The balance of anions and cations as it occurs across cell membranes is known as:

ELECTROLYTES

ELECTROLYTES. Electrolytes are molecules that, in solution, dissociate into positively charged ions (cations) and negatively charged ions (anions). Principal ions in body fluids are sodium, potassium, and chloride. A 70 kg adult has a body content of approximately 100 g sodium, 140 g potassium, and 95 g chloride. To maintain a stable body content, the amount of principal ions lost must equal the amount consumed. During growth and during pregnancy, the amount accreted for tissue formation also must be considered.

Physiological Functions

Sodium is the predominant cation in fluids outside the cells (extracellular fluid), whereas potassium is the predominant cation in the intracellular fluid. Chloride is the major anion of the extracellular fluid. Sodium plays a central role in regulating body fluid balance and distribution of fluid between the extracellular and intracellular compartments. As sodium is the major osmotically active particle in the extracellular fluid, sodium and its accompanying anion determines the osmolar concentration, or osmolarity, of this compartment. An increase in sodium concentration will increase the osmolarity of the extracellular fluid, thus causing water to move out of the cells into the extracellular compartment. It will also cause water retention by stimulating the thirst mechanism and by decreasing urine flow. The opposite occurs when sodium concentration is decreased. Thus, sodium plays a central role in regulating body fluid balance and the distribution of fluid between the extracellular and intracellular compartments.

Potassium is necessary for normal growth and plays an important function in cell metabolism, enzyme reactions, and synthesis of muscle protein. Both sodium and potassium are involved in maintaining proper acidity (pH) of the blood and in maintaining nerve and muscle functions. Normal resting membrane potentials of nerve and muscle cells range between –50 and 100 mV, with the inside of the cells negative with respect to the outside. These resting membrane potentials are maintained by the chemical gradient of potassium across cell membranes. Activation of excitable cells alters their membrane permeabilities to sodium and potassium, leading to changes in their membrane potentials. A weak stimulus causes a small depolarization (the inside of the cell is made less negative) as a result of sodium influx along its electrochemical gradient via the voltage-gated sodium channels in cell membranes. This is followed by repolarization, which is a manifestation of potassium efflux. If the stimulus is sufficiently strong, large changes in the membrane potential occur, during which the membrane potential may change from –70 mV to +30 mV, and then repolarize back to its resting membrane potential. This action potential, cause by alternation of potassium steady-state potentials with pulsed sodium potentials, gives rise to a traveling wave of depolarization that is conducted along the nerve fiber to exert an effect on the effector cells it innervates (supplies with nerves). In muscles, action potential leads to muscle contraction.

Dietary sodium chloride in foods and beverages is absorbed mostly in the small intestine. Active transport of sodium out of the small intestinal epithelial cells across their basolateral membrane provides an electrochemical gradient for the absorption of sodium across the luminal membrane. Entry of sodium through carrier proteins can either transport other solutes against their concentration gradient in the same direction (co-transport) or in an opposite direction (counter-transport). A number of transporters have receptor sites for binding sodium and glucose, galactose, or amino acids. Therefore, entry of sodium across the luminal membrane also brings in a solute. Counter-transport mechanisms operating in the kidneys allow excess hydrogen and potassium to be excreted in the urine.

Consumption of Sodium, Chloride, and Potassium

Consumption usually exceeds the needs of an individual, although the amount consumed varies widely with dietary habits. Most natural foods contain high potassium content but are lower in sodium content (Table 1). American adults consume an average of 2.5 to 3.5 g of potassium daily. Individuals consuming large amounts of fruits and vegetables may have a daily intake of as high as 11 g. Sodium is consumed mainly as sodium chloride (table salt). A small amount is consumed as sodium carbonate, sodium citrate, and sodium glutamate. Intakes of sodium vary, averaging 2 to 5 g/day of sodium or 5 to 13 g/day of sodium chloride. Only about 10 percent of sodium intake is from natural foods, the rest from sodium salts added during cooking and at the table, and from salts added during processing of foods. In regions where consumption of salt-preserved foods is customary, intake of sodium can be as high as 14 to 20 g/day.

Under normal circumstances, about 99 percent of dietary sodium, chloride, and potassium is absorbed. Absorption occurs along the entire length of the intestine, the largest fraction being absorbed in the small intestine and the remaining 5 to 10 percent in the colon. Potassium is also secreted in the colon. Various homeostatic regulatory mechanisms, the most important of which is aldosterone, modulate the absorption of sodium and secretion of potassium.

Loss of Sodium, Chloride, and Potassium

Obligatory loss of fluids through skin, urine, and feces invariably causes loss of these ions. Minimal obligatory loss for an adult consuming average intakes has been estimated to be 115 mg/day for sodium and 800 mg/day for potassium. Over 95 percent of loss is in the urine. Under most circumstances, loss of chloride parallels that of sodium. Loss of these ions can increase greatly in diuresis, vomiting, and diarrhea. Loss of sodium chloride can also increase greatly from profuse sweating.

Recommended Intake. Daily minimum needs can be estimated from the amount required to replace obligatory

losses (Table 2). The need is increased in infants and children, and during pregnancy and lactation. Estimated safe minimum intake levels are higher than the minimum requirements to account for the various degrees of physical activity of individuals and environmental conditions. Average intakes in the United States are higher than the estimated safe minimum levels of sodium chloride (1.3 g/day) and potassium (2 g/day).

The association of high salt intake with hypertension and the beneficial effects of potassium in hypertension has led to recommendations that daily intake of salt should not exceed 6 g and that of potassium should be increased to 3.5 g. This can be achieved by increasing intake of dietary fruits and vegetables.

Regulation of Sodium, Chloride, and Potassium Balance

Various mechanisms regulate excretion of these ions by the kidneys to maintain homeostatic equilibrium of body fluids. Urinary sodium excretion is controlled by varying the rate of sodium reabsorption from the glomerular filtrate by tubular cells, whereas potassium excretion is controlled by varying the rate of tubular secretion of potassium.

Abnormally low blood volume (hypovolemia) in sodium deficit increases renal sodium chloride reabsorption by increasing sympathetic discharge to the kidneys, and by stimulation of two hormonal systems, the renin-angiotensin-aldosterone and the antidiuretic systems. This results in the production of low urine volume with low sodium and chloride contents. Hypovolemia also initiates the thirst mechanism and increases an appetite for salt (or salt cravings).The presence of salt appetite in animals is to ensure an adequate intake of salt to protect the extracellular fluid volume from excessive loss of sodium due to sweating, diarrhea, pregnancy, or lactation. The development of salt appetite is of significance in the successful adaptation to a terrestrial life, especially in herbivorous animals. The need for salt can be satisfied by providing cattle and sheep with salt licks. Humans and other carnivores are less dependent on separate supplies of salt because dietary salt can be obtained from meat. However, they may develop a craving for salt when they are sodium deficient. This deficit-induced salt craving may be mediated by hormones acting on the brain and by changes in gustatory response. Abnormally high blood volume (hypervolemia) in sodium excess increases renal excretion of sodium chloride by suppression of sympathetic discharge to the kidneys, suppression of the renin-angiotensin-aldosterone and antidiuretic systems, and stimulation of the secretion of atrial natriuretic peptides.

Aldosterone is the most important hormone regulating secretion of potassium. Aldosterone secretion is triggered by angiotensin II, by high plasma potassium concentration, or by low plasma sodium concentration. Plasma concentrations of potassium and hydrogen also affect directly the secretion of potassium by the distal nephrons. The rate of potassium secretion parallels the plasma potassium concentration. Secretion of potassium in response to changes in acid-base balance (which affects plasma pH) is complex. In general, acute acidosis decreases secretion of potassium, whereas acute alkalosis increases secretion and loss of potassium from the body. Response to chronic acid-base disorders is varied.

Sodium, Chloride, and Potassium Imbalance

Acute excessive intakes do not normally result in retention of sodium, chloride, and potassium because of the capacity of the kidneys to excrete these ions. Retention occurs when kidney function is compromised. Dietary deficiency does not normally occur because normal consumption usually exceeds body needs.

Since the extracellular fluid volume changes in parallel with its sodium concentration, sodium retention in renal failure or congestive heart failure results in edema and possibly hypertension (Table 3). Excessive loss of sodium resulting in hypovolemia and hypotension can occur through diuresis, Addison's disease, severe vomiting, or diarrhea.

Changes in plasma concentration of potassium affects the excitability of nerves and muscle cells (Table 3). Retention of potassium causes hyperkalemia (plasma potassium concentration exceeding 5.0 mmol/l), and depletion causes hypokalemia (plasma potassium concentration less than 3.5 mmol/l). Retention of potassium occurs when there is a lack of aldosterone secretion, or a lack of responsiveness of the kidney to aldosterone. An important clinical manifestation of hyperkalemia is cardiac arrhythmia, which can lead to cardiac arrest. Depletion of potassium can occur through hyperaldosteronism, diuresis,

vomiting, or diarrhea. Manifestations of hypokalemia include depressed neuromuscular functions and, in more severe hypokalemia, cardiac arrhythmias.

Nutritional Considerations

Epidemiological and experimental evidence has implicated habitual high dietary salt consumption in the development of hypertension, but controversy remains regarding the importance of sodium salts in the regulation of blood pressure and the mechanisms by which salt influences blood pressure (Stamler, 1977). Intervention studies of dietary salt restrictions to lower blood pressure have produced mixed results. Nevertheless, various clinical trials indicate some beneficial effects of dietary restriction of sodium on blood pressure, and it may also decrease the incidence of stroke and ischemic heart disease.

High consumption of potassium, found in foods like oranges, apricots, and dates, on the other hand, appears to have a protective action against cardiovascular diseases, although the mechanism of action is not known. Epidemiological studies have demonstrated an inverse relationship of potassium intake with blood pressure, incidence of stroke, and other cardiovascular diseases (Young, Huabao, and McCabe). A direct relationship between blood pressure and the ratio of sodium to potassium in the urine has also been found (Stamler).

Repeated intake over a long period of salt from salted and smoked products is associated with atrophic gastritis and gastric cancer. However, experimental evidence indicates that salt alone is not carcinogenic; the high dietary salt content may enhance the initiation of cancer by facilitating the action of any carcinogen, such as polycyclic aromatic hydrocarbons, present in the diet (Cohen and Roe, 1977), or potentiating Helicobacter pylori–associated carcinogenesis (Fox et al., 1999).

See also Minerals; Nutrient Requirements; Nutrition; Salt; Sodium; Thirst.

BIBLIOGRAPHY

Cohen, A. J., and F. J. Roe. "Evaluation of the Aetiological Role of Dietary Salt Exposure in Gastric and Other Cancers in Humans." Food and Chemical Toxicology 35 (1997): 271–293.

Fox, James G., et al. "High Salt Diet Induces Gastric Epithelial Hyperplasia and Parietal Cell Loss, and Enhances Helicobacter pylori Colonization in C57BL/6 Mice." Cancer Research 59 (1999): 4823–4828.

Lentner, Cornelius, ed. Geigy Scientific Tables. 8th ed., vol. 1. Basel: Ciba-Geigy Limited, 1981.

National Research Council. Recommended Dietary Allowances. 10th ed. Washington, D. C.: National Academy Press, 1989.

Palmer, Biff F., Robert J. Alpern, and Donald W. Seldin. "Physiology and Pathophysiology of Sodium Retention." In The Kidney: Physiology and Pathophysiology, edited by Donald W. Seldin and Gerhard Giebisch. 3d ed., Philadelphia: Lippincott Williams and Wilkins, 2000. Vol II, Chapter 54, pp. 1473–1517.

Rodriguez-Soriano, Juan. "Potassium Homeostasis and Its Disturbance in Children." Pediatric Nephrology 9 (1995): 364–374.

Stamler, Jeremiah. "The INTERSALT Study: Background, Methods, Findings, and Implications." American Journal of Clinical Nutrition 65 (1997): 626S–642S.

Toto, Robert D., and Donald W. Seldin. "Salt Wastage." In The Kidney: Physiology and Pathophysiology, edited by Donald W. Seldin and Gerhard Giebisch. vol. 2, 3d ed., pp. 1519–1536. Philadelphia: Lippincott Williams and Wilkins, 2000.

Young, David B., Huabao Lin, and Richard D. McCabe. "Potassium's Cardiovascular Protective Mechanisms." American Journal of Physiology 268 (1995): R825–R837.

Hwai-Ping Sheng

Diarrhea

Daily, about 8 to 10 l of water and large amounts of ions enter the gastrointestinal tract; about 1 to 2 l are from the diet, the rest from secretions of the alimentary tract. The greater part of this fluid is absorbed by the intestinal cells so that only about 150 ml of fluid are lost daily in the stool of an adult. Stools contain a low content of sodium and chloride but a high content of potassium so that the daily losses averages 6 mmol for sodium, 12 mmol for potassium, 3 mmol for chloride, and 5 mmol for bicarbonate. Loss of this water and ions can increase greatly in diarrhea, and if extreme, several liters of fluid can be lost, leading to dehydration and electrolyte and acid-base disturbances.

Diarrhea is defined as an increase in stool liquidity and a fecal volume of more than 200 ml/day in adults. Clinically, the most common and important causes of diarrhea are osmotic and secretory. Ingestion of a poorly absorbable solute, such as magnesium sulfate, or malabsorption or maldigestion of a specific solute because of enzyme deficiencies, as seen in lactase deficiency, can cause osmotic diarrhea. The presence of these solutes increases the intestinal luminal osmolarity, causing water to be retained in the lumen.

Various viral and bacterial infections can cause secretory diarrhea. Enteroinvasive bacteria such as Shigella and Salmonella invade intestinal mucosa to produce ulceroinflammatory lesions resulting in a failure of normal absorption. On the other hand, bacteria such as Vibrio cholerae release toxins that increase secretion of sodium chloride and water. If the cholera is severe, up to 18 l of watery stools can be passed in a day. These stools contain ionic concentrations similar to that of plasma, so that large amounts of sodium, chloride, and potassium can be lost.

Dehydration caused by diarrhea ranges from mild to severe. The severity of dehydration can be assessed clinically by examining the patient for sunken eyeballs, skin turgor, mental status, blood pressure, and urine output. Fluid replacement is of utmost importance, especially in severe dehydration, to prevent circulatory collapse. Although diarrhea causes losses of sodium as well as potassium and bicarbonate, the immediate concern in treating severe diarrhea is to replace sodium and water to restore the circulatory volume. Dehydration in diarrhea can be reversed by oral or, in emergency, intravenous rehydration therapy.

The World Health Organization has recommended the use of oral rehydration therapy for treatment of mild to moderate cases of diarrhea. This program has been very successful in reducing mortality from diarrheal diseases, particularly in infants in developing countries. Oral rehydration fluid contains 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate, 1.5 g of potassium chloride, and 20 g of glucose in 1 l of water. An alternative household remedy is to make a solution containing three "finger pinches" of salt, a "fistful of sugar" and one quart of water. Addition of sugar to the oral rehydration fluid helps to increase the absorption of sodium chloride through the sodium-glucose transporter system in the small intestine.

Thermoregulation Through Perspiration

Heat is produced continuously by the body during metabolism, and it is also taken up by the body from the environment by radiation and conduction. Heat is lost from the body by radiation, conduction and convection, and evaporation. Even in the absence of perspiration, water is lost continuously from the body by evaporation from the upper respiratory tract and by passive evaporation from the skin. These insensible water losses amount to a total of about 0.6 l/day, of which slightly more than 50 percent is from the skin. For every liter of water that evaporates from the body, 580 kcal (2428 kJ) of heat is dissipated. During intense physical exertion or at a high ambient temperature, loss of heat from radiation, conduction, and insensible water loss are insufficient to prevent a rise in body temperature. Under these circumstances, heat loss is enhanced by the production and evaporation of sweat. Loss of heat by evaporation of sweat is an effective means of removing excess heat from the body, and it can be controlled by regulating the rate of sweating. When the body temperature rises above 98.6°F (37°C), stimulation of the temperature-regulating center in the hypothalamus causes sweating.

Sweat is produced by sweat glands by actively secreting into ducts a fluid similar in composition to that of plasma. As this primary secretion passes along the ducts of the sweat glands to the surface of the skin, sodium and chloride are absorbed in excess of water, resulting in the production of a dilute fluid that has a lower content of sodium and chloride. Sodium chloride content in sweat varies; it depends on the rate of flow. For a young adult, the average value is about 50 mmol/l for sodium and 30 mmol/l for chloride. The transport mechanisms for sodium and chloride are affected in patients suffering from cystic fibrosis so that their concentrations in the sweat are increased. For the purpose of diagnosis, the upper limit of the normal values for children and young adults are set at 70–80 mmol/l for sodium and 60–70 mmol/l for chloride (Lentner, ed.).

Rate of sweat production depends on the ambient temperature and humidity, and the degree of activity of the individual. For a 70 kg man doing light work at an ambient temperature of 84°F (29°C), daily loss is about 2 to 3 l. An unacclimatized individual who is performing hard physical activity in a hot, humid environment may lose, for a short time, up to 2 to 4 l/hour of sweat. As the duration of perspiration increases, the rate of production decreases to about 0.5 l/hour. Therefore, even at maximal sweating, the rate of heat loss may not be rapid enough to dissipate the excess heat from the body. Dehydration from excessive loss of water and sodium chloride stimulates the thirst mechanism, and if water intake is not increased, it can cause weakness and, if severe, circulatory collapse.

Adaptation to heat leads to physiological changes that include an increase in sweat production, an increase in plasma volume, and a decrease in concentration of sodium and chloride in the sweat and urine. These latter two effects are caused by an increase in aldosterone secretion as a result of dehydration and loss of sodium from the body. The decrease in the concentration of sodium and chloride in sweat and urine allows for better conservation of these ions in the body. An unacclimatized person who sweats profusely often loses as much as 13 to 30 g of salt per day for the first few days, but after four to six weeks of acclimatization the loss can be as low as 3 to 5 g a day.

There is a limit at which the body can lose heat even when perspiring maximally. The progressive rise in body temperature will affect the heat-regulating ability of the hypothalamus, resulting in a decrease in sweating. Therefore, a high body temperature tends to perpetuate itself unless measures are taken specifically to decrease the body temperature. When the body temperature rises beyond a critical temperature of 106°F (41°C), the person is likely to develop heat stroke. Symptoms include dizziness, abdominal distress, delirium, and eventually loss of consciousness. Some of these symptoms are exacerbated by a mild degree of circulatory shock as a result of sodium loss and dehydration.