6 Laboratory data

This chapter will consider the common biochemical and haematological tests that are of clinical and diagnostic importance. For convenience, each individual test will be dealt with under a separate heading and a brief review of the physiology and pathophysiology will be given where appropriate to explain the basis of biochemical and haematological disorders.

It is usual for a reference range to be quoted for each individual test (see Tables 6.1 and 6.4). This range is based on data obtained from a sample of the general population which is assumed to be disease-free. Many test values have a normal distribution and the reference values are taken as the mean ± 2 standard deviations (SD). This includes 95% of the population. The ‘normal’ range must always be used with caution since it takes little account of an individual’s age, sex, weight, height, muscle mass or disease state, many of which variables can influence the value obtained. Although reference ranges are valuable guides, they must not be used as sole indicators of health and disease. A series of values rather than a simple test value may be required in order to ensure clinical relevance and to eliminate erroneous values caused, for example, by spoiled specimens or interference from diagnostic or therapeutic procedures. Furthermore, a disturbance of one parameter often cannot be considered in isolation without looking at the pattern of other tests within the group.

Table 6.1 Biochemical data: typical normal adult reference values measured in serum

Table 6.4 Haematology data: typical normal adult reference values

Further specific information on the clinical and therapeutic relevance of each test may be obtained by referral to the relevant chapter in this book.

Biochemical data

The homeostasis of various elements, water and acid–base balance are closely linked, both physiologically and clinically. Standard biochemical screening includes several measurements which provide a picture of fluid and electrolyte balance and renal function. These are commonly referred to colloquially as ‘Us and Es’ (urea and electrolytes) and the major tests are described below.

Sodium and water balance

Sodium and water metabolism are closely interrelated both physiologically and clinically, and play a major role in determining the osmolality of serum.

Water constitutes approximately 60% of body weight in men and 55% in women (women have a greater proportion of fat tissue which contains little water). Approximately two-thirds of body water is found in the intracellular fluid (ICF) and one-third in the extracellular fluid (ECF). Of the ECF 75% is found within interstitial fluid and 25% within serum (Fig. 6.1). Total body water is regulated by the renal action of antidiuretic hormone (ADH), the renin angiotensin–aldosterone system, noradrenaline/norepinephrine and by thirst which is stimulated by rising plasma osmolality.

Fig. 6.1 Approximate distribution of water in a 70 kg man.

In general, water permeates freely between the ICF and ECF. Cell walls function as semipermeable membranes, with water movement from one compartment to the other being controlled by osmotic pressure: water moves into the compartment with the higher osmotic concentration. The osmotic content of the two compartments is generally the same, that is, they are isotonic, which ensures normal cell membrane integrity and cellular processes. However, the kidneys are an exception to the rule.

The osmolality of the ECF is largely determined by sodium and its associated anions, chloride and bicarbonate. Glucose and urea have a lesser, but nevertheless important, role in determining ECF osmolality. Protein, especially albumin, makes only a small (0.5%) contribution to the osmolality of the ECF but is a major factor in determining water distribution between the two compartments. The contribution of proteins to the osmotic pressure of serum is known as the colloid osmotic pressure or oncotic pressure.

The major contributor to the osmolality of the ICF is potassium.

The amount of water taken in and lost by the body depends on intake, diet, activity and the environment. Over time the intake of water is normally equal to that lost (Table 6.2). The minimum daily intake necessary to maintain this balance is approximately 1100 mL. Of this, 500 mL is required for normal excretion of waste products in urine, whilst the remaining volume is lost via the skin in sweat, via the lungs in expired air, and in faeces. The kidneys regulate water balance, water being filtered, then reabsorbed in variable amounts depending primarily on the level of ADH.

Table 6.2 Typical daily water balance for a healthy 70 kg adult

Water depletion

Water depletion will occur if intake is inadequate or loss excessive. Excessive loss of water through the kidney is unusual except in diabetes insipidus or following the overuse of diuretics.

Patients with fever will lose water through the skin and ventilated patients will lose it through the lungs. Diarrhoea causes water depletion. Water loss is usually compensated for if the thirst mechanism is intact or can be responded to, but this may not occur in patients who are unconscious, have swallowing difficulties or are disabled. Severe water depletion may induce cerebral dehydration causing confusion, fits, coma and circulatory failure.

The underlying cause for the water depletion should be identified and treated. Replacement water should be given orally, where possible, or by nasogastric tube, intravenously or subcutaneously as necessary with 5% dextrose in water or, in patients with associated sodium deficits, isotonic saline. Hypotonic saline is sometimes used, but with great caution, where neurologic effects of hypertonicity predominate. Hypernatraemia should be corrected slowly: not more than half of the water deficit should be corrected in the first 12–24 h.

Water excess

Water excess is usually associated with an impairment of water excretion such as that caused by renal failure or the syndrome of inappropriate secretion of the antidiuretic hormone arginine vasopressin (SIADH). This syndrome has several causes including chest infections and some tumours, particularly small cell carcinoma of the lung. Excess intake is rarely a cause of water excess since the healthy adult kidney can excrete water at a rate of up to 2 mL/min. Patients affected usually present with signs consistent with cerebral overhydration, although if it is of gradual onset, over several days, they may be asymptomatic. Hyponatraemia is usually present.

Water and ECF osmolality

If the body water content changes independent of the amount of solute, osmolality will be altered (the normal range is 282–295 mmol/kg of water). A loss of water from the ECF will increase its osmolality and result in the movement of water from the ICF to ECF. This increase in ECF osmolality will stimulate the hypothalamic thirst centres to promote a desire to drink while also stimulating the release of vasopressin or ADH. ADH increases the permeability of the renal collecting ducts to water and promotes water reabsorption with consequent concentration of urine.

If the osmolality of the ECF falls, there is no desire to drink and no secretion of ADH. Consequently, a dilute urine is produced which helps restore ECF osmolality to normal.

The secretion of ADH is also stimulated by angiotensin II, arterial and venous baroreceptors, volume receptors, stress (including pain), exercise and drugs such as morphine, nicotine, tolbutamide, carbamazepine and vincristine. If blood volume decreases by more than 10%, the hypovolaemia stimulates ADH release and overrides control based on osmolality.

Sodium distribution

The body of an average 70 kg man contains approximately 3000 mmol of sodium. Most of this sodium is freely exchangeable and is extracellular. The normal serum range is 135–145 mmol/L. In contrast, the ICF concentration of sodium is only about 10 mmol/L.

Each day approximately 1000 mmol of sodium is secreted into the gut and 25,000 mmol filtered by the kidney. The bulk of this is recovered by reabsorption from the gut and renal tubules. It should be clear, therefore, that partial failure of homeostatic control can potentially have major consequences.

Sodium and ECF volume

The ECF volume is dependent upon total body sodium since sodium is almost entirely restricted to the ECF, and water intake and loss are regulated to maintain a constant concentration of sodium in the ECF compartment.

Sodium balance is maintained by renal excretion. Normally, 70% of filtered sodium is actively reabsorbed in the proximal tubule, with further reabsorption in the loop of Henle. Less than 5% of the filtered sodium load reaches the distal tubule where aldosterone can stimulate further sodium reabsorption.

Other factors such as natriuretic peptide hormone can also affect sodium reabsorption. This hormone is secreted by the cardiac atria in response to atrial stretch following a rise in atrial pressure associated with, say, volume expansion. It is natriuretic (increases sodium excretion in urine) and, amongst other actions, reduces aldosterone concentration.

Sodium depletion

Inadequate oral intake of sodium is rarely the cause of sodium depletion, although inappropriate parenteral treatment may occasionally be implicated. Sodium depletion commonly occurs with water depletion, resulting in dehydration or volume depletion. The normal response of the body to the hypovolaemia includes an increase in aldosterone secretion (which stimulates renal sodium reabsorption) and an increase in ADH secretion if ECF volume depletion is severe.

The serum sodium level can give an indication of depletion, but it must be borne in mind that the serum sodium may be:

• increased, for example, where there is sodium and water loss but with predominant water loss, as occurs in excessive sweating;

• normal, for example, where there is isotonic sodium and water loss, as occurs from burns or a haemorrhage;

• decreased, for example, sodium loss with water retention as would occur if an isotonic sodium depletion were treated with a hypotonic sodium solution.

Sodium excess

Sodium excess can be due to either increased intake or decreased excretion. Excessive intake is not a common cause, although hypernatraemia can be associated with excessive intravenous saline infusion or unreplaced hypotonic water depletion, due to impaired access to free water or impaired thirst.

Sodium excess is usually due to impaired excretion. It may also be caused by a primary mineralocorticoid excess, for example, Cushing’s syndrome or Conn’s syndrome. However, it is often due to a secondary hyperaldosteronism associated with, for example, congestive cardiac failure, nephrotic syndrome, hepatic cirrhosis with ascites, or renal artery stenosis. Sodium and water retention causes oedema.

Hypernatraemia

The signs and symptoms of hypernatraemia include muscle weakness and confusion.

Drug-induced hypernatraemia is often the result of a nephrogenic diabetes insipidus-like syndrome whereby the renal tubules are unresponsive to ADH. The affected patient presents with polyuria, polydipsia or dehydration.

• Lithium and phenytoin are the most commonly implicated drugs. The diabetes insipidus-like syndrome with lithium has been reported after only 2 weeks of therapy. The syndrome is usually reversible on discontinuation. Whilst affected, however, many patients are unresponsive to exogenous ADH.

• Demeclocycline can also cause diabetes insipidus and can be used in the management of patients with the syndrome of inappropriate ADH secretion (SIADH).

• Phenytoin generally has a less pronounced effect on urinary volume than lithium or demeclocycline, and does not cause nephrogenic diabetes insipidus. It inhibits ADH secretion at the level of the central nervous system.

Hypernatraemia can be caused by a number of other drugs (Box 6.1) and by a variety of mechanisms; for example, hypernatraemia secondary to sodium retention is known to occur with corticosteroids whilst the administration of sodium-containing drugs parenterally in high doses also has the potential to cause hypernatraemia.

Box 6.1 Examples of drugs known to cause hypernatraemia

Adrenocorticotrophic hormone

Anabolic steroids

Androgens

Corticosteroids

Lactulose

Oestrogens

Oral contraceptives

Sodium bicarbonate

Hyponatraemia

A fall in the serum sodium level can be the result of sodium loss, water retention in excess of sodium usually resulting from defects in free water excretion due to low ECF volume or inappropriate secretion of ADH. Increased water intake may also contribute, or a combination of both factors. A number of drugs have also been implicated as causing hyponatraemia (Box 6.2).

Box 6.2 Examples of drugs known to cause hyponatraemia

Amitriptyline and other tricyclic antidepressants

Amphotericin

Angiotensin converting enzyme inhibitors

Carbamazepine

Cisplatin

Clofibrate

Cyclophosphamide

Diuretics

Heparin

Lithium

Miconazole

NSAIDs

Opiates

Tolbutamide

Vasopressin

Vincristine

The inappropriate secretion of ADH is the mechanism underlying many drug-induced hyponatraemias. In this syndrome, the drug may augment the action of endogenous ADH (e.g. chlorpropamide), increase the release of ADH (e.g. carbamazepine), or have a direct ADH-like action on the kidney (e.g. oxytocin or, more obviously, desmopressin). Hyponatraemia can also be induced by mechanisms different from those described above. Lithium may cause renal damage and a failure to conserve sodium. Likewise the natriuretic action of diuretics can predispose to hyponatraemia.

Potassium

The total amount of potassium in the body, like sodium, is 3000 mmol. About 10% of the body potassium is bound in red blood cells (RBCs), bone and brain tissue and is not exchangeable. The remaining 90% of total body potassium is free and exchangeable with the vast majority having an intracellular location, being pumped in and out by Na/K-ATPase pumps. This is controlled by mechanisms aimed at ensuring stable intracellular to extracellular ratios, and hence correct muscular and neuronal excitability. Only 2% of the exchangeable total body potassium is in the ECF, the compartment from where the serum concentration is sampled and measured. Consequently, the measurement of serum potassium is not an accurate index of total body potassium, but together with the clinical status of a patient it permits a sound practical assessment of potassium homeostasis.

The serum potassium concentration is controlled mainly by the kidney with the gastro-intestinal tract normally having a minor role. The potassium filtered in the kidney is almost completely reabsorbed in the proximal tubule. Potassium secretion is largely a passive process in response to the need to maintain membrane potential neutrality associated with active reabsorption of sodium in the distal convoluted tubule and collecting duct. The extent of potassium secretion is determined by a number of factors including:

• the amount of sodium available for exchange in the distal convoluted tubule and collecting duct;

• the availability of hydrogen and potassium ions for exchange in the distal convoluted tubule or collecting duct;

• the ability of the distal convoluted tubule or collecting duct to secrete hydrogen ions;

• the concentration of aldosterone;

• tubular fluid flow rate.

As described above, both potassium and hydrogen can neutralise the membrane potential generated by active sodium reabsorption and consequently there is a close relationship between potassium and hydrogen ion homeostasis. In acidosis, hydrogen ions are normally secreted in preference to potassium and potassium moves out of cells, that is, hyperkalaemia is often associated with acidosis, except in renal tubular acidosis. In alkalosis, fewer hydrogen ions will be present and potassium moves into cells and potassium is excreted, that is, hypokalaemia is often associated with alkalosis.

The normal daily dietary intake of potassium is of the order of 60–200 mmol, which is more than adequate to replace that lost from the body. It is unusual for a deficiency in intake to account for hypokalaemia. A transcellular movement of potassium into cells, loss from the gut or excretion in the urine are the main causes of hypokalaemia.

Hypokalaemia

Transcellular movement into cells

The shift of potassium from the serum compartment of the ECF into cells accounts for the hypokalaemia reported following intravenous or, less frequently, nebulised administration of β-adrenoreceptor agonists such as salbutamol. Parenteral insulin also causes a shift of potassium into cells, and is used for this purpose in the acute management of patients with hyperkalaemia. Catecholamines, for example, adrenaline/epinephrine and theophylline also have this effect.

Loss from the gastro-intestinal tract

Although potassium is secreted in gastric juice, much of this, together with potassium ingested in the diet, is reabsorbed in the small intestine. Stools do contain some potassium, but in a patient with chronic diarrhoea or a fistula, considerable amounts of potassium may be lost and precipitate hypokalaemia. Likewise, the abuse of laxatives increases gastro-intestinal potassium loss and may precipitate hypokalaemia. Analogous to the situation with diarrhoea, the potassium secreted in gastric juice may be lost following persistent vomiting and can also contribute to hypokalaemia.

Loss from the kidneys

Mineralocorticoid excess, whether it be due to primary or secondary hyperaldosteronism or Cushing’s syndrome, can increase urinary potassium loss and cause hypokalaemia. Likewise, increased excretion of potassium can result from renal tubular damage. Nephrotoxic antibiotics such as gentamicin have been implicated in this.

Many drugs which can induce hypokalaemia do so by affecting the regulatory role of aldosterone upon potassium–sodium exchange in the distal tubule and collecting duct. Administered corticosteroids mimic aldosterone and can, therefore, increase potassium loss.

The most commonly used groups of drugs that can cause hypokalaemia are thiazide and loop diuretics. Both groups of drugs increase the amount of sodium delivered and available for reabsorption at the distal convoluted tubule and collecting duct. Consequently, this will increase the amount of potassium excreted from the kidneys. Some of the drugs known to cause hypokalaemia are shown in Box 6.3.

Box 6.3 Examples of drugs known to cause hypokalaemia

Amphotericin

Aspirin

Corticosteroids

Diuretics

Gentamicin

Glucose

Insulin

Laxatives

Penicillin G (sodium salt)

Piperacillin + tazobactam

Salicylates

Sodium bicarbonate

Sodium chloride

Terbutaline

Ticarcillin + clavulanic acid

Clinical features

The patient with moderate hypokalaemia may be asymptomatic, but the symptoms of more severe hypokalaemia include muscle weakness, hypotonia, paralytic ileus, depression and confusion. Arrhythmias may occur. Typical changes on the electrocardiogram (ECG) are of ST depression, T wave depression/inversion and prolonged P–R interval. Although hypokalaemia tends to make antiarrhythmic drugs less effective, the action of digoxin, in contrast, is potentiated leading to increased signs of toxicity. Insulin secretion in response to a rising blood glucose concentration requires potassium and this mechanism may be impaired in hypokalaemia. Rarely there may be impaired renal concentrating ability with polyuria and polydipsia.

Hypokalaemia is managed by giving either oral potassium or intravenous suitability dilute potassium solutions, depending on its severity and the clinical state of the patient.

Hyperkalaemia

Hyperkalaemia may arise from excessive intake, decreased elimination or shift of potassium from cells to the ECF. It is rare for excessive oral intake to be the sole cause of hyperkalaemia. The inappropriate use of parenteral infusions containing potassium is probably the most common iatrogenic cause of excessive intake. Hyperkalaemia is a common problem in patients with renal failure due to their inability to excrete a potassium load.

The combined use of potassium-sparing diuretics such as amiloride, triamterene or spironolactone with an angiotensin converting enzyme (ACE) inhibitor, which will lower aldosterone, is a recognised cause of hyperkalaemia, particularly in the elderly. Mineralocorticoid deficiency states such as Addison’s disease where there is a deficiency of aldosterone also decrease renal potassium loss and contribute to hyperkalaemia. Those at risk of hyperkalaemia should be warned not to take dietary salt (NaCl) substitutes in the form of KCl.

The majority of body potassium is intracellular. Severe tissue damage, catabolic states or impairment of the energy-dependent sodium pump, caused by hypoxia or diabetic ketoacidosis, may result in apparent hyperkalaemia due to potassium moving out of and sodium moving into cells. If serum potassium rises, insulin release is stimulated which, through increasing activity in Na/K-ATPase pumps, causes potassium to move into cells. Box 6.4 gives examples of some drugs known to cause hyperkalaemia.

Box 6.4 Examples of drugs known to cause hyperkalaemia

Angiotensin converting enzyme inhibitors

Antineoplastic agents (cyclophosphamide, vincristine)

Non-steroidal anti-inflammatory drugs

β-Adrenoreceptor blocking agents

Ciclosporin

Digoxin (in acute overdose)

Diuretics, potassium sparing (amiloride, triamterene, spironolactone)

Heparin

Isoniazid

Lithium

Penicillins (potassium salt)

Potassium supplements

Tetracycline

Haemolysis during sampling or a delay in separating cells from serum will result in potassium escaping from blood cells into serum and causing an artefactual hyperkalaemia.

Clinical features

Hyperkalaemia can be asymptomatic but fatal. An elevated potassium level has many effects on the heart: notably the resting membrane potential is lowered and the action potential shortened. Characteristic changes of the ECG precede ventricular fibrillation and cardiac arrest.

In emergency management of a patient with hyperkalaemia (>6.5 mmol/L ± ECG changes), calcium gluconate (or chloride) at a dose of 10 mL of 10% solution is given intravenously over 5 min. This does not reduce the potassium concentration but antagonises the effect of potassium on cardiac tissue. Immediately thereafter, glucose 50 g with 20 units soluble insulin, for example, by intravenous infusion will lower serum potassium levels within 30 min by increasing the shift of potassium into cells.

If acidosis is present, bicarbonate administration may be considered.

The long-term management of hyperkalaemia may involve the use of oral or rectal polystyrene cation-exchange resins which remove potassium from the body. Chronic hyperkalaemia, in renal failure, is managed by a low potassium diet.

Calcium

The body of an average man contains about 1 kg of calcium and 99% of this is bound within bone. Calcium is present in serum bound mainly to the albumin component of protein (46%), complexed with citrate and phosphate (7%), and as free ions (47%). Only the free ions of calcium are physiologically active. Calcium metabolism is regulated by 1,25-dihydroxycholecalciferol (vitamin D) which, when serum calcium is low, is secreted to promote gastro-intestinal absorption of calcium, and by parathyroid hormone (PTH) which is inhibited by increased serum concentrations of calcium ions. PTH is secreted in response to low calcium concentrations and increases serum calcium by actions on osteoclasts, kidney and gut.

The serum calcium level is often determined by measuring total calcium, that is, that which is free and bound but the measurement of free or ionised calcium offers advantages in some situations.

In alkalosis, hydrogen ions dissociate from albumin, and calcium binding to albumin increases, together with an increase in complex formation. If the concentration of ionised calcium falls sufficiently, clinical symptoms of hypocalcaemia may occur despite the total serum calcium concentration being unchanged. The reverse effect, that is, increased ionised calcium, occurs in acidosis.

Changes in serum albumin also affect the total serum calcium concentration independently of the ionised concentration. A variety of equations are available to estimate the calcium concentration and many laboratories report total and adjusted calcium routinely. A commonly used formula is shown in Fig. 6.2. Caution must be taken when using such a formula in the presence of disturbed blood hydrogen ion concentrations.

Fig. 6.2 Formula for correction of total serum calcium concentration for changes in albumin concentration: albumin concentration = [alb] (albumin units = g/L); calcium concentration = [Ca] (total calcium units = mmol/L).

Hypercalcaemia

Hypercalcaemia may be caused by a variety of disorders, the most common being primary hyperparathyroidism in which there is autonomous growth of PTH-producing cells and malignancy. Hypercalcaemia of malignancy is seen in multiple myeloma and carcinomas which metastasise in bone. It is also seen in squamous carcinoma of the bronchus, as a result of a peptide with PTH-like activity, produced by the tumour. Hypercalcaemia also occurs in thyrotoxicosis, vitamins A and D intoxication, acute renal failure, renal transplantation and acromegaly. PTH measurement can be pivotal in the establishment of the cause of hypercalcaemia.

Thiazide diuretics, lithium, tamoxifen and calcium supplements used in the management of osteoporosis are examples of some of the drugs which can cause hypercalcaemia.

An artifactual increase in total serum calcium may sometimes be seen as a result of a tourniquet being applied during venous sampling. The resulting venous stasis may cause redistribution of fluid from the vein into the extravascular space, and the temporary haemoconcentration will affect albumin levels.

Management of hypercalcaemia involves correction of any dehydration with normal saline followed by furosemide which inhibits tubular reabsorption of calcium. Bisphosphonates are used to inhibit bone turnover.

Hypocalcaemia

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