Nutrition: Laboratory and clinical aspects

Function and sources

Carbohydrates of nutritional value include poly-, oligo-, and monosaccharides. The most abundant polysaccharide is starch, a linear polymer of glucose with α1–6 linkages that is widely distributed in plant products, including pulses, grains (cereals), and fruit. The major dietary disaccharide is sucrose (glucose–fructose), present in many processed foods, carbonated drinks, confections, and other products. Carbohydrates are not essential components of the diet but typically provide more than 50% of its energy content (4 kcal/g [16.8 MJ/g]) except in Inuits, whose major energy source is fat.

Homeostasis

The evolutionary importance of secure energy homeostasis both in times of plenty and of famine is undoubtedly the basis of the complex interaction of neural and hormonal mechanisms that controls appetite and in health adjusts food intake to the body’s requirements. This topic is considered in detail later in this chapter, but it is salutary to consider that an average healthy man may consume food providing some 9 × 10 ⁵ kcals (56.6 × 10 ⁵ MJ) of energy per year, equivalent to approximately 130 kg of nonaqueous body mass, yet maintain the same body weight year after year. In the short term, the provision of sufficient energy substrates for normal function is primarily dependent on blood glucose homeostasis, a topic that is considered in detail in Chapter 47 .

Deficiency

Because carbohydrates are not essential dietary components, there is no specific carbohydrate deficiency syndrome. However, because carbohydrates provide the major source of energy in most diets, a deficiency of dietary carbohydrate is virtually always a major contributor to generalized starvation. During starvation, even in the short term, when glycogen reserves have been depleted (see later discussion), there is some limitation of exercise capacity.

Excess

An intake of carbohydrate greater than that needed to satisfy the body’s energy requirements inevitably leads to net fat synthesis, weight gain, and, if uncorrected, to obesity. Obesity is associated with insulin resistance, the metabolic syndrome, and type 2 diabetes, but there does not appear to be a causal relationship between these and a high carbohydrate intake per se. ^,

The World Health Organization recommends that free sugar intake should not provide more than 10% (and possibly even less) of total energy intake.

Assessment of status

There are no laboratory tests for the assessment of carbohydrate status. Energy reserves are typically measured by techniques to determine overall protein-energy nutritional status, which are discussed later in this chapter. Only the liver and muscle can store significant amounts of carbohydrate (in the form of glycogen). Hepatic, but not muscle, glycogen can be converted into glucose for delivery to the bloodstream. If no carbohydrate is ingested, hepatic glycogen stores can provide glucose for 18 to 24 hours, after which blood glucose is supplied by gluconeogenesis. Although fasting blood glucose falls by 10% to 20% in the first 72 hours of a fast, it remains constant thereafter for several weeks until limited by the supply of protein during the terminal phase of starvation. The blood glucose concentration therefore provides no information about the body’s carbohydrate stores.

Dietary fiber

All foods of vegetable origin contain complex carbohydrates that cannot be digested in the small intestine; these are collectively termed dietary fiber or nonstarch polysaccharides . They can be classified as water soluble and water insoluble. The former (pectins, gums, and mucilages) can be metabolized by colonic bacteria to form small molecules such as propionic acid (which can be absorbed and contribute to the body’s metabolism) and gases such as methane, hydrogen, and carbon dioxide. Water-insoluble fibers include lignin (noncarbohydrate), celluloses, and hemicelluloses. Lignin, but not celluloses, can be metabolized by the colonic biota.

Although dietary fiber is not an essential component of the diet, it plays an important role in the normal function of the gastrointestinal (GI) tract, for example, by stimulating intestinal transport and suppressing appetite. Dietary fiber can also affect the rate of absorption of other dietary components; soluble fiber reduces plasma total and low-density lipoprotein (LDL) cholesterol concentrations without affecting high-density lipoprotein (HDL) cholesterol. Dietary fiber intake correlates inversely with the risk of cardiovascular disease, including coronary heart disease. There is a suggestion that a diet high in fiber might reduce the risk of several conditions including colon cancer.

Function and sources

Fat is a major dietary energy source, providing 9 kcal/g (56.6 MJ/g). For the most part, dietary fat comprises long-chain triglycerides (strictly, triacylglycerols) (e.g., the esters of glycerol with palmitic acid [16C] and stearic acid [18C]). In most triglycerides of mammalian origin, the fatty acids are saturated, but in fats derived from fish and vegetables, they tend to be variably unsaturated (fat derived from coconut is an exception, being mostly saturated). In unsaturated vegetable fats, ω6 fatty acids (see later discussion) predominate, but fish (particularly oily fish) have a higher content of ω3 fatty acids. Dietary fat also includes cholesterol esters and the fat-soluble vitamins (vitamins A, D, E, and K), which are discussed later in this chapter.

Homeostasis

It is beyond the scope of this chapter to describe in any detail the complex relationships and control mechanisms that ensure that sufficient energy substrates are made readily available to meet the body’s requirements and that any excess is stored. Unlike those of carbohydrate, the body’s fat stores are considerable; even in a lean man, 15% of total body weight may comprise fat, with a potential energy of 136 Mcal (570 MJ).

Deficiency

Because there is no specific requirement for dietary fat (except for fat-soluble vitamins and essential fatty acids [EFA]), there is no specific deficiency syndrome. However, during starvation, fat reserves become depleted, and there is loss of lean body mass as a result of the proteolysis required for gluconeogenesis.

Excess

As with carbohydrate, intake of energy in the form of fat in excess of the body’s requirements promotes fat storage and obesity. It has been recommended that fat should not comprise more than 20% to 35% of total energy intake with no more than one third of the fat being saturated, but the scientific basis of this advice has been challenged. Furthermore, in practice, given the high fat content of many popular/processed foods, achieving less than 35% is difficult.

Assessment of status

Fat stores can be assessed by a variety of clinical and physiologic methods ranging from the simple (e.g., skinfold thicknesses) to the complex (e.g., dual energy X-ray absorptiometry [DEXA]) (see later in this chapter). There are no reliable laboratory tests for fat stores, although correlations between plasma leptin concentrations and fat stores have been demonstrated.

Essential fatty acids

The vitamins apart, the only essential fatty components of the diet are the EFA, α-linolenic acid (C18:3, ω3,6,9) and linoleic acid (C18:2, ω6,9). (The first figure indicates the number of carbon atoms, the second the number of unsaturated bonds, and the ω-number the position of the unsaturated bonds counting from the methyl end; an alternative nomenclature uses the symbol Δ to indicate the position of the double bonds starting with the carboxyl carbon). The EFA are precursors of prostanoids. EFAs were originally collectively known as vitamin F. Arachidonic acid (C20:4, ω 6,9,12,15) is also essential for prostanoid synthesis; although it is not able to be synthesized de novo in the body, it can be produced from linoleic acid. These entities are illustrated in Fig. 46.1 .

Other functions of EFAs include maintenance of the epidermal barrier to infection and normal immune function, and a structural role in cell membranes. Features of EFA deficiency include skin rashes, hair loss and thrombocytopenia. ^, The recommended adequate intake of linoleic acid is 11 g for females and 15 g for males and for linoleic acid is 1.1 g and 1.6 g respectively. Previously, ω3 fatty acids had been thought to have considerable benefit in the prevention of cardiovascular disease. More recent evidence suggests that, while they have an effect in reducing triglycerides any reduction in cardiovascular events or mortality is slight. ^,

EFA in plasma are measured by liquid chromatography coupled to tandem mass spectrometry. However, measurements in tissues (e.g., red blood cell membranes) may be more reliable indicators of EFA status. In EFA deficiency, where α-linoleic and linolenic acids are reduced, there is decreased production of arachidonic acid (tetraene) and oleic acid is preferentially metabolized to Mead acid (triene). An elevated triene:tetraene ratio is consistent with EFA deficiency.

Other fats

Fat soluble vitamins are discussed later in this chapter. Although cholesterol and its esters are also present in dietary fat, cholesterol is synthesized in the body and is not an essential dietary component. Plasma cholesterol concentration is influenced by dietary cholesterol intake (although the intake of saturated fat has a greater influence). It was previously recommended that dietary cholesterol intake should not exceed 300 mg/day, but more recently focus has tended to be more on healthy eating patterns involving relatively low amounts of dietary cholesterol, rather than setting a numerical target. Naturally occurring unsaturated fatty acids have cis -configuration double bonds. Dehydrogenation of saturated fats creates trans- unsaturated fatty acids. These are associated with an increased risk of cardiovascular disease, and the intake of foods containing them (e.g., margarines) should be limited. Indeed, in the United States, the Food and Drug Administration has ruled that partially hydrogenated oils, the primary dietary source of artificial trans fat in processed food, is removed from products intended for human consumption by 2021.

Function and sources

Protein is not an essential dietary component per se but is the major source, in the form of amino acids, of nitrogen. Proteins have numerous functions in the body, including structural (e.g., spectrin in RBC membranes, collagen in connective tissues), transport (e.g., hemoglobin, plasma hormone-binding proteins), the maintenance of plasma oncotic pressure (largely albumin), humoral (immunoglobulins), and as enzymes and receptors. Many amino acids can be synthesized in the body, but others cannot and must be included in the diet. The essential amino acids are isoleucine, leucine, lysine, methionine, phenylalanine, tryptophan, threonine, and valine. Histidine is an essential amino acid in infants but not adults.

All animal and most vegetable foodstuffs contain proteins, but on the whole, animal proteins have a greater content of essential amino acids. The recommended minimum dietary protein intake in adults is usually expressed in terms of nitrogen, using a factor of 6.25 g protein to g nitrogen, and is approximately 0.66 g/kg body weight/day. However, protein requirements are influenced by many factors, including the type of protein (and hence essential amino acid content) and the needs for growth, reproduction, tissue repair after trauma, and so on. The energy equivalent of the carbon skeletons of amino acids is approximately 4 kcal/g (16.7 MJ/g).

Homeostasis

As with the control of energy production and expenditure, the complex processes involved in the provision of amino acids to synthesize proteins is beyond the scope of this book (additional discussion on this topic can be found in Chapter 51 ). There are no specific body stores of protein, but under some circumstances, particularly acute inflammation, catabolism of albumin can provide amino acids for the synthesis of more essential (at least in the short term) proteins. In starvation, protein catabolism is decreased, but some is required to provide glucose to tissues with an obligate requirement for glucose as a source of energy (RBCs, intestinal epithelial cells, and the renal medulla).

Deficiency

Inadequate protein intake can cause one of three major clinical syndromes: marasmus (effectively, cachexia, or chronic starvation, with generalized wasting) caused by a lack of protein and energy substrates; kwashiorkor, in which edema is a major clinical feature in affected people (usually children); and marasmic kwashiorkor, combining features of both conditions. Kwashiorkor tends to be seen in underdeveloped countries and has classically been associated with weaning and the transfer to a diet in which a low intake of protein, rather than energy, predominates, although loss of fat stores and lean body mass is also apparent. This nutritional edema is frequently associated with infection. It has been suggested that an important contributory factor may be the generation of toxic reactive oxygen species and other free radicals in combination with reduced availability of natural antioxidants, for example, vitamins A, C, and E and selenium. Oxidative damage to cell membranes might lead to increased capillary permeability and decreased synthesis of plasma proteins to hypoalbuminemia (a relatively late feature of “simple” starvation), which also contributes to the edema. However, supplementation of the diet with antioxidants has not been shown to decrease the risk of kwashiorkor in children at risk of the condition.

Excess

There are no clinical syndromes of excessive protein intake, but amino acids in excess of requirement are deaminated with the carbon skeletons for the most part becoming substrates for gluconeogenesis and nitrogen being converted to urea and excreted. A high protein intake increases the requirement for the kidneys to excrete urea and may exacerbate renal failure. There is evidence that reducing protein intake (although not below a level required to meet normal requirements) can slow the rate of progression of renal disease, although patients on renal replacement treatment may require protein supplementation to reduce losses caused through dialysis or filtration. Protein restriction (possibly with supplementation of branched chain amino acids) may be of benefit in patients with encephalopathy caused by advanced chronic liver disease, but chronic liver disease is anorexigenic, and supplementation may be required earlier in the condition to prevent malabsorption.

Assessment of status

The management of patients with or at risk of malnutrition would be helped immensely by the existence of a reliable means of assessing the body’s protein status. Numerous laboratory, physiologic, and clinical tests have been described, but all have their limitations. Although widely promoted as an index of protein status, plasma albumin concentration is of little value, except in monitoring (otherwise well) patients requiring nutritional support over the long term. Other plasma proteins are little better. This is because of the numerous factors other than nutritional status that can affect plasma protein concentration, not least the acute phase reaction seen in inflammation and sepsis, which can cause rapid decreases in the concentrations of some proteins but increases in others.

Function and sources

Water is often not mentioned in scholarly accounts of nutrition, but it is arguably more important to health than conventional nutrients because complete water deprivation usually causes death within 7 to 10 days and sooner if there are excessive losses.

All body fluids are aqueous solutions, and water is also required for the excretion of waste products in the urine. On a normal diet, given minimum insensible losses (in sweat, expired gas, and feces), water loss is approximately 10 mL/kg body weight/24 hours. The figure in children is higher because of the greater ratio of surface area to body weight and higher still in newborns because of comparative renal immaturity and poorly keratinized skin. Latent heat released by the evaporation of water from the skin in sweat is an important component of temperature control; insensible losses in sweat can be considerably increased when the ambient temperature is high and during exercise. Water loss in feces is considerably increased in diarrheal illnesses, and they are a major source of morbidity and mortality, particularly in less well-developed areas of the world.

Small amounts of water (up to <300 mL/24 hours, more in catabolic patients) are produced by the oxidation of hydrogen in carbohydrates and fats; some is present in food, but the greater part of intake is as fluids. For most individuals in the developed world, safe water is freely available, but there are many areas where this is not the case, where the supply is either limited or contaminated with toxins, infectious agents, or both.

Homeostasis

Disturbances of water homoeostasis are encountered frequently in clinical practice. Water homeostasis is a function of the hypothalamus, which contains osmoreceptors that sense plasma osmolality and respond by stimulating or suppressing the sensation of thirst and the secretion of vasopressin (antidiuretic hormone), which controls renal water excretion. Increasing osmolality stimulates thirst and the release of vasopressin; decreasing osmolality has the opposite effect. Vasopressin acts by stimulating the insertion of aquaporins (water channels) into the otherwise water-impermeable luminal membranes of the cells of the renal collecting ducts, thus allowing water to be reabsorbed in response to the concentration gradient generated by the countercurrent system. These controls are exquisitely sensitive and in health maintain plasma osmolality in the range of 285 to 295 mmol/kg. Hypovolemia can also stimulate thirst and vasopressin secretion, and if severe, can override the osmolal control.

Water can move freely between the intra- and extracellular compartments if their relative osmolalities change. Any tendency for water to be lost from the extracellular compartment increases its osmolality and water moves from the intracellular compartment in response, lessening the effect on extracellular fluid (ECF) volume. With an increase in extracellular water, the reverse occurs. Thus both deficits and excesses of water are shared by the whole-body water compartment.

In most free-living people who have ready access to water, fluid intake is determined more by habit and social factors than physiologic controls, but lack of water, unconsciousness, confusion, inability to communicate, disability, and physical restraint are all threats to adequate hydration, so too are hypothalamic conditions affecting the thirst center.

Deficiency

Pure water deficiency (i.e., without concomitant loss of sodium) causes hypernatremia and indeed is its most frequent cause. Clinical features include thirst, dryness of mucous membranes, decreased salivation, dysphagia, and oliguria with a highly concentrated urine (unless uncontrolled renal water loss is the cause, as in diabetes insipidus). Because the loss of water is borne by the whole-body water compartment, the effect on ECF volume is less obvious than with combined water and sodium loss. Other causes of hypernatremia and its investigation are discussed in Chapter 50 .

Excess

Healthy adult kidneys can excrete large amounts of water (>1 L an hour over short periods), and water excess usually occurs either when renal water excretion is impaired (as in renal failure) or if the normal inhibition of vasopressin secretion by a fall in plasma osmolality fails, as can occur acutely with stress or chronically in the syndrome of inappropriate antidiuresis. Hyponatremia is invariable. Clinical features relate mainly to cerebral overhydration as a consequence of an increased osmotic gradient with plasma and include impairment of consciousness, confusion, and convulsions. Other causes of hyponatremia and its investigation are discussed in Chapter 50 .

Assessment of status

The assessment of hydration depends on both clinical examination and laboratory investigation (particularly measurement of plasma sodium concentration and osmolality). Dehydration is easier to diagnose clinically than overhydration. Accurate assessment can be a particular challenge in critical care patients. Fluid balance charts (if kept accurately) are a valuable tool, as are short-term changes in body weight. Total body water (TBW) can be measured for research purposes using isotope dilution techniques.

Function and sources

Sodium is the major extracellular cation; whereas the concentration in ECF is approximately 140 mmol/L, it is 14 mmol/L in intracellular fluid. Cell membranes are normally relatively impermeable to sodium, the difference in concentration being maintained by the energy-requiring Na ⁺ ,K ⁺ -ATPase pump. The opening of sodium channels in the membranes of excitable tissues leads to sodium influx and membrane depolarization and initiates the action potential. The absorption of some nutrients from the gut is linked to the absorption of sodium; this fact provides the basis for the use of oral rehydration solutions containing glucose and sodium.

Sodium is widely distributed but in general is present in higher quantities in animal products than vegetable. Common salt (sodium chloride) is used in many manufactured foods as a preservative and, supposedly, as a flavor enhancer. Many people add salt to food during cooking and at the table. The kidneys are able to produce a virtually sodium-free urine, and in health, in a temperate requirement, sodium balance can be maintained in adults on an intake of less than 50 mmol/day a maximum intake of 100 mmol/day (equivalent to 2.3 g/day of sodium or 5.8 g of salt) is recommended.

Homeostasis

Sodium and water homeostasis are intimately related because sodium is the major cation contributing to plasma osmolality, which is maintained through effects on renal water excretion (see earlier discussion). As a result, body sodium content is the major factor determining ECF volume. There are obligatory losses in sweat (which can increase considerably with excessive sweating and are higher in patients with cystic fibrosis, who have a high sweat sodium content) and feces (increased in diarrheal illnesses), but sodium balance is maintained primarily through control of renal excretion. The most important factor is aldosterone, which increases sodium reabsorption in the distal nephron in response to activation of the renin–angiotensin axis by stimuli that reflect a decrease in body sodium. Other factors involved include atrial natriuretic peptide (more important pathologically, e.g., in cardiac failure, than physiologically; see Chapter 48 ), sympathetic activity, and Starling forces in the peritubular capillaries. This topic is discussed in detail in Chapter 50 .

Deficiency

Because of the wide availability of sodium, decreased intake is a rare cause of deficiency; this is more frequently a result of increased loss through the kidneys, through the GI tract, or from the skin (e.g., in burn patients). Sodium is never lost without water, and isotonic loss causes an early decrease in ECF (and thus plasma) volume, leading to peripheral circulatory insufficiency and a risk of acute kidney injury. Clinical features include hypotension, tachycardia, and cold peripheries. Small decreases in ECF volume do not increase vasopressin secretion (although this can increase massively with increases >5%), and plasma sodium concentration may be normal. In contrast to water deficiency, there are early increases in plasma urea and creatinine concentrations (urea often before creatinine). Except in renal injury or when diuretics have been used, urinary sodium concentration becomes very low and is a reliable guide to the presence of sodium depletion.

Excess

Sodium overload is usually iatrogenic and occurs in the context of decreased capacity of the kidneys to excrete sodium. In health, a high sodium intake causes thirst, ECF volume tends to increase, and the kidneys respond by excreting the excess. The most frequent cause of sodium overload is increased secretion of aldosterone, either primary or secondary to increased renin secretion. Hypernatremia may be present, particularly if the excess is acute, but most patients with sodium excess are normo- or even (paradoxically) hyponatremic. A high sodium intake predisposes to hypertension; there is a huge literature on this topic and the public health implications of a decrease in dietary sodium intake.

Assessment of status

Plasma sodium concentration reflects the relative amounts of sodium and water in the ECF. Particularly with mild sodium deficit or excess, plasma sodium concentration is often normal.

Plasma sodium concentration must be considered alongside the results of clinical assessment (of signs of abnormal ECF) or physiologic measurements (e.g., of central venous blood pressure). However, in practice, clinical assessment may be difficult because of confounding factors, particularly in critically ill patients. The value of urinary sodium measurement has been referred to earlier. Total body sodium can be measured using isotope dilution techniques, but this is never required in routine clinical practice.

Function and sources

Potassium is the major intracellular cation. It is widely available in food of vegetable and animal origin. Hyperkalemia increases the excitability of nerve and muscle cells, hypokalemia having the opposite effect. The tendency of potassium ions to move down their concentration gradient from the intra- to extracellular compartment is countered by the action of Na ⁺ ,K ⁺ -ATPase. There is considerable evidence that a high dietary potassium intake protects against hypertension, and as a result, the recommended intake is far greater than minimum requirements at 4.7 g (120 mmol/L).

Homeostasis

Potassium homeostasis is complex and mainly occurs through the control of renal potassium excretion, which has reciprocal links to both sodium and hydrogen ion excretion. Aldosterone stimulates sodium reabsorption in exchange for potassium in the distal nephron, and its secretion is directly stimulated by hyperkalemia and through the actions of renin and angiotensin II. The kidneys are less able to conserve potassium than sodium, and obligatory renal losses in health are of the order of 30 mmol/24 hours, with small losses in sweat and feces. Because most of the body’s potassium is intracellular, plasma concentration does not necessarily reflect total body potassium status (see later).

Deficiency

Potassium deficiency in free-living healthy subjects on a normal diet is very rare. It can be a feature of generalized malnutrition, but it is frequently iatrogenic, secondary to treatment with diuretics or a consequence of increased loss from the gut in patients with diarrheal illness. Potassium deficiency is not synonymous with hypokalemia, although most patients with hypokalemia are potassium deficient. The causes, investigation, and diagnosis of hypokalemia are discussed in Chapter 50 .

Excess

In health, potassium excess is rare and usually iatrogenic. However, high dietary intakes can lead to hyperkalemia in the presence of renal impairment. Potassium retention is most frequently a consequence of acute kidney injury or chronic kidney disease and is usually, but not always, associated with hyperkalemia. Hyperkalemia can occur in the absence of an excess of potassium as a result of loss of intracellular potassium to the intracellular compartment either in vivo or in vitro (hypokalemia can occur with the reverse, but this is less common). The causes, differential diagnosis, and investigation of hyperkalemia are discussed in Chapter 50 . Severe hyperkalemia (>6.5 mmol/L) is a medical emergency.

Assessment of status

For the reasons outlined, plasma potassium concentration is on its own an unreliable guide to body potassium status, although the interpretation of an abnormal potassium concentration may be aided by the results of other investigations (e.g., of renal function or by clinical information, including a drug history). Total-body exchangeable potassium can be measured for research purposes by an isotope dilution technique.

Function and sources

Chlorine is present in many foods as sodium and potassium chloride; chloride ions are the major extracellular anion in the body. It thus has a role in the maintenance of ECF volume but does not appear to have a specific role in this regard independent of sodium. Chloride is secreted together with hydrogen ions into the lumen of the stomach; gastric acid is largely hydrochloric acid and can have a pH of as low as 1.00. The recommended minimum intake is 65 mmol/day.

Homeostasis

In general, chloride homeostasis is maintained by the mechanisms responsible for sodium and potassium homeostasis, and plasma chloride concentration tends to parallel that of sodium. The exceptions are states of abnormal acid–base balance when the concentration of bicarbonate, the other major extracellular anion, is abnormal. This topic is discussed in detail in Chapter 50 .

Deficiency

Deficiencies of sodium and potassium are usually accompanied by deficiency of chloride, although this has no specific features. Two conditions are characterized by primary loss of chloride: loss of unbuffered gastric acid (e.g., in patients with vomiting and pyloric stenosis or with prolonged drainage of gastric secretion) and chloride-losing diarrhea (a rare inherited condition). These are both associated with a metabolic (nonrespiratory) alkalosis (see Chapter 50 ).

Excess

Chloride excess is usually associated with sodium excess and has no specific features. It is noteworthy, however, that the administration of intravenous (IV) 0.9 (g/v) % aqueous sodium chloride (often erroneously called “physiological” or “normal”; it is neither) can cause a hyperchloremic acidosis. This fluid is widely used in support of ECF volume but contains equimolar amounts (154 mmol/L) of sodium and chloride, and the plasma concentrations are of the order of 140 and 100 mmol/L, respectively. Overuse of this fluid can increase plasma chloride concentration at the expense of bicarbonate, causing acidosis. This “dilutional acidosis” is the reverse of the “contraction alkalosis” sometimes seen in edematous patients treated with diuretics.

Assessment of status

Plasma chloride concentration reflects the relative amounts of water and chloride in the ECF and may not accurately reflect total body chloride status. In hypochloremia, a low urinary chloride concentration (<10 mmol/L) reliably indicates chloride deficiency unless this is a result of excessive renal excretion of chloride.

Function and sources

Phosphates are present in many foodstuffs, and isolated dietary deficiency is very rare. High-energy phosphates, particularly adenosine triphosphate (ATP), are generated by metabolism and drive the body’s energy-dependent processes. Many metabolic processes are controlled by the activation and inactivation of enzymes through their phosphorylation and dephosphorylation. Phosphate is an essential structural component of bone mineral and tooth enamel, and phospholipids are key components of cell membranes. Phosphates are also important buffers of hydrogen ions in the urine. The recommended daily intake is 700 mg (22 mmol) as phosphorus. If dietary intake is low, calcitriol synthesis increases, triggering mechanisms that tend to raise the plasma concentration.

Homeostasis

Plasma phosphate concentration is maintained by the actions of parathyroid hormone and calcitriol acting on renal phosphate reabsorption. These processes are discussed in detail in Chapter 54 .

Deficiency

As stated, dietary phosphate deficiency is exceedingly rare, but deficiency can occur in patients being fed artificially, particularly when nutritional support is provided to a malnourished individual (refeeding syndrome; see later discussion). Hypophosphatemia is a common and potentially dangerous metabolic abnormality. Its causes and investigation are discussed in Chapter 54 .

Excess

Healthy kidneys can excrete phosphate readily, but phosphate overload, leading to hyperphosphatemia, is a frequent feature of renal impairment (see Chapters 34 and 49 ).

Assessment of status

Total-body phosphorus can be measured by neutron activation analysis but is not required in clinical practice, where measurements of plasma concentration and urine excretion provide more relevant information.

Function and sources

Sulfur is the third most abundant mineral in the human body (after calcium and phosphorus). It is present in foodstuffs, mainly in proteins in the amino acids cysteine and methionine, and to a lesser extent as inorganic sulfate and in other compounds. Disulfide bonds play an important role in maintaining the structure of proteins and peptide hormones (e.g., insulin), and sulfur is a component of many glycosaminoglycans (e.g., heparin sulfate). Sulfur has a key role in detoxication mechanisms. Many fat-soluble xenobiotics are rendered water soluble (and thus amenable to excretion) by sulfation, and the antioxidant function of glutathione is dependent on its sulfhydryl group. The oxidation of sulfur-containing amino acids generates sulfuric acid, which is excreted in the urine and comprises the bulk of fixed acid excretion. There are no recommendations concerning dietary intake.

Homeostasis, deficiency, and excess

There appears to be no specific homeostatic mechanism for sulfur or sulfate. No syndrome of excess has been described, and it remains uncertain whether there is a specific entity of sulfate deficiency, given that it is only likely to occur as part of overall protein deficiency. There have been suggestions that sulfur deficiency, secondary to inadequate intake of sulfur-containing amino acids, may impair oxidative stress defense mechanisms and contribute to aging.

Assessment of status

Sulfate and the individual sulfur-containing amino acid concentrations can be measured in plasma, but there is no indication to do so in standard clinical practice.

Function and sources

Calcium is present in many foodstuffs but particularly dairy products and fish that are eaten whole (e.g., sardines, whitebait). It has many essential functions: structural, in bone and teeth (these tissues contain 99% of the body’s calcium); in the control of membrane excitability; muscle contraction; neuromuscular transmission; blood coagulation; and as a second messenger. Even if there is an adequate dietary supply of calcium, its absorption may be limited by the presence of other dietary components, such as oxalate; phytates, which combine with it to form insoluble complexes; or inadequate calcitriol, which stimulates the absorption of calcium ions. The recommended calcium intake is 1000 mg/day (25 mmol/day). Greater quantities are required during pregnancy and lactation.

Homeostasis

Although the bulk of the body’s calcium has a structural role, homeostatic mechanisms primarily control the concentration of free (ionized) extracellular calcium. Factors involved include calcitriol and parathyroid hormone. Calcitonin, although regarded as a calcimimetic hormone, appears to have only a minor physiologic role. Calcium homeostasis is described in detail in Chapter 54 .

Deficiency

Adequate dietary calcium intake in childhood and adolescence is an important determinant of peak bone mass (typically attained at age 20 to 25 years), itself a determinant of the risk of osteoporosis. Plasma calcium concentration can, however, be maintained over a wide range of dietary intakes because the homeostatic mechanisms will sacrifice bone calcium to maintain the ECF concentration, if required, and excesses are usually readily excreted.

Excess

A high calcium intake may predispose to renal calculus formation, although it is rarely the sole cause. The milk-alkali syndrome, a cause of renal failure associated with a high intake of calcium-containing alkaline antacids, is now rare. There has been considerable research into the relationship between calcium intake and cancer risk. Although the results of studies have not always been in agreement, it does appear that maintenance of the recommended intake does have a modestly beneficial effect on the risk of colorectal cancer. There is evidence linking a high calcium intake with increased risk of cardiovascular disease. Syndromes of hypercalcemia are discussed in Chapter 54 .

Assessment of status

For reasons alluded to already, plasma calcium concentration does not reflect total body calcium status, which is most relevantly assessed by measurements of bone mineral density.

The most frequent measurements made in clinical practice are of plasma calcium concentration and urinary excretion. The effect of protein binding on total calcium concentration and the indications for measurement of ionized calcium concentration are discussed in Chapter 54 .

Function and sources

Magnesium is the fourth most abundant cation in the human body. The majority is present in bone and muscle, with only approximately 1% being present in the ECF. Magnesium is a cofactor in more than 300 enzyme-catalyzed reactions. These include many responsible for energy metabolism (it is an obligate cofactor in reactions involving ATP) and the synthesis of proteins and nucleic acids. It controls various transmembrane ion channels and membrane excitability. Magnesium is widely distributed in foodstuffs, green vegetables being a particular rich source because it is a component of chlorophyll. The recommended daily intake is 420 mg (18 mmol) in men and 320 mg (10 mmol) in women.

Homeostasis

Magnesium absorption from the gut is to some extent controlled by the body’s requirements, but the major organs of homeostasis are the kidneys; magnesium absorption is increased by hypomagnesemia (see Chapter 54 ).

Deficiency

Isolated magnesium deficiency is uncommon; it is usually associated with loss of other cations either from the gut (e.g., with diarrhea) or the kidneys (frequently drug induced).

Hypomagnesemia can cause hypokalemia (through adverse effects on Na ⁺ ,K ⁺ -ATPase) and hypocalcemia (parathyroid hormone release is dependent on magnesium), and these may be responsible for some of its clinical manifestations (see Chapter 54 ).