CHAPTER OUTLINE

Food is essential for human life. At the extremes, too little leads to starvation and too much leads to obesity, each with its associated effects on morbidity and mortality. Between these extremes, different people across the world follow apparently very different diets with no obvious resulting differences in their day-to-day health. It is apparent that in the long term the composition of the diet has an effect on the incidence of certain diseases, for example ischaemic heart disease and certain types of cancer, but often these associations are difficult to tease out because of the many confounding factors involved. However, this does not prevent very firm opinions being formulated and held about what is and what is not ‘good nutrition’, based on a variety of influences from basic science to religion.

Biochemistry clearly has a role in establishing the way in which the body uses various nutrients and has been important in defining certain deficiency states. Clinical biochemistry is still important in diagnosing deficiencies of certain specific nutrients, but whether there is a good biochemical marker of overall nutritional status is less clear. This chapter begins with a consideration of the various nutrients, including the effects of their deficiency or excess, and then discusses nutritional assessment. The following chapter discusses nutritional disorders and their management, both from the point of view of nutrition as an aetiological factor in disease, and disorders that are not primarily nutritional but where dietary modification or nutritional support may be important in treatment.

Part of the explanation of the fact that apparently very different diets can sustain life equally well is the concept that individual foodstuffs actually comprise different combinations of certain basic nutrients, and that it is the supply of these basic nutrients that is important rather than their origin. However, even when individual nutrients are considered, the definition of the ‘correct’ intake is problematical since this may be taken, for example, to be any of the following: the intake that avoids clinical signs of deficiency; the intake that maintains a given circulating concentration or tissue content of the nutrient; the intake that cures symptoms or signs of clinical deficiency; the intake that maintains a balance between intake and consumption or loss from the body over a defined period, or any one of a variety of other definitions. Even if a suitable measure can be determined for a specific nutrient, there are further problems in setting the absolute figure, since within a population, requirements will vary between individuals (owing, for example to differences in age, gender size and body composition) and even in an individual, requirements may vary in the short term (owing, for example to pregnancy, illness or environmental stress).

It is thus difficult to accurately estimate average requirements for a nutrient, and most attempts to make recommendations about intakes have depended on setting levels where most of the population will not be deficient, although it is also possible to define intakes below which most of a population will develop deficiency, and in some cases intakes that are high enough to be toxic.

The body uses energy in the maintenance of metabolic processes, in physical activity and in growth. In the resting individual, energy-requiring processes include the active pumping of ions across cell membranes, thermoregulation, cell division and basal function of all of the body’s systems. Resting energy expenditure appears to alter with energy intake to some extent. Physical activity, particularly if vigorous, can increase energy expenditure markedly, although such activity is not usually sustained for long enough to make the increase substantial when measured over a 24 h period. The laying down of new tissues represents an investment of energy, so it is not surprising that energy requirements, expressed in terms of body weight, are highest in infants and young children, with a gradual decline from the third decade into old age.

Thus, the energy requirement of an individual varies with body size and composition, gender, age, nutritional status and climate. In women, energy expenditure is increased during pregnancy and lactation, and in any individual, illness or response to trauma (e.g. systemic infection, burns) may cause a considerable increase.

Energy expenditure and energy intake do not always rise and fall in parallel. A sustained deficiency in energy intake generally leads to consumption of body stores of energy, including protein as well as glycogen and fat. Excessive energy intake (if sustained) results in obesity. Both of these conditions are considered further in the next chapter.

Dietary energy is mainly obtained from a combination of fat and carbohydrate. In a Western diet, each may account for 40–50% of total energy intake, although in developing countries the proportion from carbohydrate tends to be higher and that from fat, lower. Although dietary protein is generally thought of as a source of materials (amino acids) for endogenous protein production, it may also be used for energy production, for example if protein intake is adequate but non-protein energy intake is low. Ethanol also has to be considered as a significant energy source in certain populations; for example, in the UK, it forms 7% of average energy intake. (Interestingly, at higher ethanol intakes – 25–35% of dietary energy – ethanol appears not to be completely utilized as a source of energy, although the reason for this is not clear.)

Dietary carbohydrate provides 4.1 kcal/g and most is derived from sugars and starch. The sugars are mainly the monosaccharides glucose, fructose and galactose, and the disaccharides sucrose, lactose and maltose. Dietary sugars can be divided into those which are present in intact cells, such as in whole fruit (intrinsic sugars), and those which are free and readily absorbed as a result of having been added to food, usually as sucrose (extrinsic sugars). Milk sugars are usually considered as intrinsic. A high intake of extrinsic sugars is associated with an increased prevalence of dental caries. Sugar derivatives, such as the sugar alcohols sorbitol and xylitol, can be partially digested and can provide 2.4 kcal/g.

In the UK, it is recommended that in the adult, 40–50% of energy intake should be provided by carbohydrate, but non-milk extrinsic sugars should not exceed 11% of energy intake. There is considerable debate about whether a high intake of non-milk extrinsic sugars may have harmful effects in addition to the increased risk of dental caries. If such an intake results in an increased energy intake, then obesity is likely to be a problem, but in any case, ingestion of large amounts of extrinsic sugars can lead to raised plasma glucose, insulin and lipid concentrations, all of which are potentially harmful.

A deficiency in dietary carbohydrate will either lead to energy deficiency or result in potentially harmful amounts of other energy sources being required in the diet if energy intake is to be maintained. However, certain tissues have an obligatory requirement for glucose as an energy substrate (e.g. brain and nervous system (in the short term), red blood cells) and, while this need can be met by gluconeogenesis, some carbohydrate is necessary in the diet if ketosis is to be avoided.

Vitamins and certain trace elements are essential components of the diet required in very small amounts. Deficiency of individual micronutrients classically results in typical symptoms and signs according to the vitamin or trace element involved; recognition and treatment of deficiency of a single micronutrient deficiency is relatively easy. However, milder forms of deficiency, particularly of multiple micronutrients concurrently, may be difficult to recognize clinically.

Micronutrient status is likely to be affected by acute illness, owing to a combination of reduced intake and increased demand. Such increased demand may be due to catabolism resulting from the illness, subsequent anabolism and from disease-specific increased losses, for example loss from fistulae, diarrhoea and dialysis. As laboratory concentration of micronutrients may be perturbed in the acute phase, deficiencies in this group of patients can be particularly difficult to assess.

It is increasingly being recognized that subclinical deficiencies of micronutrients may have detrimental effects, some of which are described in the following pages. As the assessment of micronutrients can be important in patients receiving supplementation, consideration is also given to aspects of micronutrient toxicity.

Vitamins are traditionally classified into those that are fat soluble (A, D, E and K) and the remainder, which are water soluble. This is probably still a useful distinction, as it predicts when deficiency is likely (e.g. fat-soluble vitamins in steatorrhoea), and is retained here.

The fat-soluble vitamins A, E and K are structurally different, but are all non-polar, water-insoluble lipids. Absorption of each of them requires micelle formation in the gut lumen, for which bile salts are necessary.

The nutritional requirement for vitamin E is approximately proportional to the intake of polyunsaturated fatty acids. However, since foods rich in these (e.g. vegetable oils) also tend to contain large amounts of vitamin E, deficiency states are rare.

Vitamin E is not easily transported across the placenta and the first vitamin E deficiency state to be firmly established was in premature infants, who developed haemolytic anaemia, thrombocytosis and oedema. In children and adults who are unable to absorb or utilize vitamin E adequately (e.g. in cystic fibrosis or abetalipoproteinaemia), a progressive spinocerebellar degeneration may develop. The full syndrome consists of ataxia of the limbs, loss of position and vibration senses, absent deep tendon reflexes and pigmentary degeneration of the retina. Treatment with vitamin E supplements can prevent these neurological features or, if they are already present, arrest or even reverse them. For α-tocopherol to be made available to the tissues from very low density lipoprotein, it must first bind to hepatic α-tocopherol transfer protein. Individuals with a deficiency of this transfer protein develop a very similar clinical syndrome (ataxia with vitamin E deficiency, AVED).

There is some evidence that increased tissue concentrations of antioxidants, in particular vitamin E, may protect against conditions such as cancer and ischaemic heart disease, but this remains controversial.

Vitamin E supplements have also been taken to improve general well-being and sexual performance, but the only firm conclusion that can be drawn is that quite high intakes of vitamin E are non-toxic, although very high intakes may antagonize vitamin K and potentiate anticoagulant therapy.

The main dietary form of vitamin K is phytomenadione (K₁), with leafy green vegetables being the richest source, although other vegetable sources are important in most diets. Menaquinones (K₂) produced by the intestinal bacteria may also be important, since while circulating vitamin K is mainly phytomenadione, hepatic reserves are mainly menaquinones.

Vitamin K deficiency in its severest form leads to a bleeding syndrome, but dietary deficiency is rare after the first few months of life, unless there is an underlying disease affecting the absorption or utilization of the vitamin. However, vitamin K is undetectable in the blood of new-born babies, their hepatic reserves are low compared with adults and human breast milk contains barely adequate amounts. Thus, deficiency may present in infants as vitamin K deficiency bleeding (VKDB), within the first 24 h from the time of birth (early), between two and seven days (classic) or after seven days (late). Intracranial haemorrhage is rare in the early form, but occurs in more than 50% of babies with the late form and is likely to lead to death or severe neurological sequelae. The administration of vitamin K in the neonatal period abolishes the risk of deficiency. A single intramuscular injection of 1 mg of phytomenadione is highly effective for this purpose but suspicions, which now appear to be unfounded, were raised that its use led to an increased risk of childhood malignancy, particularly leukaemia. This adverse association has not been found for the administration of oral vitamin K, but the latter requires a multi-dose regimen. The current UK recommendation is that either intramuscular or oral vitamin K should be offered to all neonates after informed discussion with the parents.

Toxicity from naturally occurring K vitamins would appear to be rare, even in quite high doses. However, the use of synthetic preparations of menadione for nutritional purposes is best avoided, as serious unwanted effects have been recorded (e.g. haemolysis and liver damage in neonates).

The physiologically active form of thiamin (vitamin B₁) is thiamin pyrophosphate (TPP). This functions as a cofactor in the conversion of pyruvate to acetyl-CoA by the pyruvate dehydrogenase complex and in the conversion of 2–oxoglutarate to succinyl-CoA by the 2–oxoglutarate dehydrogenase complex. It acts as a cofactor to the enzyme transketolase in the pentose phosphate pathway and plays a part in the metabolism of branched chain amino acids. Thiamin also has non-cofactor roles: thiamin triphosphate is found in nerve and muscle cells, where it activates membrane ion channels, possibly by phosphorylating them.

Thiamin is found in most foodstuffs, but wheatgerm, oatmeal and yeast are particularly rich sources. However, the body store of about 30 mg is only 30 times the daily requirement and so an inadequate diet is likely to lead to deficiency of thiamin sooner than of any other vitamin. Thiamin deficiency used to be widespread in areas where rice formed a major part of the diet, resulting from the consumption of polished rice (from which the husk had been removed). In present times, thiamin deficiency is seen more typically in alcoholics (alcohol decreases the absorption of thiamin). Diets high in carbohydrate require more thiamin for their assimilation than diets high in fat, and subclinical deficiency may be unmasked by refeeding with a carbohydrate-rich diet. Patients on long-term renal replacement treatment may become deficient in thiamin (and other water-soluble vitamins) unless given supplements.

Most of the clinical features of the disease beriberi respond to treatment with thiamin, suggesting that it is mainly due to thiamin deficiency. Two forms are described, one in which there is peripheral neuropathy, muscle weakness, general fatigue and reduced attention span (‘dry’ beriberi) and one in which there is also oedema and heart failure (‘wet’ beriberi). Some of these features may be the result of coexisting protein deficiency.

Patients with thiamin deficiency (commonly alcoholics) may present with a neuropathy and cardiomyopathy, but may also develop an encephalopathy, the Wernicke–Korsakoff syndrome. Wernicke encephalopathy and Korsakoff psychosis were originally described as two separate conditions, but now appear to be the acute and chronic manifestations, respectively, of a single condition. Wernicke encephalopathy has an acute onset, with ophthalmoplegia, nystagmus, ataxia and stupor or apathy. It is a medical emergency: the ophthalmoplegia, ataxia and lowered consciousness respond, in most cases within two days, to treatment with thiamin but, in up to 80% of cases, the mental changes fail to resolve completely and Korsakoff psychosis develops. Once established, this responds only slowly or not at all to thiamin treatment. The main features are retrograde amnesia, difficulty in assimilating new ideas and confabulation. Susceptibility to the development of this syndrome in thiamin deficiency may be greater in people who have a genetic variant of transketolase that binds thiamin less avidly than usual.

Thiamin is relatively non-toxic and can be given safely if deficiency is suspected. However, anaphylaxis has occurred after parenteral administration, and a wide variety of toxic effects has been described in adults with chronic intakes in excess of 50 mg/kg body weight or 3 g/24 h.

Riboflavin (Vitamin B₂