Energy

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

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.

Energy requirements

There are two approaches to assessing energy requirements for subjects who are weight stable and close to energy balance:

Assessment of energy intake

Assessment of total energy expenditure.

Energy intake

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.

Energy expenditure

Daily energy expenditure (Fig. 5.2) is the sum of:

The basal metabolic rate (BMR)

The thermic effect of food eaten

Occupational activities

Non-occupational activities.

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.

Table 5.1 Equations for the prediction of basal metabolic rate (in MJ/day)

Age range (years)	Equation for predicting BMRa	95% confidence limits
Men
10–17	0.0740 × (wt) + 2.754	±0.88
18–29	0.0630 × (wt) + 2.896	±1.28
30–59	0.0480 × (wt) + 3.653	±1.40
60–74	0.0499 × (wt) + 2.930	N/A
75+	0.0350 × (wt) + 3.434	N/A
Women
10–17	0.0560 × (wt) + 2.898	±0.94
18–29	0.0620 × (wt) + 2.036	±1.00
30–59	0.0340 × (wt) + 3.538	±0.94
60–74	0.0386 × (wt) + 2.875	N/A
75+	0.0410 × (wt) + 2.610	N/A

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).

Table 5.2 Physical activity ratio (PAR) for various activities (expressed as multiples of BMR)

	PAR
Occupational activity
Professional/housewife	1.7
Domestic helper/sales person	2.7
Labourer	3.0
Non-occupational activity
Reading/eating	1.2
Household/cooking	2.1
Gardening/golf	3.7
Jogging/swimming/football	6.9

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:

for a 55-year-old female – 8100 kJ (1940 kcal)

for a 55-year-old male – 10 600 kJ (2550 kcal).

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.

Energy stores

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.

Figure 5.3 Available energy reserves from different fuels expressed in MJ (upper) and as a percentage of total (lower) in a lean hypothetical 70 kg adult and an obese 140 kg adult.

Bodyweight

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.

Protein

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:

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.

Fat

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).

Table 5.3 The main fatty acids in foods

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.

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.

Carbohydrate

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.

Health promotion

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:

Reductions in dietary sodium and cholesterol have also been suggested. There would be no disadvantage in this, and most studies have suggested some benefit.

Vitamin A

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.

Function

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.

Table 5.10 Classification of xerophthalmia by ocular signs

Ocular signs	Classification
Night blindness	XN
Conjunctival xerosis	XIA
Bitot’s spot	X2
Corneal xerosis	X2
Corneal ulceration/keratomalacia < corneal surface	X3A
Corneal ulceration/keratomalacia > corneal surface	X3B
Corneal scar	XS
Xerophthalmic fundus	XF

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.)

Vitamin A in malnourished children

Vitamin A supplementation (single oral dose of 60 mg retinol palmitate) appears to improve morbidity and mortality from measles. It has also been suggested that a similar supplementation reduces morbidity and/or mortality from diarrhoeal diseases and respiratory infections and improves growth. Despite low circulating concentrations of vitamin A in HIV-infected individuals, supplementation of HIV-infected pregnant women does not appear to reduce the risk of mother-to-child transmission of HIV.

Vitamin D

Vitamin D is discussed in more detail in Chapter 11, where the most common manifestations of deficiency are discussed (bone and calcium disorders, Chapter 24; rickets and osteomalacia, Chapter 24). Vitamin D receptors are distributed widely in human tissues, but their function in many non-musculoskeletal tissues still remains poorly understood. Vitamin D status has been linked to a wide range of diseases, including:

It has therefore been suggested that vitamin D may have a role in global health, and not just the health of the musculoskeletal system. Studies of the relationship between vitamin D status and risk for these conditions has led to different definitions of various levels for adequate status, implying that there are different requirements for vitamin D in different diseases. However, randomized controlled trials (RCTs) of vitamin D supplementation have not been as promising in averting some of these conditions as might have been anticipated from the observational relationships.

Vitamin K

Vitamin K is found as phylloquinone (vitamin K₁) in green leafy vegetables, dairy products, rapeseed and soya bean oils. Intestinal bacteria can synthesize the other major form of vitamin K, menaquinone (vitamin K₂), in the terminal ileum and colon. Vitamin K is absorbed in a similar manner to other fat-soluble substances in the upper small gut. Some menaquinones must also be absorbed as this is the major form found in the human liver.

Vitamin E

Vitamin E includes eight naturally occurring compounds divided into tocopherols and tocotrienols. The most active compound and the most widely available in food is the natural isomer d- (or RRR) α-tocopherol, which accounts for 90% of vitamin E in the human body. Vegetables and seed oils, including soya bean, saffron, sunflower, cereals and nuts, are the main sources. Animal products are poor sources of the vitamin. Vitamin E is absorbed with fat, transported in the blood largely in low-density lipoproteins (LDL).

An individual’s vitamin E requirement depends on the intake of polyunsaturated fatty acids (PUFAs). Since this varies widely, no daily requirement is given in the UK. The requirement stated in the USA is approximately 7–10 mg/day, but average diets contain much more than this. If PUFAs are taken in large amounts, more vitamin E is required.

Thiamin (vitamin B₁)

Riboflavin

Riboflavin is widely distributed throughout all plant and animal cells. Good sources are dairy products, offal and leafy vegetables. Riboflavin is not destroyed appreciably by cooking, but is destroyed by sunlight. Riboflavin is a flavo-protein that is a cofactor for many oxidative reactions in the cell.

There is no definite deficiency, although many communities have low dietary intakes. Studies in volunteers taking a low riboflavin diet have produced:

Conjunctivitis with vascularization of the cornea and opacity of the lens has also been described. It is probable, however, that many of the above features are due to multiple deficiencies rather than the riboflavin itself.

Riboflavin 5 mg daily can be tried for the above conditions, usually given as the vitamin B complex.

Niacin

This is the generic name for the two chemical forms, nicotinic acid and nicotinamide, the latter being found in the two pyridine nucleotides, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Both act as hydrogen acceptors in many oxidative reactions, and in their reduced forms (NADH and NADPH) act as hydrogen donors in reductive reactions. Many oxidative steps in the production of energy require NAD, and NADP.

Niacin is found in many foodstuffs, including plants, meat (particularly offal) and fish. Niacin is lost by removing bran from cereals but is added to processed cereals and white bread in many countries.

Niacin can be synthesized in humans from tryptophan, 60 mg of tryptophan being converted to 1 mg of niacin. The amount of niacin in food is given as the ‘niacin equivalent’, which is equal to the amount of niacin plus one-60th of the tryptophan content. Eggs and cheese contain tryptophan.

Kynureninase and kynurenine hydroxylase, key enzymes in the conversion of tryptophan to nicotinic acid, are both B₆ and riboflavin dependent, and deficiency of these B vitamins can also produce pellagra.

Clinical features

The classical features are of dermatitis, diarrhoea and dementia. Although this is an easily remembered triad, not all features are always present and the mental changes are not a true dementia.

Pellagra. (a) Hyperpigmentation with desquamation of the dorsal aspects of the hands and forearms. (b) Hyperpigmented desquamation of the distal lower extremity. Note the shiny, shellac-like appearance on the lateral ankle.

(From: Bolognia J, Jorrizzo J, Rapini R (eds). Dermatology, 2nd edn. St Louis: Mosby; 2008: Fig. 51.9, with permission.)

Dermatitis. In the areas of skin exposed to sunlight, initially there is redness followed by cracks with occasional ulceration. Chronic thickening, dryness and pigmentation develop. The lesions are always symmetrical and often affect the dorsal surfaces of the hands. The perianal skin and vulva are frequently involved. Casal’s necklace or collar is the term given to the skin lesion around the neck, which is confined to this area by the clothes worn.

Diarrhoea. This is often a feature but constipation is occasionally seen. Other gastrointestinal manifestations include a painful, red, raw tongue, glossitis and angular stomatitis. Recurring mouth infections occur.

Dementia. This occurs in chronic disease. In milder cases there are symptoms of depression, apathy and sometimes thought disorders. Tremor and an encephalopathy frequently occur. Hallucinations and acute psychosis are also seen with more severe cases.

Pellagra may also occur in the following circumstances:

Isoniazid therapy can lead to a deficiency of vitamin B₆, which is needed for the synthesis of nicotinamide from tryptophan. Vitamin B₆ is now given concomitantly with isoniazid.

In Hartnup’s disease, a rare inborn error, in which basic amino acids including tryptophan are not absorbed by the gut. There is also loss of this amino acid in the urine.

In generalized malabsorption (rare).

In alcohol-dependent patients who eat little.

Very low protein diets given for renal disease or taken as a food fad.

In the carcinoid syndrome and phaeochromocytomas, tryptophan metabolism is diverted away from the formation of nicotinamide to form amines.

Vitamin B₆

Vitamin B₆ exists as pyridoxine, pyridoxal and pyridoxamine, and is found widely in plant and animal foodstuffs. Pyridoxal phosphate is a cofactor in the metabolism of many amino acids. Dietary deficiency is extremely rare. Some drugs (e.g. isoniazid, hydralazine and penicillamine) interact with pyridoxal phosphate, producing B₆ deficiency. The polyneuropathy occurring after isoniazid usually responds to vitamin B₆.

Sideroblastic anaemia may respond to vitamin B₆ (see p. 380).

A polyneuropathy has occurred after high doses (>200 mg) given over many months. Vitamin B₆ is used for premenstrual tension: a daily dose of 10 mg should not be exceeded.

Biotin and pantothenic acid

Biotin is involved in a number of carboxylase reactions. It occurs in many foodstuffs and the dietary requirement is small. Deficiency is extremely rare and is confined to a few people who consume raw eggs, which contain an antagonist (avidin) to biotin. It has also been reported in patients receiving long-term parenteral nutrition without adequate amounts of biotin. It causes a dermatitis that responds to biotin replacements.

Pantothenic acid is widely distributed in all foods and deficiency in humans has not been described.

Vitamin C

Ascorbic acid is a powerful reducing agent controlling the redox potential within cells. It is involved in the hydroxylation of proline to hydroxyproline, which is necessary for the formation of collagen. The failure of this biochemical pathway in vitamin C deficiency accounts for virtually all of the clinical effects seen.

Humans, along with a few other animals (e.g. primates and the guinea-pig), are unusual in not being able to synthesize ascorbic acid from glucose.

Vitamin C is present in all fresh fruit and vegetables. Unfortunately, ascorbic acid is easily leached out of vegetables when they are placed in water and it is also oxidized to dehydro-ascorbic acid during cooking or exposure to copper or alkalis. Potatoes are a good source as many people eat a lot of them, but vitamin C is lost during storage.

It has been suggested that ascorbic acid in high dosage (1–2 g daily) will prevent the common cold. While there is some scientific support for this, clinical trials have shown no significant effect. Vitamin C supplements have also been advocated to prevent atherosclerosis and cancer, but again a clear benefit has not been demonstrated.

Vitamin C deficiency is seen mainly in infants fed boiled milk and in the elderly and single people who do not eat vegetables. In the UK, it is also seen in Asians eating only rice and chapattis and in food faddists.

Scurvy

In adults, the early symptoms of vitamin C deficiency may be nonspecific, with weakness and muscle pain. Other features are shown in Table 5.11. Parafollicular haemorrhages and corkscrew hairs occur. In infantile scurvy, there is irritability, painful legs, anaemia and characteristic subperiosteal haemorrhages, particularly into the ends of long bones.

Table 5.11 Clinical features of vitamin C deficiency (scurvy)

Keratosis of hair follicles with ‘corkscrew’ hair Perifollicular haemorrhages Swollen, spongy gums with bleeding and superadded infection, loosening of teeth Spontaneous bruising Spontaneous haemorrhage Anaemia Failure of wound healing

Scurvy. Corkscrew hairs and perifollicular haemorrhage on the lower extremities.

(From: Bolognia J, Jorrizzo J, Rapini R (eds). Dermatology, 2nd edn. St Louis: Mosby; 2008: Fig. 51.8A, with permission.)

Vitamin B₁₂ and folate

These are dealt with on page 381 and daily requirements are shown in Table 5.8.

Folate. In many developed countries, up to 15% of the population have a partial deficiency of 5,10-methylene tetrahydrofolate reductase, a key folate-metabolizing enzyme. This is due to a point mutation and is associated with an increase in neural tube defects and hyperhomocysteinaemia, which has been linked to cardiovascular disease. Autoantibodies against folate receptors have been found in serum from women who have had a pregnancy complicated by neural tube defects. However, the role of this in the pathogenesis is unclear.

In the USA and some other countries, enriched cereals are fortified with 1.4 mg/kg grain of folic acid to increase daily requirements.

Dietary antioxidants

Free radicals are generated during inflammatory processes, radiotherapy, smoking, and during the course of a wide range of diseases. They may cause uncontrolled damage of multiple cellular components, the most sensitive of which are unsaturated lipids, proteins and DNA, and they also disrupt the normal replication process. They have been implicated as a cause of a wide range of diseases, including malignant, acute inflammatory and traumatic diseases, cardiovascular disease, neurodegenerative conditions such as Alzheimer’s disease, senile macular degeneration, and cataract. The defence against uncontrolled damage by free radicals is provided by antioxidant enzymes (e.g. catalase, superoxide dismutase) and antioxidants, which may be endogenous (e.g. glutathione) or exogenous (e.g. vitamins C and E, carotenoids). A possible causal link between lack of antioxidants and cardiovascular disease has emerged from epidemiological studies although several RCTs have not confirmed this.

Homocysteine, cardiovascular disease and B vitamins

The circulating concentration of the amino acid homocysteine is an independent risk factor for cardiovascular disease (p. 728). A high concentration is related to ischaemic heart disease, stroke, thrombosis, pulmonary embolism, coronary artery stenosis, and heart failure. The strength of the association is similar to smoking or hyperlipidaemia.

Proposed mechanisms, based on experimental evidence, by which homocysteine detrimentally affects vascular function, include:

Homocysteine is not found in food, but results from metabolism within the body which depends on folic acid, vitamin B₁₂ and pyridoxine (vitamin B₆) (Fig. 5.7). Deficiency of one or more of these vitamins is common in the elderly, which would increase the concentration of homocysteine. If an elevated homocysteine concentration was causally linked to cardiovascular disease then it should be possible to lower the risk by administering one or more of these vitamins to lower the homocysteine concentration. However, several recent studies suggest that lowering homocysteine concentrations in this way does not reduce the risk of cardiovascular disease.

Figure 5.7 Homocysteine metabolism.

Iron

Iron deficiency (see also p. 379) is common worldwide, affecting both developing and developed countries. It is particularly prevalent in women of reproductive age. Dietary iron overload is seen in South African men who cook and brew in iron pots.

Copper

Zinc

Zinc is involved in many metabolic pathways, often acting as a coenzyme; it is essential for the synthesis of RNA and DNA.

Deficiency

Acrodermatitis enteropathica is an inherited disorder caused by malabsorption of zinc. Infants develop growth retardation, severe diarrhoea, hair loss and a skin rash, which can occur anywhere on the body, but most often around the mouth, genitalia and hands (a similar rash occurs in adults suffering from zinc deficiency due to other causes (see below). There are also associated Candida and bacterial infections. This condition provides a model for zinc deficiency. Zinc supplementation results in a complete cure. Zinc deficiency probably also plays a role in PEM and in many diseases in children in the developing world. Zinc supplementation has been shown to be of some benefit in, for example, the prevention of diarrhoeal diseases and acute respiratory infections; it also improves growth.

Zinc deficiency (genetic).

(From: Bolognia J, Jorrizzo J, Rapini R (eds). Dermatology, 2nd edn. St Louis: Mosby; 2008: Fig. 51.11A, with permission.)

Zinc levels have also been shown to be low in some patients with malabsorption or skin disease, and in patients with AIDS, but the exact role of zinc in these situations is disputed. Zinc has low toxicity, but high zinc levels from water stored in galvanized containers interfere with iron and copper absorption. Conversely, administration of copper or iron to treat deficiencies such as iron deficiency anaemia can precipitate zinc deficiency. Wound healing is impaired with moderate zinc deficiency and is improved by zinc supplements. Impaired taste and smell, hair loss and night blindness are also features of severe zinc deficiency.

Iodine

Iodine exists in foodstuffs as inorganic iodides which are efficiently absorbed. Iodine is a constituent of the thyroid hormones (p. 960).

Fluoride

In areas where the level of fluoride in drinking water is less than 1 p.p.m. (0.7–1.2 mg/L), dental caries is relatively more prevalent. Fluoridation of the water provides 1–2 mg daily, resulting in a reduction of about 50% of tooth decay in children. There is little fluoride in food. Fluoride-containing toothpaste may add up to 2 mg/day.

Excessive fluoride intake in areas where the water fluoride level is above 3 mg/L can result in fluorosis, in which there is infiltration into the enamel of the teeth, producing pitting and discoloration.

Selenium

Clinical deficiency of selenium is rare except in areas of China where Keshan disease, a selenium-responsive cardiomyopathy, occurs. Selenium deficiency may also cause a myopathy. Toxicity has been described with very high intakes.

Calcium

Calcium absorption (see also p. 513) from the gastrointestinal tract is vitamin D-dependent. Some 99% of body calcium is in the skeleton.

Increased calcium is required in pregnancy and lactation, when dietary intake must be increased. Calcium deficiency is usually due to vitamin D deficiency.

Phosphate

Phosphates (see also p. 519) are present in all natural foods, and dietary deficiency has not been described. Patients taking large amounts of aluminium hydroxide can, however, develop phosphate deficiency owing to binding in the gut lumen. It can also be seen in total parenteral nutrition. Symptoms include anorexia, weakness and osteoporosis.

Other trace elements

The possible significance of cadmium, chromium, cobalt, manganese, molybdenum, nickel and vanadium is shown in Table 5.13.

Table 5.13 Other trace elements (see text)

Early origins of health and disease in older adults

A low birth weight (and/or length) is associated with reduced height, as well as reduced mass and fat-free mass in adult life. These relationships are independent of genetic factors: the smaller of identical twins becomes a shorter and lighter adult.

Relationships have also been reported between growth of the fetus and a variety of diseases and risk factors for disease in adults and older people. These include cardiovascular disease (especially ischaemic heart disease), hypertension and diabetes, and even obesity and fat distribution. However, the strength of association for some of these conditions is weak. Animal studies involving dietary modifications (e.g. protein and zinc, even within the normal range) during pregnancy or in early postnatal life have clearly demonstrated effects, such as hypertension. The effects can persist, not only through the lifetime of the offspring, but also through to their offspring.

The extent to which these findings apply to humans is uncertain, and the mechanisms are poorly understood. Since relationships have been reported between cardiovascular disease in old age and growth in the first few years of life, as well as starvation during puberty, it is likely that cumulative environmental stresses, including nutritional stress, from the time of implantation of the fertilized egg, to fetal and postnatal growth and development, and into adult life, summate to produce an overall disease risk (Fig. 5.8).

Nutritional requirements in the elderly

These are qualitatively similar to the requirements of younger adults: the diet should contain approximately the same proportions of nutrients, and essential nutrients are still required. However, the RNIs stated earlier (p. 195) are intended for healthy people without disease; specific requirements in disease, which is common in older people, are less well-defined.

Maintenance of physical activity continues to be necessary for overall health, regardless of age. However, energy expenditure by the elderly is less, so they have a lower energy requirement. For people aged 60 and above, irrespective of age, the daily energy requirement has been set to be approximately 1.5 × BMR. Because they have reduced fat-free mass, from an average of 60 kg to 50 kg in men and from 40 kg to 35 kg in women, their BMR is reduced.

Nutritional deficits in the elderly are common and may be due to many factors, such as dental problems, lack of cooking skills (particularly in widowers), depression and lack of motivation. Significant malnourishment in developed countries is usually secondary to social problems or disease. In elderly people who are in institutions, multiple nutrient deficiencies are common. Vitamin D supplements may be required because often elderly people do not go into the sunlight. Owing to the high prevalence of osteoporosis in elderly people, increased daily calcium intake (1–1.5 g/day) is often recommended.

Suggested mechanisms

Control of appetite

Appetite is the desire to eat and this usually initiates food intake. Following a meal, satiation occurs. This depends on gastric and duodenal distension and the release of many substances peripherally and centrally.

Following a meal, cholecystokinin (CCK), bombesin, glucagon-like peptide 1 (GLP-1), enterostatin, and somatostatin are released from the small intestine, and glucagon and insulin from the pancreas. All of these hormones have been implicated in the control of satiety. Centrally, the hypothalamus – particularly the lateral hypothalamic area, and paraventricular and arcuate nuclei – plays a key role in integrating signals involved in appetite and bodyweight regulation (Fig. 5.9). There are two main pathways in the arcuate nucleus (Fig. 5.9):

The central appetite-stimulating (orexigenic) pathway in the ventromedial part of the arcuate nucleus, which expresses NPY (neuropeptide Y) and AgRP (agouti-pathway) related protein). Animal studies suggest that this pathway also decreases energy expenditure.

The central appetite-suppressing (anorexigenic pathway or leptin-melanocortin pathway) in the dorsolateral part of the arcuate nucleus, which expresses POMC/CART (pro-opiomelanocortin/cocaine-and-amphetamine-regulated transcript). In this pathway, α-MSH (α-melanocyte-stimulating hormone), formed by cleavage of POMC by PC1 (prohormone convertase), exerts its appetite-suppressing effect via the Mc4R (melanocortin-4 receptors) in areas of the brain that regulate food intake and autonomic activity. Animal studies suggest that this pathway also increases energy expenditure.

Figure 5.9 Peripheral signals and central pathways involved in the control of food intake. The stimulatory (orange) and suppressive (green) signals and pathways are shown. In the arcuate nucleus POMC is converted to melanocortins, including α-MSH, through the action of prohormone convertase. The solid red areas represent receptors for a variety of signals (see list below). Asterisks (*) indicate mutations that have resulted in human obesity. Receptors: GhR, ghrelin receptor; LepR, leptin receptor; InsR, insulin receptor; Mc3R, melanocortin 3 receptor; Mc4R, melanocortin 4 receptor; Y1R, Y1 subtype of neuropeptide Y (NPY) receptor. Other abbreviations: CCK, cholecystokinin; CRH, corticotrophin-releasing hormone; GLP-1, glucagon-like peptide; LHA, lateral hypothalamic area; α-MSH, α-melanocyte-stimulating hormone; NPY/AgRP, neuropeptide Y/agouti-related protein; POMC/CART, pro-opiomelanocortin/cocaine-and-amphetamine-regulated transcript; PVN, paraventricular nucleus; PYY, peptide YY; TRH, thyrotrophin-releasing hormone.

These pathways interact with each other and feed into the lateral hypothalamus, which communicates with other parts of the brain, and influence the autonomic nervous system and ingestive behaviour. These central pathways are in turn influenced by a variety of peripheral signals which can also be classified as appetite stimulating or appetite suppressing.

Peripheral appetite-suppressing signals: Leptin and insulin act centrally to activate the appetite-suppressing pathway (while also inhibiting the appetite-stimulating pathway). Since these hormones circulate in proportion to adipose tissue mass, they can be regarded as long-term signals, although they probably also modulate short-term signals (insulin also responds acutely to meal ingestion). Peptide YY (PYY) is produced by the L cells of the large bowel and distal small bowel in proportion to the energy ingested. The release of this rapidly responsive (short-acting) signal begins shortly after food intake, suggesting that the initial response involves neural pathways, before ingested nutrients reach the site of PYY production. PYY is thought to reduce appetite, at least partly through inhibition of the appetite-stimulating pathway (NPY/AgRP-expressing neurones). There are a large number of other peripheral appetite suppressing signals, including glucagon-like peptide 1 (GLP-1) and oxyntomodulin, which, like PYY, are produced by the gut in a nutrient dependent manner.

Peripheral appetite-stimulating signals: Ghrelin is a 28-amino-acetylated peptide produced by the oxyntic cells of the fundus of the stomach. It is the first known gastrointestinal tract peptide that stimulates appetite by activating the central appetite-stimulating pathway. The circulatory concentration is high before a meal and is reduced rapidly by ingestion of a meal or glucose (cf. peptide YY, which increases after a meal). It may also act as a long-term signal, as its circulating concentration in weight-stable individuals is inversely related to BMI over a wide range (cf. insulin and leptin which are positively related to BMI, see below). It is also increased in several situations in which there is a negative energy balance, e.g. long-term exercise, very low-calorie diets, anorexia nervosa and both cancer and cardiac cachexia (an exception is vertical banded gastric bypass surgery, where its concentration is low rather than high). Recent studies suggest that another peptide, obestatin, produced by the same gene that encodes ghrelin, counteracts the increase in food intake induced by ghrelin.

The single gene mutations affecting this pathway in humans, e.g. leptin, leptin receptor, POMC, Mc4R, PC1 and SIM1, are rare and recessive, with the exception of the Mc4R, which is common and dominant with incomplete penetrance. It appears that the Mc4R mutation accounts for 2–6% of human obesity. Affected individuals are obese without disturbances in pituitary function or resting energy expenditure, although children tend to be tall. However, these mutations are of little significance as obesity is predominantly polygenic in origin (the human obesity gene map has already identified several hundreds of candidate genes).

Another system, the endocannabinoid system, is involved in both central and peripheral regulation of food intake and control of energy balance. There are two receptors: endocannabinoid in the brain and CB₂ in the periphery. CB₁ receptors are located in the cerebral cortex, cerebellum and hippocampus.

The control of appetite is extremely complex. For example, if one considers only one signal, i.e. leptin, there can be leptin resistance where obese individuals have high circulating leptin but with no reduction of appetite. In contrast, in acute starvation, leptin concentrations decrease to lower levels than expected from the prevailing adipose tissue mass. It is known that cytokines, such as TNF and IL-2, which are elevated in a wide range of inflammatory and traumatic conditions, also suppress appetite, although the exact pathways involved are not entirely clear. Finally, there is a range of transmitters in the central nervous system that appear to affect appetite:

Appetite inhibitors: dopamine, serotonin, γ-aminobutyric acid

Appetite stimulators, e.g. opioids.

FURTHER READING

Wynne K, Bloom SR. The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control. Nat Clin Prac Endocrinol Metab 2006; 2:612–620.

Morbidity and mortality

Obese patients are at risk of early death, mainly from diabetes, coronary heart disease and cerebrovascular disease. The greater the obesity, the higher the morbidity and mortality rates. For example, men who are 10% overweight have a 13% increased risk of death, while the increase in mortality for those 20% overweight is 25%. The rise is less in women, and in men over 65, obesity is not an independent risk factor. Weight reduction reduces this mortality and therefore should be strongly encouraged. The benefits are probably greater in more obese subjects (Table 5.15).

Table 5.15 Potential benefits that may result from the loss of 10 kg in patients who are initially 100 kg and suffer from co-morbidities

Clinical features

Most patients recognize their own problems, although often they are unaware of the main foods that cause obesity. Many symptoms are related to psychological problems or social pressures, such as the woman who cannot find fashionable clothes to wear.

The degree of obesity can be assessed by comparison with tables of ideal weight for height, from the BMI (Box 5.6), and by measuring skinfold thickness. The latter should be measured over the middle of the triceps muscle; normal values are 20 mm in a man and 30 mm in a woman. A central distribution of body fat (a waist/hip circumference ratio of >1.0 in men and >0.9 in women) is associated with a higher risk of morbidity and mortality than is a more peripheral distribution of body fat (waist/hip ratio <0.85 in men and <0.75 in women). This is because fat located centrally, especially inside the abdomen, is more sensitive to lipolytic stimuli, with the result that the abnormalities in circulating lipids are more severe.

Table 5.16 shows the conditions and complications that are associated with obesity. The relationship between cardiovascular disease (hypertension or ischaemic heart disease), hyperlipidaemia, smoking, physical exercise and obesity is complex. Difficulties arise in interpreting mortality figures because of the number of factors involved. Many studies do not differentiate between the types of physical exercise taken or take into account the cuff-size artefact in the measurement of blood pressure (an artefact will occur if a large cuff is not used in patients with a large arm). Nevertheless, obesity almost certainly plays a part in all of these diseases and should be treated. An exception is that stopping smoking, even if accompanied by weight gain, is more beneficial than any of the other factors. Physical fitness is also helpful, and there is some evidence to suggest that a fit obese person may have similar or even lower cardiovascular risk than a leaner unfit person.

Table 5.16 Conditions and complications associated with obesity

Metabolic syndrome

There are two classification systems which are shown in Table 5.17. The differences are:

Table 5.17 Classification systems for metabolic syndrome: ATP III of the National Cholesterol Education Programme (NCEP) and International Diabetes Federation (IDF)

ATP III, Adult Treatment Panel 3.

This means that the prevalence of metabolic syndrome will be higher using the IDF criteria and the IDF criteria will identify at-risk patients at an earlier stage. This could lead to further investigations following on from the initial screening, and earlier institution of preventative as well as therapeutic measures. Other classification systems also exist, e.g. using BMI (an overall measure of obesity) instead of waist circumference (a measure of central obesity, which is more likely to be associated insulin resistance).

Overweight/central obesity and insulin resistance, which causes glucose and lipid disturbances, seem to form the basis of many features of the metabolic syndrome. Early treatment of obesity and the metabolic syndrome can avoid development of clinical diabetes and its complications.

The metabolic syndrome is a combination of risk factors (Table 5.17). Its overall role in the prediction of the risk of cardiovascular disease has been questioned as the sum of the combined risk factors in the syndrome does not offer more than the individual factors added together.

Dietary control

This largely depends on a reduction in calorie intake. The most common diets allow a daily intake of approximately 4200 kJ (1000 kcal), although this may need to be nearer 6300 kJ (1500 kcal) for someone engaged in physical work. Very low calorie diets are also advocated by some, usually over shorter periods of time, but unless they are accompanied by changes in lifestyle, weight regain is likely. Patients must realize that prolonged dieting is necessary for large amounts of fat to be lost. Furthermore, a permanent change in eating habits is required to maintain the new low weight. It is relatively easy for most people to lose the first few kilograms, but long-term success in moderate obesity is poor (no more than 10%). Most obese people oscillate in weight; they often regain the lost weight, but many manage to lose weight again. This ‘cycling’ in bodyweight may play a role in the development of coronary artery disease.

Many dietary regimens aim to produce a weight loss of approximately 1 kg/week. Weight loss will be greater initially owing to accompanying protein and glycogen breakdown and consequent water loss. After 3–4 weeks, further weight loss may be very small because only adipose tissue is broken down and there is less accompanying water loss.

Patients must understand the principles of energy intake and expenditure, and the best results are obtained in educated, well-motivated patients. Constant supervision by healthcare professionals, by close relatives or through membership of a slimming club helps to encourage compliance. It is essential to establish realistic aims. A 10% weight loss, which is regarded by some as a ‘success’ (see Table 5.15), is a realistic initial aim.

An increase in exercise will increase energy expenditure and should be encouraged – provided there is no contraindication – since weight control is usually not achieved without exercise. The effects of exercise are complex and not entirely understood. However, exercise alone will usually produce little long-term benefit. On the other hand there is evidence to suggest that in combination with dietary therapy, it can prevent weight being regained. In addition, regular exercise (30 min daily) will improve general health.

The diet should contain adequate amounts of protein, vitamins and trace elements (Box 5.7).

A balanced diet, attractively presented, is of much greater value and safer than any of the slimming regimens often advertised in magazines.

A wide range of diets are available, including low-fat or low-carbohydrate diets, and some suit certain individuals better than others. The following general statements can be made about them:

Behavioural modification

The aim of behavioural modification is to encourage the patient to take personal responsibility for changing lifestyle, which will determine dietary habits and physical activity. Family therapy may also be useful, especially when it involves obese children. It can be time-consuming and expensive. Cognitive behavioural therapy is even more time-consuming and expensive.

Drug therapy

Drugs can be used in the short term (up to 3 months) as an adjunct to the dietary regimen, but they do not substitute for strict dieting.

Surgical treatment

Surgery is used in some cases of morbid obesity (BMI >35 kg/m²) or patients with a BMI >30 kg/m² and obesity related complications, after conventional medical treatments have failed. It can be used as a first-line option for individuals with a BMI >50 kg/m². Fitness for surgery should be checked, especially in older people. A variety of gastrointestinal surgical procedures have been used. They fall into three main groups (Fig. 5.10):

Figure 5.10 Examples of surgery procedures to treat morbid obesity. (a) Restrictive procedure: gastric banding with subcutaneous port attached to anterior abdominal wall so that fluid can be injected into the adjustable band around the upper stomach. (b) Restrictive plus malabsorptive procedures: Roux-en-Y gastric bypass, in which food bypasses through a small stomach pouch and bypasses the proximal small bowel.

(Courtesy of Mr Amit Patel.)

Restrictive procedures, which restrict the ability to eat (e.g. adjustable gastric banding, vertical banded gastroplasty and sleeve gastroplasty).

Malabsorptive procedures, which reduce the ability to absorb nutrients (e.g. biliopancreatic diversion and Roux-en-Y gastric bypass). The malabsorptive procedures cause nutrient deficiencies, malnutrition and in some cases, anastomotic leaks and the dumping syndrome (e.g. with the duodenal switch).

Restrictive plus malabsorptive procedures (e.g. duodenal switch, Roux-en-Y gastric bypass, intragastric balloon).

The procedures all have advantages and disadvantages, and there is controversy about the procedure of choice for specific groups of patients. The restrictive procedures are more straightforward than the complex bypass procedures. The adjustable gastric banding procedure, although attractive in concept, especially since it can be undertaken laparoscopically with a lower perioperative mortality (<0.3%) than the other procedures (~1%), can be associated with erosion and slippage of the band, as well problems with the port, making repeat operations a frequent requirement (>10% of cases). The sleeve gastrectomy is associated with heartburn and greater risk of weight regain, but a biliary pancreatic diversion (duodenal switch) can be added at a later time.

There is a need to carefully monitor nutrient status with blood tests and provide supplements of vitamins and minerals (including iron and calcium). Weight loss following the combined restrictive and malabsorptive procedures tends to be greater than with either procedure alone.

A systematic analysis of several bariatric surgical procedures concluded that, in comparison to non-surgical treatments, they produced significantly more weight loss (23–37 kg), which was maintained to 8 years and associated with improvement in quality of life and co-morbidities.

Liposuction, the removal of large amounts of fat by suction (liposuction), does not deal with the underlying problem and weight regain frequently occurs. There appears to be no reduction in cardiovascular risk factors with the procedure.

Prevention

Preventing obesity must always be the goal because most obese people find it difficult to maintain any weight loss they have managed to achieve. All health professionals must be aware of the dangers of obesity and encourage children, young as well as older adults, from gaining too much weight. A small gain each year over a long period produces an obese individual for whom treatment is difficult. Public health policies should consider creation of public places to encourage physical activity and fitness, education about the benefits of losing weight or not gaining it, through healthy eating and physical activity, and changes in food composition (alternatives to high-fat, high-energy-dense foods).

Since the present obesity epidemic has resulted from lifestyle changes, it is appropriate to promote lifestyle changes, not only as the first-line therapy for most overweight and obese individuals, but also in the prevention of overweight and obesity. Lifestyle modification would involve changes in the amount of time watching television and using computers, use of bicycle paths, dietary changes and educational activities of patients and public, parents and children. To prevent long-term weight gain after any of the therapies discussed above, each therapy should be part of a package that involves lifestyle modification.

Principles

Some form of nutritional supplementation is required in those patients who cannot eat, should not eat, will not eat or cannot eat enough. All patients should be screened for malnutrition on admission and the findings linked to a care plan, preferably under the supervision of a trained multidisciplinary team. The Council of Europe has produced 10 key characteristics of good nutritional care in hospital (see: bapen.org.uk). Plans are discussed with patients and consent is taken for any invasive procedure (e.g. nasogastric tube, parenteral nutrition). If the patient is unable to give consent, the healthcare team should act in the patient’s best interest, taking into account previously expressed wishes of the patient and views of the family. It is usually necessary to provide nutritional support for:

Enteral rather than parenteral nutrition should be used if the gastrointestinal tract is functioning normally.

In re-feeding syndrome, the shifts of water and electrolytes that occur after parenteral and enteral nutrition can be life-threatening. Carbohydrate intake stimulates insulin release which leads to cellular uptake of phosphate, potassium and magnesium. Complications include hypophosphataemia, hypokalaemia, hypomagnesaemia and fluid overload because of sodium retention (decreased renal excretion of sodium and water). Patients who have eaten little or nothing for more than 5 days should initially receive no more than 50% of their energy requirements (NICE guidelines).

Nutritional requirements for adults

Figure 5.11 Trace elements. Recommended intravenous intake in absolute values and as a percentage of recommended oral intake. *Trace elements for which there is too little information to establish a recommended value for dietary oral intake; the midpoint of estimated safe and adequate oral intake is shown.

Figure 5.12 Vitamins. Recommended intravenous intake in absolute values and as a percentage of recommended oral intake. *Vitamins for which there is too little information to establish recommended dietary oral intake; the midpoint of estimated safe and adequate oral intake is shown.

Enteral nutrition (EN)

Feeds can be given by various routes:

Figure 5.13 Percutaneous endoscopic gastrostomy (PEG).

Parenteral nutrition

Food allergy

Food allergy, which is estimated to affect up to about 5% of young children and about 1–2% of adults, may be IgE mediated or non-IgE mediated (T-cell mediated). The IgE-mediated reactions tend to occur early after a food challenge (within minutes to an hour). Adults tend to be allergic to fish, shellfish and peanuts, while children tend to be allergic to cow’s milk, egg white, wheat and soy. Peanuts are very allergenic and peanut allergy persists throughout life. The following conditions can result from food allergy:

Food intolerance

A number of other inborn errors of metabolism can also be regarded as forms of food intolerance.

Food intolerance may be due to a constituent of food (e.g. the histamine in mackerel or canned food or the tyramine in cheeses); chemical mediators released by food (e.g. histamine may be released by tomatoes or strawberries); or toxic chemicals found in food (e.g. the food additive tartrazine). Many other additives and compounds with certain E numbers have been implicated as causing reactions, but the evidence is poor.

There is little or no evidence to suggest that diseases such as arthritis, behaviour and affective disorders and Crohn’s disease are due to ingestion of a particular food. Multiple vague symptoms such as tiredness or malaise are also not due to food allergy. Most of the patients in this group are suffering from a psychiatric disorder (p. 1185).

Effects of excess alcohol consumption

Excess consumption of alcohol leads to two major problems, both of which can be present in the same patient:

Each unit of alcohol (defined as one half pint of normal beer, one single measure of spirit or one small glass of wine) contains 8 g of ethanol (Fig. 5.14). All the long-term effects of excess alcohol consumption are due to excess ethanol, irrespective of the type of alcoholic beverage, i.e. beer and spirits are no different in their long-term effects. Short-term effects, such as hangovers, depend on additional substances, particularly other alcohols such as isoamyl alcohol, which are known as congeners. Brandy and bourbon contain the highest percentage of congeners.

Figure 5.14 Measures of 1 unit of alcohol.

The amount of alcohol that produces damage varies and not everyone who drinks heavily will suffer physical damage. For example, only 20% of people who drink heavily develop cirrhosis of the liver. The effect of alcohol on different organs of the body is not the same; in some patients, the liver is affected, in others, the brain or muscle. The differences may be genetically determined.

Thiamin deficiency contributes to both neurological (confusion, Wernicke–Korsakoff syndrome; see p. 1091) and some of the non-neurological manifestations (cardiomyopathy). Susceptibility to damage of different organs is variable and the figures given in Box 5.9 are given only as a guide to sensible drinking. Heavy persistent drinkers for many years are at greater risk than heavy sporadic drinkers.