalamus is necessary for long-term energy balance and appetite regulation.

Neuropeptide Y is a 36-amino acid peptide member of the family of peptides comprising NPY, pancreatic polypeptide (PP) and peptide YY (PYY). Neuropeptide Y is one of the most potent stimulators of feeding. At least five distinct G-protein coupled receptors (Y1, Y2, Y4, Y5 and Y6) mediate the actions of NPY, PYY and PP. In rodents, repeated administration of NPY leads to hyperphagia and obesity associated with decreased thermogenesis in brown adipose tissue, hyperinsulinaemia, hypercorticosteronaemia, reduced plasma testosterone concentrations, and insulin resistance in skeletal muscle.

Agouti-related protein increases food intake by acting as an antagonist at central melanocortin-3 and melanocortin-4 receptors (see below). In contrast to the fairly short-lived effects of NPY, central administration of a single dose of AgRP to rodents leads to an increase in food intake for up to one week. Repeated administration leads to hyperphagia and obesity.

Melanocortins are peptides that are cleaved from the POMC precursor molecule by tissue-specific post-translational cleavage (e.g. in the anterior pituitary, POMC gives rise to adrenocorticotrophic hormone, ACTH). They bind to a family of melanocortin receptors (MC1-R to MC5-R). In the arcuate nucleus, αMSH is released from POMC-expressing neurons that project to the PVN, where it acts through MC3-R and MC4-R to inhibit food intake. The endogenous antagonist AgRP (see above) is released from the terminals of arcuate NPY/AgRP neurons at the PVN: AgRP stimulates food intake by blocking the anorectic effect of αMSH. The MC4 receptor, in particular, seems to be critical to regulation of body weight; thus far, the most common cause of monogenic obesity in humans is mutation in MC4-R.

Cocaine- and amfetamine-regulated transcript is co- expressed with POMC in arcuate neurons, and these neurons are directly stimulated by leptin (see later). Central administration of CART to rats inhibits feeding and completely blocks the feeding response stimulated by NPY. Food-deprived animals show decreased expression of CART mRNA in the arcuate nucleus. CART may thus be another endogenous inhibitor of food intake.

5-Hydroxytryptamine (5-HT) is a monoamine neurotransmitter that is synthesized in both the central nervous system and in the chromaffin cells of the gastrointestinal tract. There are numerous 5-HT receptor subtypes: in the brain these receptors occur mainly in the limbic system and the hypothalamus. 5-Hydroxytryptamine modifies mood and behaviour, and a number of different types of drug that increase the effects of 5-HT are used as antidepressants. Drugs that either mimic 5-HT at its receptors or inhibit its reuptake at synapses generally also reduce feeding. The mechanism for this is not clear.

Peripheral signals influencing food intake can be broadly divided into those that cause satiety and those that are secreted in proportion to the amount of fat in the body. The gut and the brain seem to have a close evolutionary relationship. Peptides discovered in the hypothalamus have also been identified in the gut, and gut peptides have been found to be produced by the brain.

Slow gastric emptying increases stomach distension, which activates stretch receptors. The vagus nerve carries afferent signals related to stomach distension to the NTS, facilitating satiety by projections to the appetite-regulating nuclei of the hypothalamus, for example the PVN. Cholecystokinin (CCK) is a potent inhibitor of gastric emptying by vagal afferent-mediated central mechanisms, and this may explain its anorectic actions. Peptide YY and GLP-1 (see below) may also cause anorexia by reducing gastric emptying in this way.

The main neural connection from the gastrointestinal tract to the brain is through the vagal afferent fibres, via the nodose ganglion. Sympathetic afferent fibres in the spinal nerves also carry satiety signals to the brain stem, as previously described.

The endocrinological capacity of the gut is diverse, as diffuse populations of endocrine cells are scattered throughout the mucosa. Primary gastrointestinal functions such as motility, secretion and absorption are regulated by gut hormones, which simultaneously provide feedback to the CNS on the availability of nutrients, thereby regulating food intake.

Insulin was the first hormonal candidate, related to adipose tissue, to be postulated as the circulating factor that regulates the hypothalamic control of food intake. Insulin was also thought to be important in achieving the usual long-term stability of body weight and fat mass. The rise in circulating insulin in response to a glucose load is proportional to fat mass. Insulin reaches the CNS via receptor-mediated transport across the BBB and through areas of relative permeability. Central nervous system administration of insulin to rodents causes a reduction in food intake, while brain-specific insulin receptor knockout mice and insulin receptor substrate-2 knockout mice develop obesity. However, when insulin is commenced in patients with type 2 diabetes, weight gain rather than weight loss is observed, possibly as a result of a loss of the anorexigenic effect of hyperglycaemia and the lipogenic actions of insulin.

Cholecystokinin was the first gut hormone described to relay the signal of nutrient intake to the brain, thus leading to the inhibition of further food intake. Cholecystokinin is produced by endocrine cells (I cells) present within the jejunum and duodenum and it is also found in enteric nerves in the ileum and colon. Plasma concentrations of CCK increase in response to the intraluminal presence of the digestion products of protein and fats. Gastric emptying is potently inhibited by CCK through a vagal afferent-mediated central mechanism. In addition to causing satiety via vagally mediated pathways, CCK can cross the BBB and bind directly to specific receptors in the area postrema.

Peptide YY is secreted from the endocrine L cells of the small and large bowel. It is a 36-amino acid peptide related to NPY. The highest PYY tissue concentrations are in the distal gastrointestinal tract. Postprandial PYY concentrations are proportional to meal energy content. Two isoforms exist, and both PYY_1–36 and PYY_3–36 may have local effects on gut motility, inhibit secretion of gastric acid and pancreatic enzymes, and inhibit gallbladder emptying. Obese individuals have lower circulating concentrations of PYY.

It is proposed that PYY_3–36, released into the circulation after a meal, inhibits appetite by acting directly on the arcuate nucleus via the Y2R, a presynaptic inhibitory autoreceptor, leading to an inhibition of the NPY neurons and a possible reciprocal stimulation of the POMC neurons. There is a tonic GABA-mediated inhibition of POMC neurons by NPY neurons, and thus decreased GABA-mediated tone as produced by leptin may lead to disinhibition of POMC neurons. Thus, peripheral PYY_3–36 reduces the expression of NPY mRNA and increases that of POMC. Exogenous PYY_3–36 reduces food intake in rodents, rhesus monkeys and in normal weight and obese humans.