Chapter 1 LABORATORY MEDICINE
Laboratory medicine is the branch of clinical medicine dealing with changes in the human body that can be detected only by analyzing the body’s chemical components in the laboratory. Essential for the assessment of health status and various clinical problems, the services of laboratory medicine can be used for many purposes, but the most important applications are as follows:
Diagnostic disease-oriented laboratory testing. Such testing is usually ordered by the attending physician and is part of the initial work-up on almost all patients. These tests are routinely performed in all hospitals and ambulatory medical facilities.
Follow-up after treatment. Patients treated in hospitals or ambulatory clinics are regularly tested to determine the effects of treatment. For example, diabetics treated with insulin must regularly monitor their blood sugar levels to determine if their dosage of insulin or other medications is correct.
Screening for diseases. Screening tests are performed for populations at risk for a certain condition, such blood lipid profiles in patients with a history of familial hyperlipidemia, or after a person reaches a certain age, such as prostate specific antigen test in men older than 55 years.
Periodic monitoring of the state of health. Laboratory tests are typically part of the yearly medical examination recommended to monitor well-being. Additionally, they are almost invariably performed in special circumstances, such as pregnancy, infancy, and childhood. Many jobs require a pre-employment medical examination and school districts mandate preadmittance examinations that include routine laboratory testing. Together with physical examination, laboratory testing represents the most important part of the yearly medical examination performed by numerous health care providers.
Research. Laboratory tests are usually included in monitoring patients or normal persons being treated with new drugs (clinical trials) or those enrolled in research studies aimed at elucidating the pathophysiology of various diseases.
Routine laboratory tests are most often performed on blood and urine, but on occasion the same tests can be performed on other body fluids such as the cerebrospinal fluid; joint fluid; or effusions in the abdominal, thoracic, or other cavity.
Blood may be submitted in tubes that either contain or do not contain anticoagulants. The tops of these tubes are color-coded to avoid confusion. Blood collected into a tube that does not contain an anticoagulant (red tubes) will clot, and the red blood cells, leukocytes, and platelets will separate from the serum (Fig. 1-1). The separation of blood cells from serum can be accelerated by collecting the blood in tubes that are not coated with anticoagulant. Such tubes contain a gel at the bottom that activates clotting and promotes the separation of the clot from the serum (“red/green,” also known as “tiger-top tubes” or “light green-mint tubes”). These tubes are used in the laboratories that perform automated testing. Serum contains all the normal minerals, enzymes, immunoglobulins, and proteins besides the coagulation factors, and is thus used for most routine laboratory tests.
Acute-phase proteins Proteins that appear in increased concentration in blood in response to inflammation are called positive acute-phase proteins. This group includes C-reactive protein, transferrin, ceruloplasmin, fibrinogen, α1-antitrypsin, and several others. Proteins, like albumin, whose concentrations are is decreased in response to inflammation, are called negative acute-phase proteins.
Alkaline phosphatase Enzyme that hydrolyzes orthophosphoric esters, present in many cells of the body and in serum. Serum alkaline phosphatase is elevated in biliary obstruction, but it may also be derived from growing bones, bone undergoing remodeling (as in Paget’s disease), osteoblastic metastases, and bone-forming tumors.
Aminotransferase Also known as transaminase. A group of enzymes transferring amino groups from one amino acid to another. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have clinical significance in liver function tests. ALT and AST are found in many other organs, and their serum concentration is elevated in other pathologic conditions as well (e.g., myocardial and lung infarctions).
Blood urea nitrogen (BUN) Blood nitrogen present in the form of urea. This test does not measure nitrogen included in proteins, accounting for approximately 18% of total blood nitrogen. BUN is elevated in renal failure. Since urea is a highly diffusible molecule its blood concentration falls rapidly after renal dialysis. BUN can be increased due to heart failure, shock, dehydration, and many other conditions and is a less specific marker of renal failure than elevated levels of creatinine.
Calcium A bivalent chemical element (Ca2+) present predominantly in the extracellular compartment in ionized form or in the form of salts. It is essential for many cellular functions. Hypercalcemia may be caused by hyperparathyroidism or several nonparathyroid-related conditions such a malignant tumors with metastases to bone. Hypocalcemia is less common and may be caused by reduced absorption or increased loss of calcium. Increased and decreased serum concentrations of calcium are associated with distinct pathophysiologic consequences.
Carbon dioxide (CO2) Gas produced in the body during oxidative respiration of cells and exhaled through the lungs into the atmosphere. Carbon dioxide along with bicarbonate (HCO3−) forms the most powerful of the body’s buffer systems in the blood. Hypercapnia (excessive CO2) and hypocapnia (decreased CO2) are mostly caused by respiratory and renal disturbances and are related to acid–base imbalance.
Glucose Monosaccharide, formed from the degradation of glycogen, cellulose, and other complex carbohydrates. Blood glucose is elevated in diabetes mellitus and lowered in various conditions that cause hypoglycemia.
Lipoprotein A complex between proteins and lipids, found in the cell membranes and in the blood. By ultracentrifugation, blood lipoproteins can be separated into four categories: chylomicrons, very low density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). These lipoproteins carry other lipids, such as cholesterol, phospholipids, and triglycerides, throughout the body. Hyperlipidemia, which may be congenital or acquired, is associated with an increased risk for coronary atherosclerosis.
Phosphorus A monovalent chemical element (P), which is present predominantly in the extracellular space (in the form of monophosphates [PO4−] and diphosphates [PO42−]) or linked with calcium in complex salts that form the matrix of bones. Its metabolism is intimately linked with the metabolism of calcium. Inside the cells phosphorus is often attached to major macromolecules and energy-rich compounds such as adenosine triphosphate (ATP).
Potassium A monovalent chemical element (K+) predominantly found inside the cells, but also in the extracellular compartment. For example the ratio of K+ inside the red blood cells and in plasma is 20:1. Hyperkalemia or hypokalemia are caused by several diseases and are associated with distinct pathophysiologic consequences, mostly pertaining to the contraction of cardiac and skeletal muscle.
Protein Group of macromolecules composed of amino acids. Proteins are essential for the maintenance of life, acting as structural elements, enzymes, membrane channels, and other vital cell components. They are also found in body fluids. Serum proteins can be divided by electrophoresis into two major groups: albumin and globulins. Hypoproteinemia may be caused by several diseases (most notably malnutrition, malabsorption of nutrients, and liver and kidney disease) and is associated with distinct pathophysiologic events.
If the blood is collected into a tube that contains anticoagulants, such as lavender-top tubes containing ethylenediaminetetraacetic acid (EDTA) or green-top tubes with lithium heparin, the red cells, leukocytes, and platelets remain in suspension inside the tube; the blood cells can be separated from the plasma by centrifugation. Plasma contains fibrinogen and all other coagulation factors and is used for specialized tests, such as measurement of the concentration of coagulation factors, lipids and lipoproteins, or folic acid. For the measurement of lactic acid or the optimal measurement of glucose, the blood is collected in gray-top tubes containing fluoride oxalate (an inhibitor of glycolysis), which does not interfere with the measurement of these analytes.
Specialized tests are not performed in all hospital laboratories but are sent to highly specialized reference laboratories. Specialized tests often require that the specimens be collected in a specified manner or under highly controlled circumstances. Most of these tests are performed in specialized reference laboratories or manually by specially trained technicians. This category of tests includes the testing of rare oligominerals such as copper or selenium, certain hormones such as vasoactive intestinal polypeptide (VIP) or parathyroid hormone-related protein (PTHrP), certain drugs and toxins, and DNA analysis. Many tests that were considered specialized in the past have become routine. One example is the troponin test, which is today routinely performed on the serum of patients thought to have suffered a myocardial infarction. Testing for human immunodeficiency virus (HIV) or hepatitis C virus was initially performed only in specialized laboratories but is routine in most hospitals today.
The samples for specialized tests are often collected in a unique manner. For example diurnal variation of hormones can be measured on several specimens collected at predetermined times. The sweat test for cystic fibrosis requires stimulation of sweat production with pilocarpine. Enzyme deficiency, which is the hallmark of some inborn errors of metabolism, requires tissue samples containing cells. DNA analysis requires samples containing nucleated cells from a buccal smear or white blood cells.
Emergency tests are performed on samples obtained during surgery or as part of the work-up on critically ill patients. Intraoperative testing for parathyroid hormone (PTH) may help the surgeon determine whether a PTH-secreting adenoma was removed. Analysis for drugs such as salicylic acid, acetaminophen, or digitalis may be important in diagnosing possible drug toxicity. Blood gasses and electrolytes are measured on an emergency basis in patients with acid–base disorders.
Good laboratory tests must be precise (reliable) and accurate and have high sensitivity and specificity.
In the United States the results for most analytes are expressed as concentrations in grams (g), milligrams (mg), micrograms (μg), or nanograms (ng) or as moles (mol) or millimoles (mmol) per liter (L), deciliter (dL), or milliliter (mL) of fluid. The activity of enzymes is expressed in activity units per liter (U/L). In other countries, laboratory data are reported according to the Système International (SI), using metric units. In many major U.S. hospitals, both systems are used in parallel.
The precision, or reliability, of a test can be determined by repeating the same test on the same sample. Ideally the same result should always be obtained, but in practice this does not always occur. So the standard deviation (SD) from the mean must be calculated for lab results. A highly precise test has a low SD, meaning that the results occur within a narrow range. In most instances the reference range is determined by adding 2 SD to the mean, which means that 95% of the results fall in that range, and only 1:20 (5%) fall outside it.
The accuracy of a test reflects how close the measured value is to the true value. An ideal test should have high precision and high accuracy. Like the target-shooting analogy shown in Figure 1-2, the outcome of each measurement should be as close as possible to the bull’s eye (“true value”) and the results should be as close together as possible (low scatter). These results can be graphically presented and typically have a bell-shaped (Gaussian) distribution with a low standard deviation from the mean. A test is unacceptable if it has high precision but does not reflect the true value (i.e., low accuracy). A test could have low precision but, if repeated several times, could have a statistically acceptable accuracy. Such tests have a wide standard deviation. Tests that have low precision and low accuracy are not used in clinical laboratories. Such tests may have a Gaussian distribution with a very high standard deviation or do not form a bell-shaped curve.
Specificity measures the incidence of “true negative” (TN) results; that is, normal values occur in all tested persons who do not have a disease—those who presented as “true negatives” or “false positives” (FP) (Fig. 1-3). Specificity is calculated according to the following formula:
Figure 1-3 A, Sensitivity and specificity of laboratory tests. An average laboratory test will detect most persons who have a disease (“true positives”—TP), but some persons with the disease will not be detected (“false negatives”—FN). Some healthy persons will be also positive (“false positives”—FP), whereas most of those who are healthy will be negative (“true negatives”—TN). B, Raising the cut-off point increases specificity (“negativity in health”). Lowering the cut-off point increases the sensitivity of the test (“positivity in disease”).
Specificity (%) = [TN/(TN + FP)] × 100
Sensitivity measures the incidence of “true positive” (TP) results among all persons who have the disease irrespective of whether they tested positively or negatively, thus representing a sum of “true positives” plus “false negatives” (FN). Sensitivity is calculated according to the following formula:
Sensitivity (%) = [TP/(TP + FN)] × 100
> Specificity is thought of as negativity in health. Sensitivity is thought of as positivity in disease. High sensitivity is a hallmark of an ideal screening test. Tests of high specificity should be used for final diagnosis, especially if the treatment is risky or could have adverse consequences.
The specificity and the sensitivity of a test can be adjusted by raising or lowering the cut-off point for a positive result (see Fig. 1-3). A test with high specificity will be always negative in health; that is, it will be negative for both FP and TN. Tests with a high sensitivity will be positive for all those who have a disease and will include all TP and FN.
Predictive value. The positive predictive value of a test predicts how many persons with a disease will have a positive result, whereas a negative predictive test predicts how many persons who do not have a disease will have a negative result. These predictive values are calculated according to the following formulas:
Predictive value of a positive test (%) = [TP/(TP + FP)] × 100
Predictive value of a negative test (%) = [TN/(TN + FN)] ×100
For example, if a test has a positive predictive value of 90%, it will be positive in 90% of persons with the disease, whereas 10% will have false negative results and will not be detected with this test. In a test with a 90% negative predictive value, 90% of all persons who do not have the disease will have a negative result, but 10% will have a false positive result.
Efficiency (%) = [(TP + TN)/(TP + TN + FP + FN)] × 100
Body water contains solutes that are unequally distributed in the ICV and ECV. Among these solutes are organic compounds, such as proteins, glucose, or lipids, and inorganics in the form of electrolytes and gases. Sodium (Na+) is the most important electrolyte in the ECV, and potassium (K+) is the most important electrolyte in the ICV (Fig. 1-4). Active maintenance of Na+ and K+ gradients across the cell membranes by energy-dependent pumps regulates the distribution of water in the body.
(Redrawn from Edwards, CRW, Bouchier AD, Haslett C, Chivers ER [eds]: Davidson’s Principles and Practice of Medicine, 17th ed, Churchill Livingstone, Edinburgh, 1995, p 590.)
The body of an adult man weighing 70 kg contains approximately 4200 mmol of Na+. Approximately 50% of this is in the extracellular fluid, 40% is in the bone, and 10% is inside the cells. All the Na+ in the extracellular and intracellular fluid and approximately 50% in bone form the so-called exchangeable sodium, which is in constant intercompartmental flux. Serum concentration of Na+ is in the range of 135 to 145 mmol/L.
The concentration of sodium in the body depends on the amount of water and is controlled by kidneys and several hormones.
A regular diet contains more Na+ than the body needs, and the intestines can absorb unlimited amounts of this mineral. Thus intake of sodium is almost never a problem, and the body can adjust even if the exogenous salt is dramatically reduced. Most of the Na+ is excreted in urine. Small amounts of Na+ are lost in feces and sweat. Hence the excretion and loss equal the total intake (Fig. 1-5).
Sodium is in balance with body water content. A 70-kg adult male requires approximately 2.5 L of water, 2.1 L of which is derived from food and drinks and 400 mL from intermediate metabolism. Most of the water is excreted in urine, and the rest in feces and by insensible loss in exhaled air or perspiration.
Thirst. If one ingests too much sodium or loses too much water the osmoreceptors in the hypothalamus react to increase the osmolality of the plasma, thereby activating the thirst center. Intake of water brings down the osmolality of the plasma, ending the sensation of thirst.
Antidiuretic hormone (ADH, or arginine vasopressin). Increased osmolality caused by a loss of water stimulates the release of ADH from the hypothalamic center. ADH stimulates the resorption of water in the kidney until the osmolality of the plasma is reduced to normal. Depletion of the intravascular volume may stimulate thirst and ADH release independently of the changes in osmolality.
Aldosterone. Loss of ECV affects the glomerular filtration rate (GFR), causing a release of renin from the juxtaglomerular apparatus. Renin acts on angiotensinogen, which leads to an increased production of aldosterone from the zona glomerulosa of the adrenal cortex. Aldosterone promotes the exchange of Na+ for K+ or hydrogen (H+) in the distal renal tubules, causing retention of Na+ and expansion of the ECV.
Sodium plays a role in forming the electric charges across the cell membrane and in acid–base regulation and is the most important electrolyte regulating the osmolality of the extracellular fluid.
Even though Na+ represents the most abundant ECV cation, its functions are not fully understood. It is known that Na+ participates in several physiologic processes, the most important of which are as follows:
Acid–base balance. Sodium is an important cation that binds to several anions such as chloride, phosphates, and bicarbonates. Thus, it plays an important role in the maintenance of the acid–base balance.
Cell membrane polarity. Sodium is distributed differentially inside and outside the cell; it contributes to the formation of the electric charges across the cell membranes. The maintenance of the Na+ gradient across the cell membrane requires expenditure of energy, which is needed for the fueling of the Na+/K+ ATPase, the cell membrane pump, moving Na+ and K+ in or out of the cell.
Osmolality of body fluids. As the most abundant cation, Na+ is essential for the maintenance of the osmolality of body fluids in the normal range from 285 to 295 mOsm/kg. Thus, Na+ is essential for the maintenance of the volume of extracellular fluid (ECF), and indirectly also the volume of intracellular fluid. Even a small increase of osmolality of ECF stimulates osmoreceptors, which initiate thirst, ADH release, and water reabsorption in the kidneys. Reduced osmolality owing to overhydration reduces water intake and inhibits ADH secretion, allowing the excretion of water in urine.
Osmolality of the serum depends mostly on the concentration of Na+, and to a lesser degree of glucose and urea (expressed as BUN, blood urea nitrogen). The contribution of anions is less than 10% of the total value of serum osmolality, and thus a formula for calculating serum osmolality takes into account only Na+, glucose, and BUN as follows:
Serum osmolality is measured to determine the water content of ECF and exclude the possibility of overhydration or dehydration. In such cases the measured osmolality corresponds to the calculated osmolality, and the difference is usually less than 10 mOsm/kg. When an osmolal gap (>10 mOsm/kg) occurs, the discrepancy between the measured and calculated osmolality is usually caused by the presence of a low-molecular-weight substance (e.g., alcohol, ethylene glycol) in the blood. The study of the osmolal gap is especially useful in patients who are comatose or suspected of intoxication. The most common causes of increased serum osmolality are listed in Table 1-2.
|INCREASED OSMOLALITY||DECREASED OSMOLALITY|
BUN, blood urea nitrogen; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
Based on data from Bakerman S, Strausbauch P: Bakerman’s ABC’s of Interpretative Laboratory Data, 3rd ed, Interpretative Laboratory Data, Myrtle Beach, SC, 1998.
Hyponatremia is a common condition defined as a serum concentration of Na+ below 136 mmol/L. Mild hyponatremia is found in 2 to 3% of all hospitalized patients. In most instances it is just a sign of illness, reflecting the inability of cells to maintain the normal gradient and flux of electrolytes across the cell membranes (“sick cell syndrome”). Severe hyponatremia is usually a consequence of water intoxication.
Figure 1-6 Pathogenesis of hyponatremia. It can be classified as dilutional, due to water excess, or depletional, due to a net loss of sodium. ECV, extracellular volume; GI, gastrointestinal; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
Increased water intake. This may occur due to obsessive water drinking (neurotic polydipsia), or in some lung cancer patients who have the paraneoplastic syndrome of inappropriate ADH secretion (SIADH).
Hypoproteinemia. Inadequate production of serum proteins in end-stage liver disease (cirrhosis) or a loss of proteins in nephrotic syndrome or chronic protein-losing gastroenteropathy results in hypoalbuminemia. Since albumin concentration is partly responsible for the oncotic pressure that keeps fluids inside the blood vessels, hypoalbuminemia leads to a shift of water from the vessels into the interstitial spaces and consequent hypovolemia. This loss of fluid triggers the ADH and the renin–angiotensin–aldosterone response, resulting in a net retention of water and dilutional hyponatremia.
Shift of water from cells into the ECV. This occurs in hyperglycemia of diabetes mellitus, paraproteinemia of multiple myeloma, or hyperlipidemia. In all these conditions, osmotically active substances in the blood and extracellular fluids cause a shift of fluids from the intracellular to the extracellular compartment. The total amount of Na+ remains the same but it is diluted by the influx of water into the ECV.
Syndrome of inappropriate antidiuretic hormone secretion (SIADH). ADH may be secreted by some tumors. Such a paraneoplastic syndrome may cause “water poisoning” due to excessive retention of water in the kidneys under the influence of ADH.
Hyponatremia is usually mild and, thus, asymptomatic. Slowly evolving hyponatremia, especially if dilutional, is well tolerated, and even if the Na+ concentration drops to 100 mmol/L it may cause few if any symptoms. On the other hand rapidly developing hyponatremia of 120 or even 125 mmol/L may cause significant neurologic symptoms.
Hyponatremia may be associated with increased total body water levels, relative increase in extracellular water, loss of Na+ in excess relative to body water or increase in total body water in excess to increased Na+ (Table 1-3).
When the plasma volume is reduced by 5% in chronic hyponatremia, ADH is released in spite of the osmoreceptor-generated inhibitory effects on its secretion. Due to the effects of ADH in chronic hyponatremia the volume of urine is reduced and it will be concentrated.
Treatment of hyponatremia should be directed at its causes and the correction of sodium–water balance. Water restriction will suffice in mild cases of dilutional hyponatremia. Severe hyponatremia may cause brain injury, but likewise, too rapid correction of hyponatremia with infusion of salts can cause central pontine myelinolysis.
Hypernatremia is defined as serum concentration of Na+ over 150 mmol/L. It is much less common than hyponatremia, but if it occurs, it has more severe clinical repercussions. Most affected patients are either very young or very old, critically ill, or neurologically impaired (e.g., patients in coma).
Theoretically, hypernatremia may result from a loss of water or a gain of Na+. These changes lead to hyperosmolality, to which the body responds by either increasing water intake or conserving water excretion through the kidneys. The second compensatory mechanism includes the release of ADH, thereby reducing urinary excretion of water.
Drinking of water corrects hypernatremia in most instances. Clinically significant hypernatremia develops only in persons who have no access to water or are unconscious and cannot drink (e.g., comatose patients, persons in deep anesthesia, very old immobile persons, or infants). Hypothalamic injury may affect adversely the thirst center and thus cause hypernatremia. It also may lead to diabetes insipidus and excessive loss of water in urine due to ADH deficiency.
Renal loss of water. Hypernatremia is a symptom of diabetes insipidus, which may be central or nephrogenic in origin. Central diabetes insipidus may be primary (i.e., related to the injury of the hypothalamus or the posterior lobe of the pituitary) or secondary to drug treatment (e.g., lithium). Nephrogenic diabetes insipidus is a consequence of end-stage renal disease. In the postsurgical period, the patient may develop renal tubular necrosis and lose excessive amounts of water relative to Na+, especially during the polyuric phase of tubular necrosis. Other iatrogenic causes of hypernatremia include the use of loop and osmotic diuretics.
Gastrointestinal loss of water. Water may be lost during diarrhea or prolonged vomiting, but also because of prolonged suction through a nasogastric tube. Osmotic cathartic agents like lactulose may cause water loss.
Adrenal cortical lesions. Most commonly adrenal cortical abnormalities are responsible for hypercortisolism, causing Na+ retention. Such hypercortisolism may be due to benign or malignant adrenal cortical tumors.
Infusion of sodium-rich solutions. This may occur while infusing sodium bicarbonate (NaHCO3) during resuscitation, hypertonic saline feeding, administration of NaCl-rich emetics or enemas, or intrauterine injection of hypertonic saline.
Clinically, hypernatremia must be always evaluated in the context of hydration of the body. If hypovolemia is present, urinary or intestinal water loss must be suspected. In euvolemic patients central or nephrogenic diabetes insipidus, dermal or respiratory loss of water, or inadequate intake of water (hypodipsia) must be considered. In hypervolemic patients an excess of mineralocorticoids, such as occurs in primary hyperaldosteronism, is a possibility (Fig. 1-7).
Symptoms depend on the degree of hypernatremia and usually appear when the Na+ concentration reaches 155 to 160 mmol/L. The rate and the time over which hypernatremia develops are also important. Typically the affected person is thirsty, but many are either unconscious or too young to say so. There is oliguria. Neurologic symptoms, such as irritability, restlessness, confusion, and agitation, predominate. In some cases generalized muscle weakness is present. Low-grade fever from dehydration is present, and the skin appears flushed and dry. The plasma volume depletion in hypovolemic hypernatremia may adversely affect the function of the heart and the kidneys. It presents with hypotension, tachycardia, and renal failure due to hypoperfusion. Ultimately the patient becomes lethargic and comatose.
Chloride is the major extracellular anion and it is tightly linked to intake, excretion and metabolism of sodium.
Chloride (Cl−) is the major anion of plasma and interstitial fluids, accounting with bicarbonate (HCO3−) for most of the anionic charge of plasma. As such its functions include maintenance of hydration, osmotic pressure, and electrolyte balance. The reference range for chloride is 98 to 106 mmol/L.
Hyperchloremic metabolic acidosis. Depletion of HCO3− in metabolic acidosis is usually accompanied by formation of organic anions, which will replace the lost HCO3−. If this does not occur, the gap is filled with Cl−. Hyperchloremia in this condition is not accompanied by hypernatremia.
Hypochloremic metabolic alkalosis. Metabolic alkalosis caused by a loss of Cl− in the GI tract is associated with an anion gap that is filled with HCO3−. The concentration of Na+ is in the normal range, and the condition can be treated with Cl− infusion.
The body contains somewhat less K+ than Na+ (3500 mmol), of which approximately 98% is inside the cells and only 2% is in the extracellular fluid. Ninety percent of the intracellular K+ is in the exchangeable intracellular pool, whereas 8% is structurally bound to the bone, brain cells, and red blood cells. The extracellular K+ may be exchanged with the rapidly exchangeable pool, and the shifts between these two pools occur quite often.
The plasma contains only 0.4% of the total body K+. The normal reference interval in the serum is 3.5 to 5.0 mmol/L. It is slightly higher in serum than in plasma, because some K+ is released from platelets during coagulation of blood.
Figure 1-8 Potassium intake and excretion. Intake in the food is balanced by excretion in the urine and, to a smaller extent, in the feces and sweat (not shown here). Most of the K+ is stored in the intracellular volume (ICV), and only 2% is found in the extracellular fluid volume (ECF). Only 0.4% of total K+ is in the plasma. Most of the intracellular fluid (ICF) contains exchangeable K+, but 8% is tightly bound in tissues. The balance of K+ critically depends on the function of the kidneys. The modulators of K+ excretion in the kidneys are the Na+ and K+ concentration in the plasma and inside the kidney compartments, aldosterone, acid–base balance, and the glomerular filtration rate (GFR).
The kidneys can regulate the excretion of K+, although approximately 30 mmol/day is excreted as obligatory renal loss. Potassium is filtered through the glomeruli but is almost completely absorbed in the proximal tubules (Fig. 1-9). The concentration of K+ in the blood and the glomerular filtration rate (GFR) regulate K+ excretion, because these two factors determine the amount of K+ available in the interstitial fluid of the kidneys for the exchange that occurs in the distal tubule and the collecting duct.
Potassium reenters from the interstitial fluid into the cells of the distal tubules and collecting duct. A small part of it is actively secreted into the lumen, but mostly K+ enters passively through diffusion. This diffusion occurs in response to the active reabsorption of Na+ from the lumen of tubular and ductal cells. Active Na+ reabsorption generates an electric membrane gradient, and K+ and hydrogen ions (H+) cross the membranes to neutralize these electric charges. Aldosterone promotes secretion of K+ in the distal tubule but also promotes, reabsorption of Na+, thus stimulating the sodium–potassium exchange (i.e., the excretion of K+ in urine). Remember that aldosterone secretion is stimulated by the renin–angiotensin system, but can also be increased directly by a high intake of K+.
Potassium and hydrogen ions are in a balance, and the excretion of K+ in urine depends on the availability of H+. In acidosis, the excess of H+ favors the exchange of Na+ for H+. The urinary excretion of K+ is reduced, and renal acidosis is therefore associated with hyperkalemia. The reverse happens in alkalosis, when less H+ is available for exchange; higher excretion of K+ results in hypokalemia, which is typical of renal alkalosis. The reverse is also true: Since hypokalemia of any origin makes less K+ available for the exchange with Na+ in the distal nephron, hypokalemia tends to produce alkalosis.
Intercellular potassium concentration depends on the transmembrane exchange between the extracellular and intracellular pool of potassium.
The concentration of K+ inside the cells is an order of magnitude (approximately 25 times) higher than in the interstitial fluid. Such a huge gradient can be maintained only by the constant work of the sodium–potassium adenosine triphosphatase (Na+/K+ ATPase), which requires a huge expenditure of energy. Cell injury caused by ischemia or toxins may reduce the energy supply or impair the function of ATPase, resulting in a net increase of the efflux of K+ from the cells (Fig. 1-10).
Figure 1-10 Potassium flux across the cell membrane. A, In the normal cell the intracellular potassium (K+) concentration is several times higher than in the interstitial fluid. The gradient is maintained by the Na/K-ATPase in the cell membrane. B, Cell injury leads to a leakage of K+ from the cytoplasm into the interstitial fluid. C, In acidosis the hydrogen ions (H+) enter the cells from the interstitial fluid, displacing K+, which is translocated into the interstitial fluid (hyperkalemia). Lack of insulin in diabetes mellitus favors efflux of K+ from cells. D, In alkalosis the intracellular H+ enters the interstitial fluid and the K+ enters the cells, causing hypokalemia. Insulin also favors the entry of K+ into the cells.