After completing this chapter, the reader should be able to
Describe the homeostatic mechanisms involved in sodium and water balance, hyponatremia, and hypernatremia
Describe the physiology of intracellular and extracellular potassium regulation as well as the signs and symptoms of hypokalemia and hyperkalemia
List common causes of serum chloride abnormalities
List common conditions resulting in serum magnesium abnormalities and describe signs and symptoms of hypomagnesemia and hypermagnesemia
Describe the metabolic and physiologic relationships among the metabolism of calcium, phosphate, parathyroid hormone, and vitamin D
List common conditions resulting in serum calcium abnormalities and describe signs and symptoms of hypocalcemia and hypercalcemia
List common conditions resulting in altered copper, zinc, manganese, selenium, and chromium homeostasis and describe the signs and symptoms associated with their clinical deficiencies
Interpret the results of laboratory tests used to assess sodium, potassium, chloride, calcium, phosphate, magnesium, copper, zinc, manganese, selenium, and chromium (in the context of a clinical case description, including history and physical examination)
Serum or plasma electrolyte concentrations are among the most commonly used laboratory tests by clinicians in assessing a patient’s health status, clinical conditions, and disease progression. The purpose of this chapter is to present the physiologic basis for the need to assess serum concentrations of common electrolytes and minerals. Interpretation of these laboratory results and the clinical significance of abnormal results are addressed.
Serum concentrations of sodium, potassium, chloride, and total carbon dioxide content (often referred to as serum bicarbonate) are among the most commonly monitored electrolytes in clinical practice. Magnesium, calcium, and phosphorus are also monitored, as determined by a patient’s disease states and clinical indication. The homeostasis of calcium and phosphate is frequently discussed in the context of the endocrine system because of the effects of vitamin D and the parathyroid hormone (PTH) on the regulation of these minerals. Serum total carbon dioxide content, often measured in conjunction with electrolytes, is discussed in Chapter 13 because of its significance for the assessment of acid–base status. Listed in Table 11-1 are the current dietary reference intake for electrolytes, minerals, and trace elements.
Recommended Dietary Reference Intake of Electrolytes and Minerals for Healthy Adults According to the Dietary Guidelines 2015 to 2020
†Adequate intakes according to Institute of Medicine (U.S.) Food and Nutrition Board. Dietary reference intakes. Washington, DC: National Academies Press; 2001.
The traditional units, International System (SI) units, and their conversion factors for electrolytes, minerals, and trace elements discussed in this chapter are listed in Table 11-2. Although the normal ranges of serum concentrations for each of the electrolytes are listed later, clinicians should always confirm with the institutional clinical laboratory department for their institutional reference range because of the variance introduced by equipment, analytical technique, and quality assurance data.
Conversion Factors to SI Units
CONVERSION FACTORS TO SI UNITS
Normal range: 135 to 145 mEq/L (135 to 145 mmol/L)
Sodium is the most abundant cation in the extracellular fluid and is the major regulating factor for bodily fluid and water balance. Extracellular (ie, intravascular and interstitial) and intracellular sodium contents are closely affected by body fluid status. Thus, an accurate interpretation of serum sodium concentration must include an understanding of body water homeostasis and the interrelationship between the regulation of sodium and water.1
Sodium is essential for maintaining the optimal transmembrane electric potential for action potential and neuromuscular functioning as well as regulating serum osmolality and water balance. Serum osmolality is an estimate of the water–solute ratio in the vascular fluid. It can be measured in the laboratory or estimated using the following equation:
By strict definition, there is a difference between osmolality, which refers to the number of solute particles in 1 kg of solvent (expressed as mOsm/kg), and osmolarity, which describes the number of solute particles per 1 L of solvent (expressed as mOsm/L). Osmolality is generally used to describe serum and other physiologic solutions, whereas osmolarity is the term for intravenous (IV) solutions for infusion, such as IV fluids and parenteral nutrition solutions.
The normal range of serum osmolality is 285 to 295 mOsm/kg. The measured osmolality should not exceed the estimated value by more than 10 mOsm/kg. A difference of >10 mOsm/kg between the measured and estimate values is considered an increased osmolal gap, which may suggest the presence of other unmeasured solutes (eg, organic solvents, alcohol) and is useful to providing assessments in clinical toxicology. Decreased serum osmolality usually suggests a water excess, whereas increased serum osmolality suggests a water deficit. Although serum osmolality may be helpful in assessing water status, especially the intravascular volume, it should not be the primary and only parameter in assessing fluid status. Also, the results should be interpreted in the context of the ability of the solute to cross cellular membranes (eg, uremia causing hyperosmolality without relative intracellular depletion) and a patient’s symptoms and signs of disease. Figure 11-1 summarizes the interrelationship and regulation between water and sodium.
Changes in body water and total plasma volume can affect the serum sodium concentration. For example, as the result of changes in effective circulating volume, baroreceptors and osmoreceptors respond accordingly to restore an isovolemic state of the body. Baroreceptors are located in the carotid sinus, aortic arch, cardiac atria, hypothalamus, and juxtaglomerular apparatus in the kidney. An increase in plasma volume stimulates these receptors and promotes urinary loss of water and sodium. Osmoreceptors are present primarily in the hypothalamus. The three major effectors in response to the stimulation of the osmoreceptors include vasopressin or antidiuretic hormone (ADH), the renin–angiotensin–aldosterone system, and natriuretic peptides. The resultant renal effects from these three distinct pathways collectively regulate the homeostasis of water and sodium.
The kidneys are the primary organ responsible for the retention and excretion of body sodium and water. The glomeruli receive and filter approximately 180 L of plasma fluid daily. On average, <2 L of water and between 0.1 and 40 g of sodium is excreted in the urine, depending on the fluid status and sodium intake of the individual. Although almost 100% of the serum sodium is filtered by the glomeruli, <1% is eventually excreted in the urine under normal circumstances. The proximal tubule and the loop of Henle collectively account for up to 90% of sodium reabsorbed from the kidneys.
The homeostatic mechanism for water and sodium involves equilibrium among intravascular, interstitial, and intracellular fluids.2,3 Net movement of water occurs from areas of low osmolality to areas of high osmolality. This effect can be readily observed in patients with a low serum osmolality due to a deficit of serum sodium or excess of plasma water. In patients with hyponatremia, water moves from the plasma to the higher osmolality in the interstitial space. In the presence of high hydrostatic and oncotic pressure gaps across capillary walls, the net effect is excessive interstitial water accumulation and edema formation.2,3
Antidiuretic hormone (vasopressin)
Antidiuretic hormone, also known as arginine vasopressin, is a nine amino acid peptide hormone that regulates renal handling of free water. By altering the amount of water reabsorbed by the kidney, ADH has an indirect, but pivotal, effect in changing or maintaining serum sodium concentration. ADH is produced by the magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus, in which both osmoreceptors and baroreceptors are present to detect fluid changes in the vasculature. ADH release by the posterior pituitary is stimulated by (1) hypovolemia (detected by baroreceptors); (2) thirst; (3) increased serum osmolality; and (4) angiotensin II. The plasma half-life of ADH is 10 to 20 minutes, and it is rapidly deactivated and eliminated by the liver, kidneys, and a plasma enzyme vasopressinase.
Antidiuretic hormone regulates urinary water loss by augmenting the permeability of the collecting tubules to increase the net reabsorption of water. Circulating serum ADH binds to type 2 vasopressin (V2) receptors starting at the thick ascending loop, which contributes to the corticomedullary gradient and mechanism of water retention. More importantly, ADH also binds to the V2 receptors in the collecting tubule and promotes the formation of a water channel, known as aquaporin-2 (AQP2). AQP2 facilitates the reabsorption of water from the lumen back into the renal blood supply in the systemic circulation, causing a decrease in diuresis and net retention of water. However, if serum sodium is high but blood volume is normal (eg, normovolemia with hyperosmolality), the effect from the baroreceptors overrides the further release of ADH, thus preventing volume overload (ie, hypervolemia).2
The changes in plasma water content associated with ADH may alter serum osmolality and affect serum sodium concentration. In patients with the syndrome of inappropriate ADH (SIADH) secretion, an abnormally high quantity of ADH is present in the systemic circulation. This condition results in increased water reabsorption, which could cause a dilutional effect in serum sodium. In conjunction with increased free water intake, a low serum sodium concentration is commonly observed in these patients. Urine osmolality and urine electrolyte concentrations are often increased in SIADH because of decreased urinary excretion of free water associated with the increased effect of ADH. Conversely, in patients with central diabetes insipidus (DI), hypothalamic ADH synthesis or its release from the posterior pituitary gland is decreased. Patients with DI commonly present with hypernatremia due to the increased renal wasting of free water. In some cases, the kidneys fail to respond to the circulating ADH despite appropriate synthesis ADH from the hypothalamus and release of ADH from the posterior pituitary. This condition is called nephrogenic diabetes insipidus. In either central or nephrogenic DI, patients usually produce a large quantity of diluted urine, characterized by low specific gravity, low urine osmolality, and low urine sodium.2 (Chapter 10 offers an in-depth discussion of the effects of other diseases on urine composition.)
Drugs may alter ADH release from the posterior pituitary gland or the biological response to the hormone in the renal epithelial tissues. This may produce an imbalance of water and sodium in the body and exacerbate SIADH or DI.4,5 SIADH is not uncommon with the use of cyclophosphamide, carbamazepine, oxcarbazepine, some analgesics, oxytocin, a number of anticancer agents, phenothiazines, some tricyclic antidepressants, and a number of selective serotonin reuptake inhibitors (Table 11-3).6 Because of their ability to increase renal reabsorption of free water via the ADH pathway, some of these drugs play an established role in the treatment of chronic hypernatremia or DI. For example, carbamazepine stimulates ADH release and enhances renal cell response to ADH by increasing AQP2 expression.7 This antidiuretic effect also has established its role as an off-label pharmacotherapeutic option for DI, however. In contrast, demeclocycline and lithium decrease the action of ADH on the renal epithelial water reabsorption mediated by aquaporin. They have been used off-label in the treatment of SIADH. Other drugs that decrease the release and impair the renal response to ADH also may precipitate DI (Table 11-4). Based on published data, lithium, foscarnet, and clozapine are the most commonly reported causes of drug-induced DI. In addition, conivaptan, a vasopressin receptor antagonist (V1A and V2 receptors), and tolvaptan, a selective V2 receptor antagonist, both modulate the renal handling of water by reducing renal water absorption and affect sodium homeostasis. These two drugs are approved by the U.S. Food and Drug Administration for the treatment of euvolemic and hypervolemic hyponatremia.
Medications That Can Cause Hyponatremia Based on Published Data
Drugs that alter sodium and water homeostasis
Drugs that alter water homeostasis
Stimulator of central ADH production or release
Monoamine oxidase inhibitors
Selective serotonin reuptake inhibitors
Tricyclic antidepressants (more common with amitriptyline, desipramine, protriptyline)
*Likely also involves central effect by inhibiting ADH release.
†Currently no longer available in the United States although still available in some other countries.
Renin is a glycol-protein that catalyzes the conversion of angiotensinogen to angiotensin I, which is further converted to angiotensin II, primarily in the lungs. However, angiotensin II also can be formed locally in the kidneys. Angiotensin II, a potent vasoconstrictor, is important in maintaining optimal perfusion pressure to end organs, especially when plasma volume is decreased. In addition, it induces the release of aldosterone, ADH, and, to a lesser extent, cortisol.
Aldosterone is a hormone with potent mineralocorticoid activity. It affects the distal tubular reabsorption of sodium, which also contributes to plasma volume retention.3 This hormone is released from the adrenal cortex. Besides angiotensin II, various dietary and neurohormonal factors, including low serum sodium, high serum potassium, and low blood volume, can stimulate its release. Aldosterone acts on renal sodium–potassium–adenosine triphosphate (Na-K-ATPase) to increase urinary excretion of potassium from the distal tubules in exchange for sodium reabsorption. Because of its effect on renal Na-K exchange, aldosterone has a profound effect on serum potassium, although its effect on serum sodium is relatively modest. As serum sodium increases, so does water reabsorption, which follows the osmotic gradient.3 Renal arteriolar blood pressure (BP) then increases, which helps maintain the glomerular filtration rate (GFR). Ultimately, more water and sodium pass through the distal tubules, overriding the initial effect of aldosterone.2,3
Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide, is a vasodilatory hormone synthesized and primarily released by the right atrium. It is secreted in response to plasma volume expansion as a result of increased atrial stretch. ANF inhibits the juxtaglomerular apparatus, zona glomerulosa cells of the adrenal gland, and the hypothalamus–posterior pituitary. As a result, a global downregulation of renin, aldosterone, and ADH, respectively, is achieved. ANF directly induces glomerular hyperfiltration and reduces sodium reabsorption in the collecting tubule. A net increase in sodium excretion is achieved. Therefore, ANF can decrease serum and total body sodium. Brain natriuretic peptide (BNP) is produced and secreted primarily by the ventricles in the brain, and to a much smaller extent, the atrium. Similar to atrial natriuretic peptide, BNP also regulates natriuretic, endocrine, and hemodynamic responses and may affect sodium homeostasis. An increase in blood volume or pressure, such as chronic heart failure (CHF) and hypertension, enhances BNP secretion, which induces a significant increase in natriuresis and to a lesser extent, urinary flow (ie, diuresis). Plasma BNP concentrations correlate with the magnitude of left ventricular heart failure and the clinical prognosis of patients with heart failure.
Hyponatremia is defined as a serum sodium concentration <135 mEq/L (<135 mmol/L). Although it can be the direct result of sodium deficit, hyponatremia may also occur when total body fluid content is low (ie, volume depletion, dehydration), normal, or high (ie, fluid overload). Therefore, natremic status must be evaluated in concert with volume status to determine the nature of an underlying disorder. Fluid status should be assessed based on history of oral intake; vital signs; other supportive laboratory findings if available (eg, serum blood urea nitrogen [BUN]–serum creatinine [SCr] ratio, hematocrit to hemoglobin [Hgb] concentration ratio, or urine electrolyte assessment); recent changes in body weight; recent medical, surgical, and nutrition history; and findings from the physical examination. More important, a patient’s renal function, hydration status, and fluid intake and output must be thoroughly evaluated and closely monitored.
Most patients with hyponatremia remain asymptomatic until serum sodium approaches 120 mEq/L. In most cases, hyponatremia can be effectively and safely managed with mild fluid restriction and the use of physiologic saline solution (eg, NaCl 0.9%). Infusion of hypertonic saline (eg, NaCl 3%) is usually not necessary unless serum sodium concentration is <120 mEq/L, altered mental status is present, or the patient is fluid restricted (eg, CHF, chronic renal failure). As with most electrolyte disorders, the chronicity of the imbalance is a major determinant of the severity of signs and symptoms. For example, hyponatremia in a patient with CHF secondary to chronic, progressive volume overload and decreased renal perfusion is less likely to be symptomatic than a patient who is hyponatremic due to rapid infusion of a hypotonic solution. The most commonly reported symptom associated with hyponatremia is altered mental status (Table 11-5). If serum sodium continues to fall, cerebral edema can worsen and intracranial pressure continue to rise. More severe symptoms such as seizure, coma, and, subsequently, death may result.2-6
Signs and Symptoms of Hyponatremia
Depressed deep tendon reflexes
The most common causes of hyponatremia can be broken down into two types: (1) sodium depletion in excess of total body water loss (eg, severe hypovolemia with true depletion of total body sodium); or (2) dilutional hyponatremia (ie, free water intake greater than water output with no change in sodium loss). Dilutional hyponatremia can be further categorized into five subtypes: (1) primary dilutional hyponatremia (eg, SIADH and renal failure); (2) neuroendocrine conditions (eg, adrenal insufficiency and myxedema); (3) psychiatric disorder (eg, psychogenic polydipsia); (4) osmotic hyponatremia (eg, severe hyperglycemia); and (5) thiazide diuretic-induced conditions.
Hyponatremia associated with total body sodium depletion
Hyponatremia associated with low total body sodium reflects a reduction in total body water, with an even larger reduction in total body sodium. This condition is primarily caused by depletion of extracellular fluid, which stimulates ADH release to increase renal water reabsorption, even at the expense of causing a transient hypoosmotic state. Some common causes include vomiting, diarrhea, intravascular fluid losses due to burn injury and pancreatitis, Addison disease, and certain forms of renal failure (eg, salt-wasting nephropathy).2 This type of hyponatremia may also occur in patients treated too aggressively with diuretics who receive sodium-free solutions as replacement fluid.
Hyponatremia associated with normal total body sodium
Also called euvolemic or dilutional hyponatremia, this condition refers to impaired free water excretion without alteration in sodium excretion. Etiologies include any mechanism that enhances ADH secretion or potentiates its action at the renal collecting tubules. This condition can occur as a result of glucocorticoid deficiency, severe hypothyroidism, and administration of water to a patient with impaired water excretion capacity.2,5 SIADH is associated with excessive renal reabsorption of free water in the body due to continued ADH secretion, despite low serum osmolality. This results in hyponatremia and increased urinary sodium loss. Patients with SIADH produce concentrated urine with high urine osmolality (usually greater than serum osmolality) and urine sodium excretion (as reflected in a urine sodium concentration that is usually >20 mEq/L). They have normal renal, adrenal, and thyroid function and no evidence of volume abnormalities.2,4,5
Impaired ADH response can be precipitated by many factors, including medications. SIADH has been reported in patients with certain tumors, such as lung cancer, pancreatic carcinoma, thymoma, and lymphoma. ADH release from the parvicellular and magnocellular neurons may be stimulated by cytokines such as interleukin-1β, 2, 6, and tumor necrosis factor-α. Likewise, head trauma, subarachnoid hemorrhage, hydrocephalus, Guillain-Barré syndrome, pulmonary aspergillosis, and occasionally tuberculosis may increase hypothalamic ADH production and release, leading to SIADH (Figure 11-2).
In some cases, hyponatremia may not be associated with a sodium deficit. This scenario is associated with normal or even slightly elevated total body sodium, which is distributed in a much larger volume of total body water. It is frequently observed in hypervolemic states with compromised renal function, such as CHF, cirrhosis, nephrotic syndrome, and chronic kidney disease (CKD). In these patients, renal handling of water and sodium is often impaired.2,5
The initial goal of therapy for most patients with hyponatremia, based on the most recent European and American consensus guidelines, is to raise the serum sodium concentration by 5 mEq/L.8 Mild, asymptomatic hyponatremia (>125 mEq/L) can usually be safely managed with a sodium-containing oral rehydration solution or an increase in oral sodium intake, provided that the oral route is viable (ie, vomiting and diarrhea are controlled, evidence of functional gastrointestinal [GI] tract). IV sodium therapy is preferred in severe cases of hyponatremia or in patients with severe symptoms. In most cases, sodium chloride 0.9% is used, although the recent guidelines recommend using NaCl 3.0% in symptomatic patients.8 If a hypertonic saline solution (eg, ≥NaCl 3.0%) is used, it must be infused via a central venous catheter because of its high osmolarity.
The initial goal for treating acute hyponatremia is to prevent further decline in serum sodium concentration, reverse or prevent neurologic symptoms, and avoid excessive correction of serum sodium in patients at risk for osmotic demyelination syndrome. In patients with sodium concentration >120 mEq/L with no or mild symptoms, acute correction of serum sodium concentration may not be warranted. In symptomatic patients with serum sodium concentration <120 mEq, increase serum sodium by up to 4 to 6 mEq/L within 24 hours of baseline or until symptoms improve. The risk of osmotic demyelination syndrome has been reported after correction by 9 mEq/L per day.8 Neurologic deficits would improve with this target rate of change in serum sodium concentration. The average rate of increase in serum sodium should not exceed 1 to 2 mEq/L/hr and a total of 9 mEq/L in any given 24-hour period. Excessive correction of serum sodium concentration during the course of treatment, and not just the first or second day, may result in osmotic demyelination syndrome. There is no evidence that the first day’s correction should be greater than on other days. There is no evidence that correction of serum sodium by >10 mEq/L in 24 h or 18 mEq/L in 48 hours improves outcomes in patients with acute or chronic hyponatremia8,9 (Minicase 1).
TESTS FOR ASSESSING FLUID STATUS
Fractional Excretion of Sodium
Normal range: 1% to 2%
In most cases, natremic disorders cannot be effectively managed without first optimizing the overall fluid status of the patient. Therefore, when a serum sodium value is abnormal, the clinician should first evaluate whether vascular volume is optimal. In addition to physical examinations and history, the fractional excretion of sodium (FENa) may help validate these findings, especially in patients whose physical examination results may be limited by other confounders (eg, use of antihypertensive drugs, CHF, or with acute renal failure). FENa is most useful in the acute onset of oliguria in which a clinical history cannot be ascertained.10 The value may be determined by the use of a random urine sample to determine renal handling of sodium. FENa, the measure of the percentage of filtered sodium excreted in the urine, can be calculated using the following equation:
Values >2% usually suggest that the kidneys are excreting a higher than normal fraction of the filtered sodium, implying likely renal tubular damage. Conversely, FENa values <1% generally imply preservation of intravascular fluid through renal sodium retention, suggesting prerenal causes of renal dysfunction (eg, hypovolemia and cardiac failure). Because acute diuretic therapy can increase the FENa to 20% or more, urine samples should be obtained at least 24 hours after diuretics have been discontinued.
A Case of Hyponatremia
Jessica F., a 24-year-old woman, presents to the emergency department with lower abdominal pain, fatigue, headache, and dizziness. She has had four episodes of vomiting and six episodes of diarrhea in the last 24 hours. She had salad at a salad bar for lunch the day before. About 2 hours after her lunch, she started to feel nauseated. The abdominal pain and vomiting started shortly thereafter, and the diarrhea started in the evening. She vomited her lunch, and her diarrhea was mostly watery without blood. She also experienced a headache this morning. She has not been eating for the last 24 hours and can tolerate only small sips of water.
Upon presentation, she looks pale with sunken eyes. She is alert and oriented to time, person, and place. Neurologic examination reveals no deficits. Her vital signs include BP 105/70 mm Hg in supine position (standing BP 90/65 mm Hg), heart rate (HR) 92 beats/min (standing 108 beats/min), and respiratory rate (RR) 20 breaths/min. She also has a temperature of 100.6°F. Blood work for serum electrolytes and complete blood count is ordered. Her electrolyte panel shows the following results:
Sodium, 128 mEq/L
Potassium, 3.3 mEq/L
Chloride, 90 mEq/L
CO2 content, 21 mEq/L
BUN, 28 mg/dL
Creatinine, 1.05 mg/dL
Glucose, 77 mg/dL
She has not taken any medication prior to this admission.
QUESTION: How would you interpret this patient’s serum sodium concentration?
DISCUSSION: The patient’s serum sodium concentration is lower than the normal range, suggesting hyponatremia. However, as mentioned previously, sodium disorder cannot be fully assessed without evaluating a person’s fluid status. Based on the history, she had excessive fluid loss due to repeated episodes of vomiting and diarrhea. Fever also will increase insensible fluid loss. Therefore, her headache is likely caused by hypovolemia with hyponatremia. Her vital signs (orthostatic hypotension with reflex tachycardia) and the findings from physical exam support volume depletion. The laboratory results show an elevated BUN:SCr ratio of 28:1, which also is consistent with volume depletion. Increased loss of body fluids, especially from the GI tract, will lead to increased water and sodium loss. Her fluid intake has been limited and likely inadequate to replenish the continued sodium loss, which results in hyponatremia. She is likely experiencing hyponatremia associated with total sodium deficiency due to uncontrolled vomiting, diarrhea, and insufficient oral intake.
The onset of the patient’s hyponatremia is likely acute because there are no other established factors that would lead to chronic hyponatremia (eg, use of diuretic drugs, selective serotonin reuptake inhibitors). Her symptoms of hyponatremia are mild as she shows no neurologic deficit. Her headache is likely associated with her volume depletion, mild hyponatremia, and possibly acid–base changes.
In summary, this patient has mild hyponatremia with hypovolemia. The cause seems to be from her acute illness—uncontrolled vomiting and diarrhea leading to increased water and sodium loss with insufficient sodium intake. She does not seem to experience major acute symptoms associated with hyponatremia at this point. The logical treatment approach for her involves controlling her nausea, diarrhea, and vomiting as well as treating hypovolemia with a sodium-containing fluid (eg, oral rehydration solution or IV NaCl 0.9%) and managing other electrolyte disturbances.
Blood Urea Nitrogen: Serum Creatinine Ratio
Normal range: <20:1
The BUN:SCr ratio can provide useful information to assess fluid status. When this ratio is higher than 20:1, contraction of plasma volume is usually present. While the terms dehydration and volume depletion are often used interchangeably, dehydration implies total body water depletion with most of which being intracellular, so the patient may or may not have hemodynamic compromise. On the other hand, volume depletion generally refers to a loss of plasma or intravascular volume, which tends to have a more profound cardiovascular effect.11 As intravascular volume decreases, the rate of increase in serum urea is faster than that with SCr. Therefore, BUN increases by a larger magnitude than the SCr concentration in plasma volume depleted individuals, leading to a rise in the BUN:SCr ratio. However, it should be noted that BUN increases in the face of internal bleeding, CHF, renal failure, high dose corticosteroids, or high protein intake. Conversely, in patients with sarcopenia, low muscle mass, or low caloric intake, BUN concentration may remain low regardless of status of the plasma volume. If any of these conditions are present, additional signs and symptoms of volume depletion should be assessed along with the increased BUN:SCr ratio.
Hypernatremia is defined as a serum sodium concentration >145 mEq/L (>145 mmol/L). By definition, all hypernatremic states lead to increased serum osmolality. There are four main causes of hypernatremia: inadequate water intake, extrarenal hypotonic fluid loss, renal concentrating defect, and excessive salt intake.12 Depending on the etiology, hypernatremia may occur in the presence of high, normal, or low total body water content.2,12
The clinical manifestations of hypernatremia primarily involve the neurologic system. These manifestations are the consequence of dehydration, particularly in the brain. In adults, acute elevation in serum sodium >160 mEq/L (>160 mmol/L) may result in death. To assess the etiology of hypernatremia, it is important to evaluate (1) urine production, (2) sodium intake, and (3) renal solute concentrating ability, which reflects ADH activity. In most cases, history of presentation and urine analysis, including urine osmolality and urine sodium concentration, would help establish the cause of hypernatremia.12
Hypernatremia associated with low total body water
This occurs when the loss of water exceeds the loss of sodium (ie, free water deficit).3 The thirst mechanism generally increases water intake, but this adjustment is not always possible (eg, patients unable to tolerate oral intake or patients who are obtunded). This condition also may be iatrogenic when hypotonic fluid losses (eg, profuse sweating and diarrhea) are replaced with an excessive amount of salt-containing fluids, such as NaCl 0.9%. In these circumstances, fluid loss should be replaced with IV dextrose solutions or solutions with lower sodium content, such as NaCl 0.45%, which serve as a source of free water.3,12 In patients with hypernatremia who present with high urine osmolality (>800 mOsm/kg, roughly equivalent to a specific gravity of 1.023) and low urine sodium concentrations (<10 mEq/L), these laboratory results reflect an intact renal concentrating mechanism. Signs and symptoms of dehydration should be carefully monitored. These include orthostatic hypotension, flat neck veins, tachycardia, poor skin turgor, and dry mucous membranes. In addition, the BUN:SCr ratio may be >20 secondary to dehydration.2,11
Hypernatremia may be associated with normal total body water, also known as euvolemic hypernatremia
This condition refers to an increased loss of free water without concurrent sodium loss.2,12,13 Because of water redistribution between the intracellular and extracellular fluid, no plasma volume contraction is usually evident unless water loss is substantial. In most cases, intravascular volume is further maintained by increased fluid intake. Etiologies include increased insensible water loss (eg, fever, extensive burns) and central and nephrogenic DI. It is worth noting that hypercalcemia, hypokalemia, acute tubular necrosis, amyloidosis, Sjögren’s syndrome, sarcoidosis, and a number of medications can all independently precipitate nephrogenic DI. In evaluating a patient with hypernatremia, the clinician should carefully evaluate potential contribution by the existing pharmacotherapeutic agents and determine whether therapy should be modified. (Table 11-4).13,14 Mild cases of DI can be safely and effectively managed by sufficient water intake. The removal of aggravating factors, if feasible, can further improve polyuria. If oral or enteral water intake in not adequate or tolerated, IV fluid administration with dextrose 5% is necessary for correcting hypernatremia and preventing hypovolemia. If the diagnosis of central DI is subsequently established, vasopressin or desmopressin, a synthetic analog of vasopressin, is a reasonable option for long-term maintenance therapy.
Hypernatremia also may be associated with increased total body water. This form of hypernatremia is the least common because sodium homeostasis is maintained indirectly through the control of water, and defects in the system usually affect total body water more than total body sodium.3,13 Primary hyperaldosteronism and Cushing syndrome may cause total body water to increase. In other patients, high total body water usually results from exogenous administration of solutions containing large amounts of sodium (Minicase 2):
Resuscitative efforts using large amount of sodium-containing solutions
Inadvertent IV infusion of hypertonic saline solutions
Inadvertent dialysis against high sodium-containing solutions
Sea water, near drowning
Normal range: 3.8 to 5.0 mEq/L (3.8 to 5.0 mmol/L)
Potassium is the primary intracellular cation with an average intracellular fluid concentration of about 140 mEq/L (140 mmol/L). The major physiologic role of potassium is in the regulation of muscle and nerve excitability. It may also play important roles in the control of intracellular volume (similar to the ability of sodium in controlling extracellular volume), protein synthesis, enzymatic reactions, and carbohydrate metabolism.14,15
The most important aspect of potassium physiology is its effect on action potential, especially on muscle and nervous tissue excitability.16,17 During periods of potassium imbalance, the cardiovascular system is of principal concern because of the life-threatening arrhythmias that may result from either high or low serum potassium concentrations. Cardiac muscle cells depend on their ability to change their electrical potentials, with accompanying potassium flux when exposed to the proper stimulus, to result in muscle contraction and nerve conduction.16 One important aspect of potassium homeostasis is its distribution equilibrium. In a 70-kg man, the total body potassium content is about 4,000 mEq. Of that amount, only a small fraction (about 60 mEq) is distributed in the extracellular fluid; the remainder resides within cells. The average daily Western diet contains 50 to 100 mEq of potassium, which is completely and passively absorbed in the upper GI tract. To enter cells, potassium must first pass through the extracellular compartment.
A Case of Hypernatremia After Resection of Pituitary Tumor
Mrs. Lee, a 49-year-old woman with a recently diagnosed pituitary tumor, was admitted to the hospital 2 days ago for tumor resection. On postoperative day 2, she reports that she feels thirsty and a little dizzy. The nurse reports that she has been asking for water throughout the morning. She also has used the bathroom four times this morning.
Current vital signs: BP 108/80 mm Hg supine (standing BP 105/80 mm Hg); HR 84 to 90 beats/min; RR 10 to 14 breaths/min; SpO2 (saturation of peripheral oxygen via pulse oximetry) 99% on room air; breathing comfortably. Intake (last 24 hours): five 8-oz glasses of water, 200 mL juice from breakfast, and two cups of hot tea.
Output: 3,130 mL of urine in the last 16 hours; weight: 63.7 kg today (64.2 kg yesterday; 64.7 kg before surgery).
Her laboratory results are as follows:
Sodium, 155 mEq/L
Potassium, 3.2 mEq/L
Chloride, 101 mEq/L
BUN, 18 mg/dL
CO2 content, 24 mEq/L
Creatinine, 1.02 mg/dL
Glucose, 72 mg/dL
Urine osmolality, 105 mOsm/kg H2O
Urine specific gravity, 1.001
QUESTION: How would you interpret this patient’s serum sodium concentration?
DISCUSSION: The patient’s serum sodium concentration is elevated, suggesting hypernatremia. The next step is to assess her fluid status and determine the cause(s) of the disorder(s). Based on her history, the patient has an unusually high urine output (>3 L in 16 hours and frequent urination). Her urine osmolality and specific gravity show that she has diluted urine, which suggests that an excessive loss of free water likely has contributed to her hypernatremia. She is currently not volume depleted (based on her vital signs, BUN:SCr ratio) because she has been able to catch up with her urinary fluid loss with oral fluid intake due to thirst. Her weight change suggests that she is trending toward a mild fluid deficit. Thus, she can be described as having normovolemic hypernatremia.
The onset of her hypernatremia is likely acute because it occurred within 2 days after her surgery, and hyponatremia is more commonly seen after surgery because of elevated ADH releases. Her symptom of hypernatremia is limited to dizziness. Surgical procedures that could potentially affect pituitary gland function are a major risk factor for sodium disorders because the release and regulation of ADH may be affected. In this patient’s case, the supraopticohypophyseal tract was likely affected during removal of the tumor, which precipitated the symptoms and signs that are currently observed. The elevated urine output with persistent thirst suggests that an ADH-related disorder, central DI, is likely present with a serious risk of altered sodium homeostasis. Her relatively normal vital signs were maintained by her ability to temporarily increase oral fluid intake. If the DI defect is not corrected, however, she will develop hypovolemia quickly. This is an acute medical problem, and the diagnosis should be established quickly with the help of several laboratory tests, such as urine sodium, serum sodium, and urine osmolality.
In summary, this patient has hypernatremia, which appears to be manifested by altered renal water/salt regulation based on the urine osmolality. Although her volume status appears normal at this point, she can quickly develop hypovolemia if she is unable to keep up with oral fluid intake. The cause of hypernatremia is likely related to the pituitary gland resection that caused central DI. The logical treatment approach for her involves free water provision to prevent free water deficit and treatment of DI. If her oral water intake is unable to match the urinary water loss, she will require concurrent IV fluid therapy to prevent severe hypovolemia.
If the serum potassium concentration rises above 6 mEq/L (>6 mmol/L), symptomatic hyperkalemia is usually expected. Potassium homeostasis is altered by insulin, aldosterone, adrenergic responses, changes in acid–base balance, renal function, or GI and skin losses. These conditions can be modulated by various pathologic states as well as pharmacotherapy. Although potassium may affect different bodily functions, its effect on cardiac muscle is by far the most important clinical monitoring parameter.15,16,18
When the serum potassium concentration is high, the body has two different mechanisms to restore potassium balance. A short-term solution is to shift the serum potassium into cells, whereas the other slower mechanism is renal elimination.16 The kidneys are the primary organs involved in the control and elimination of potassium. Potassium is freely filtered at the glomeruli and almost completely reabsorbed before the filtrate reaches the collecting tubules. Only about 10% of the filtered potassium is secreted into the urine at the distal and collecting tubules. Virtually all the potassium recovered in urine is, therefore, regulated via tubular secretion rather than glomerular filtration.
In the distal tubule, potassium is secreted whereas sodium is reabsorbed. There are several mechanisms that can modulate this sodium–potassium exchange. Aldosterone plays an important role because it increases potassium secretion into the urine (Figures 11-1 and 11-3).16 The hormone is secreted by the adrenal glands in response to high serum potassium concentrations. The delivery of large quantities of sodium and fluid to the distal tubules may also cause potassium secretion and its subsequent elimination, as seen in diuretic-induced hypokalemia. As the delivery of sodium and fluid is decreased, potassium secretion declines.
The presence of other anions in the distal tubules can increase renal potassium loss because the negatively charged anions attract positively charged potassium ions. This mechanism is responsible for hypokalemia caused by renal tubular acidosis and the administration large amount of sodium (eg, hypertonic saline solutions, or using sodium containing solution exclusively as vehicles for drugs).16 Potassium secretion also is influenced by the potassium concentration in distal tubular cells. When the intracellular potassium concentration is high, such as during intravascular volume depletion, potassium secretion into the urine is increased. The modulation of renal potassium excretion by these mechanisms may take hours to correct a serum potassium concentration, even during drastic, acute changes. Extrarenal mechanisms, therefore, often play important roles in keeping the serum potassium concentration within the narrow acceptable range. Although the kidneys are the primary route of elimination, potassium secretion into the colon becomes important in patients with advanced renal failure.
Another potentially relevant factor influencing renal potassium secretion is serum pH. When arterial pH increases due to metabolic alkalosis, a compensatory efflux of hydrogen ions from the cells into the extracellular fluid (bloodstream) takes place with a concurrent influx of potassium ions into the cells to maintain an electropotential gradient.17 During the early phase of metabolic alkalosis, the serum potassium concentration is transiently reduced because of a pH-dependent intracellular influx of serum potassium from the serum without altering the total body amount. Thus, although there is no immediate change in the amount of total body potassium, this movement of ions increases the cellular potassium content and results in hypokalemia. However, a shift in potassium and hydrogen ions also takes place in the renal distal tubular cells. In the presence of persistent alkalemia, renal potassium secretion into the urine is increased. Over time, the serum potassium concentration declines through increased renal loss, resulting in a reduced body store.
Metabolic acidosis has the opposite effect. Decreased pH results in an extracellular shift of potassium as a result of an intracellular shift of hydrogen ions, causing an elevated serum potassium concentration.17 Because the intracellular potassium content of the distal tubular cell is decreased, secretion of potassium in the urine is diminished. Chronically, however, renal potassium loss gradually increases due to unknown mechanisms.
When a severe metabolic acid–base abnormality exists, adjustment of the measured serum potassium concentration may be necessary to more accurately estimate body potassium status when pH is normalized. For every 0.1 unit reduction in arterial pH from 7.40, roughly 0.6 mEq/L (range: 0.2 to 1.7 mEq/L) could be added to the serum potassium value.17,19
Figure 11-3 summarizes the acute homeostatic mechanism involved in potassium distribution. During hyperkalemia, along with the release of aldosterone, increased glucagon and insulin release also contribute to reducing the serum potassium concentration. Glucagon stimulates potassium secretion into the distal tubules and collecting ducts whereas insulin promotes intracellular potassium uptake. Although insulin is not a major controlling factor in potassium homeostasis, it is useful for the emergency treatment of hyperkalemia. Administration of IV sodium bicarbonate may cause a transient intracellular shift of serum potassium.14,16
Pharmacological stimulation of β-2 adrenergic receptors may also affect the transcellular equilibrium of potassium. It leads to the movement of potassium from extracellular fluid to the intracellular fluid compartment. Therefore, β-2 adrenergic agonists (eg, albuterol) can be used short-term to treat certain hyperkalemic patients.16,18
Hypokalemia is defined as a serum potassium concentration <3.5 mEq/L (<3.5 mmol/L).16 To interpret the significance of low potassium values, clinicians should determine whether hypokalemia is caused by intracellular shifting of potassium (apparent deficit) or increased loss from the body (true deficit) (Table 11-6). Intracellular shifting occurs as a result of metabolic alkalosis, after administration of insulin, or giving large doses of β-2 adrenergic agonists (eg, continuous or hourly use of albuterol in patients in the intensive care unit (ICU) who are receiving mechanical ventilation). Increased elimination of potassium can occur in the kidneys or the GI tract. Other causes of hypokalemia include targeted temperature management, toxin exposure, refeeding syndrome, hyperaldosteronism, and Cushing syndrome. In children, several inherited disorders are associated with increased potassium wasting.16,20,21
Etiologies of Hypokalemia
Apparent deficit—intracellular shifting of potassium
Corticosteroids, especially fludrocortisone and hydrocortisone
Loop and thiazide diuretics
Proximal tubular damage can occur with amphotericin B therapy, resulting in renal tubular acidosis. Amphotericin B directly impairs the reabsorption of potassium, magnesium, and bicarbonate and leads to hypokalemia, hypomagnesemia, and metabolic acidosis. A concurrent deficiency in magnesium may affect the ability to restore potassium balance. Magnesium functions as a cofactor to maintain the sodium–potassium ATP pump activity and facilitates renal preservation of potassium. A patient with concurrent hypokalemia and hypomagnesemia does not respond to potassium replacement therapy effectively unless magnesium balance is restored first.22,23 Lipid formulations of amphotericin B may still affect potassium homeostasis, although the magnitude may be less severe and the presentation is less acute.
Non–potassium-sparing diuretic agents are drugs most commonly associated with renal potassium wasting. Although their mechanisms of natriuretic action differ, diuretic-induced hypokalemia is primarily caused by increased secretion of potassium at the distal sites in the nephron in response to an increased load of exchangeable sodium. Diuretics increase the distal urinary flow by inhibiting sodium reabsorption. This increased delivery of fluid and sodium in the distal segment of the nephron results in an increase in sodium reabsorption at that site. To maintain a neutral electrochemical gradient in the lumen, potassium is excreted as sodium is reabsorbed. Therefore, any inhibition of sodium absorption by diuretics proximal to or at the distal tubules can increase potassium loss. Renal potassium excretion is further enhanced when nonabsorbable anions are present in the urine.
Loop diuretics (eg, furosemide) or thiazides (eg, hydrochlorothiazide) are associated with hypokalemia and the effect is dose-dependent. Serum potassium concentrations should be monitored regularly, especially in patients receiving high doses of loop diuretics, to avoid the increased risk of cardiovascular events secondary to hypokalemia and other electrolyte imbalances. In addition, elderly patients with ischemic heart disease and patients receiving digoxin are more susceptible to the adverse consequences of hypokalemia. Other drugs commonly used in managing hypertension and other cardiac diseases such as spironolactone, triamterene, amiloride, eplerenone, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor antagonists are not expected to cause potassium loss due to their mode of action. On the contrary, they cause retention of potassium because of their effects related to aldosterone-dependent exchange sites in the collecting tubules.24
Conditions that cause hyperaldosteronism, either primary (eg, adrenal tumor) or secondary (eg, renovascular hypertension), can produce hypokalemia.21 Cushing syndrome leads to increased circulation of mineralocorticoids such as aldosterone. Corticosteroids with strong mineralocorticoid activity (eg, fludrocortisone and hydrocortisone) also can cause hypokalemia. The hypokalemic effect of fludrocortisone is sometimes utilized to treat patients with chronic hyperkalemia.25,26
Gastrointestinal loss of potassium can be important. Aldosterone influences both renal and intestinal potassium handling.17 A decrease in extracellular volume increases aldosterone secretion, which promotes renal and colonic potassium wasting. The potassium concentration in the GI fluid varies depending on the location of the GI tract, ranging from 5 mEq/L (bile, duodenum) to 30 mEq/L (colon). Therefore, profuse and uncontrolled diarrhea can result in potassium depletion. In contrast, upper GI secretion contains a much lower amount of potassium, and loss secondary to vomiting is unlikely to be significant. However, with severe vomiting, the resultant metabolic alkalosis may lead to hypokalemia due to intracellular shifting of potassium and enhanced urinary elimination. Finally, patients receiving potassium-free parenteral fluids can develop hypokalemia if not monitored properly.
Signs and symptoms of hypokalemia involve many physiologic systems. Abnormalities in the cardiovascular system may result in serious consequences, including disturbances in cardiac rhythm. Hypokalemia-induced arrhythmias are of particular concern in patients receiving digoxin. Both digitalis glycosides and hypokalemia inhibit the sodium–potassium ATP pump in the cardiac cells. Together, they can deplete intracellular potassium, which may result in fatal arrhythmias. The signs and symptoms of hypokalemia are listed in Table 11-7.1,20,21
Signs, Symptoms, and Effects of Hypokalemia on Various Organ Systems
Decrease in T-wave amplitude
Development of U waves
Increased risk of digoxin toxicity
PR prolongation (with severe hypokalemia)
ST segment depression
QRS widening (with severe hypokalemia)
Metabolic/endocrine (mostly serve as compensatory mechanisms)
Decreased aldosterone release
Decreased insulin release
Decreased renal responsiveness to antidiuretic hormone
Areflexia (with severe hypokalemia)
Loss of smooth muscle function (ileus and urinary retention with severe hypokalemia)
Inability to concentrate urine
Hyperkalemia is generally defined as a serum potassium concentration >5.5 mEq/L (>5.5 mmol/L). As with hypokalemia, hyperkalemia may indicate a true or apparent potassium imbalance, although the signs and symptoms are indistinguishable.16 To interpret a high serum potassium value, the clinician should determine whether hyperkalemia is due to apparent excess caused by extracellular shifting of potassium or true potassium excess in the body caused by increased intake with diminished excretion (Table 11-8).14,16-18
Etiologies of Hyperkalemia
Extracellular shifting of potassium associated with acidemia
Increased release of intracellular potassium into bloodstream
Tumor lysis syndrome
Muscle crush injuries
Increased total body potassium
Increased potassium intake (eg, salt substitute, diet)
Decreased excretion or increased retention
Chronic or acute renal failure
Nonsteroidal antiinflammatory agents
Aldosterone receptor antagonists
Angiotensin II receptor antagonists
Trimethoprim (including drugs such as cotrimoxazole)
Deficiency of adrenal corticosteroids (especially mineralocorticoids)
Because renal excretion is the major route of potassium elimination, renal failure is the most common cause of hyperkalemia. However, potassium handling by the nephrons is relatively well-preserved until the GFR falls to <10% of normal. Therefore, many patients with renal impairment can maintain a near normal, serum potassium concentration. They are still prone to developing hyperkalemia if excessive potassium is consumed and when renal function deteriorates.16,17 It should also be noted that acid-base disorders can lead to changes in serum potassium concentration. For example, acidemia causes an efflux of intracellular potassium which may lead to hyperkalemia. The change is generally transient and serum potassium concentration would decline quickly with the correction of serum pH. However, if an excessive renal loss of serum potassium happens (eg, diuresis) during the transient period of potassium efflux, a total body potassium deficit may occur even after the normalization of serum pH.
Increased potassium intake rarely causes any problem in subjects in the absence of significant renal impairment. With normal renal function, increased potassium intake leads to increased renal excretion and redistribution to the intracellular space through the action of endogenous aldosterone and insulin, respectively. Interference with either mechanism may result in hyperkalemia. Decreased aldosterone secretion can occur with Addison disease or other defects affecting the hormone’s adrenal output. Pathologic changes affecting the proximal or distal renal tubules also can lead to hyperkalemia.16,17
Use of potassium-sparing diuretics (eg, spironolactone) is a common cause of hyperkalemia, especially in patients with renal function impairment. Concurrent use of potassium supplements (including potassium-rich salt substitutes) also increases the risk. Similar to hypokalemia, hyperkalemia can result from transcellular shifting of potassium. In the presence of severe acidemia, potassium shifts from the intracellular to the extracellular space, which may result in a clinically significant increase in the serum potassium concentration.19
The cardiovascular manifestations of hyperkalemia are of major concern. They include cardiac rhythm disturbances, bradycardia, hypotension, and, in severe cases, cardiac arrest. At times, muscle weakness may occur before these cardiac signs and symptoms. To appreciate the potent effect of potassium on the heart, one has to realize that potassium is the principal component of cardioplegic solutions commonly used to arrest the rhythm of the heart during cardiac surgeries.14,16,18
Causes of spurious laboratory results
Several conditions result in transient hyperkalemia, in which the high serum concentration reported is not expected to have significant clinical sequelae. Erythrocytes also have high potassium content. When there is substantial hemolysis in the specimen collection tube, the red cells release potassium in quantities large enough to produce misleading results. Hemolysis may occur when a small needle is used for blood draw, when the tourniquet is too tight, or when the specimen stands too long or is mishandled. When a high serum potassium concentration is reported in a patient without pertinent signs and symptoms, the test needs to be repeated to rule out hemolysis. A similar phenomenon can occur when the specimen is allowed to clot (when nonheparinized tubes are used) because platelets and white cells are also rich in potassium.
Management of chronic hyperkalemia includes decreasing dietary intake of potassium, use of diuretics if feasible, and treatment of metabolic acidosis if present. If the cause is drug induced (eg, ACE inhibitors), the use of an alternative therapeutic agent should be considered. When changing to an alternative therapy is not an option (eg, tacrolimus in transplant patients), the addition of a chronic potassium-lowering agent, such as fludrocortisone or sodium-zirconium cyclosilicate, may be needed. For rapid correction of acute, symptomatic hyperkalemia, measures include correcting metabolic acidosis with IV sodium bicarbonate; administering IV dextrose and regular insulin or inhaled β-adrenergic agonists to shift potassium from the extracellular to the intracellular space; using high doses of loop diuretics to enhance renal excretion of potassium; administering patiromer, sodium zirconium cyclosilicate, or sodium polystyrene sulfonate to increase colonic elimination of potassium; and initiating dialysis in the most severe cases (Minicase 3).
Normal range: 95 to 103 mEq/L (95 to 103 mmol/L)
Chloride is the most abundant extracellular anion with a low intracellular concentration (about 4 mEq/L). Chloride is passively absorbed from the upper small intestine. In the distal ileum and large intestine, its absorption is coupled with bicarbonate ion secretion. Chloride excretion is primarily regulated by the renal proximal tubules, where it is exchanged for bicarbonate ions. Throughout the rest of the nephron, chloride passively follows sodium and water. In addition, the luminal and interstitial chloride-bicarbonate (Cl/HCO3) exchangers in the collecting duct also contribute to the renal regulation of chloride.
Chloride is influenced by the extracellular fluid balance and acid–base balance.19,20 Although homeostatic mechanisms do not directly regulate chloride, they indirectly regulate it through changes in sodium and bicarbonate. The physiologic role of chloride is primarily passive. It balances out positive charges in the extracellular fluid and, by passively following sodium, helps to maintain extracellular osmolality.
Hypochloremia and Hyperchloremia
Serum chloride values are used as confirmatory tests to identify fluid balance and acid–base abnormalities.27,28 Like sodium, a change in the serum chloride concentration does not necessarily reflect a change in total body content. Rather, it indicates an alteration in fluid status and acid–base balance. One of the most common causes of hyperchloremia in hospitalized patients results from saline infusion.29 Chloride has the added feature of being influenced by bicarbonate. Therefore, it would be expected to decrease to the same proportion as sodium when serum is diluted with fluid and increase to the same proportion as sodium during intravascular volume depletion. However, when a patient has been receiving continuous or frequent nasogastric suction, or has profuse vomiting, a greater loss of chloride than sodium can occur because gastric fluid contains 1.5 to 3 times more chloride than sodium. Gastric outlet obstruction, protracted vomiting, and self-induced vomiting also can lead to hypochloremia.
A Case of Hyperkalemia
Raj P. a 68-year-old man, is admitted to the cardiology service for further examination of dyspnea and shortness of breath. His chief complaints include worsening of shortness of breath in the last 2 days, swelling of his legs, and the need for extra pillows before he can go to bed for the past week. He experiences worsening fatigue and dyspnea with ordinary activities.
He missed his furosemide doses for the past 2 to 3 days because it makes him go the bathroom a lot. He has been told that he needs furosemide for worsening shortness of breath. Otherwise, he takes his other medications consistently as instructed by his healthcare providers.
Past medical history includes congestive heart failure (ejection fraction of 31% checked 5.5 months ago), chronic atrial fibrillation, and type 2 diabetes mellitus. His home medications are as follows:
Carvedilol, 12.5 mg PO q 12 hours
Furosemide, 60 mg PO every morning and 20 mg every evening
Glargine insulin, 30 units SC daily
Lisinopril, 20 mg PO Twice daily
Potassium chloride, 20 mEq PO daily
Spironolactone, 12.5 mg PO daily
Warfarin, 5 mg PO daily
Vital signs on admission: BP 110/78 mm Hg (baseline BP 118/82 mm Hg), HR 69 beats/min (baseline HR 68 beats/min), and weight 90 kg (4 weeks ago, clinic record; 80 kg upon clinic admission).
Other tests include EKG and oxygen saturation 92% on room air.
QUESTION: How would you interpret this patient’s serum potassium concentration?
DISCUSSION: His serum potassium concentration, at 5.7 mEq/L, is elevated. It is possible that his baseline potassium concentration is mildly elevated because there are several factors that would contribute to hyperkalemia: (1) he is taking a potassium supplement, (2) he is taking two drugs that can increase serum potassium (spironolactone and lisinopril), (3) he has renal insufficiency at baseline (creatinine 1.5 mg/dL). It is likely that his potassium concentration has increased more significantly in the last 2 days. His current state of hyperkalemia is likely exacerbated by two recent events: (1) nonadherence with furosemide in the last 3 days, which results in decreased renal potassium loss; and (2) worsening of heart failure (as suggested by increased BNP, weight gain of 10 kg, and increased leg swelling), which in turn decreases renal blood flow and results in worsening of acute renal failure (as suggested by an increased serum creatinine from 1.5 to 2.1 mg/dL).
The primary goal for managing hyperkalemia is to prevent/reverse cardiac symptoms. With a serum potassium of 5.7 mEq/L, there is a definite risk for arrhythmias. Therefore, a 12-lead EKG should be obtained. If EKG changes are present and consistent with hyperkalemia, interventions to decrease serum potassium concentration, such as IV insulin and dextrose or IV sodium bicarbonate, should be initiated right away. IV calcium (calcium gluconate 1 g) also should be administered to reduce the risk of arrhythmias. Note that IV calcium administration has no effect in removing serum potassium and should never be used alone in the management of symptomatic hyperkalemia. Regardless of the cardiac symptoms, his potassium supplement should be withheld. Because his blood pressure is not elevated, it also is reasonable to withhold spironolactone for now until the potassium concentration starts to decline.
In summary, this patient has hyperkalemia, most likely exacerbated by acute renal failure and continued use of a potassium supplement. Assessment of symptoms and signs of hyperkalemia should be performed as soon as possible.
Drug and IV fluid-associated causes
Although drugs can influence serum chloride concentrations, they rarely do so directly. For example, although loop diuretics (eg, furosemide) and thiazide diuretics (eg, hydrochlorothiazide) inhibit chloride uptake at the loop of Henle and distal nephron, respectively, the hypochloremia that may result is due to the concurrent loss of sodium and contraction alkalosis.30,31 Because chloride ions passively follow sodium ions, salt and water retention can transiently raise serum chloride concentrations. This effect occurs with corticosteroids and nonsteroidal antiinflammatory agents such as ibuprofen. Also, IV fluids or parenteral nutrition solutions with high chloride concentrations are associated with an increased risk of hyperchloremia. Replacing some of the cations with an acetate salt instead of a chloride salt (eg, potassium acetate instead of potassium chloride) can reduce this risk. The sources of chloride ions should be carefully monitored daily, especially among hospitalized patients receiving multiple IV drips and medications using a saline-based fluid as the vehicle.
Acid–base status and other causes
Acid–base balance is partly regulated by renal production and excretion of bicarbonate ions. The proximal tubules are the primary regulators of bicarbonate. These proximal tubules cells exchange bicarbonate with chloride to maintain the intracellular electrochemical gradient. Renal excretion of chloride increases during metabolic alkalosis, resulting in a reduced serum chloride concentration.
The opposite situation also may be true: metabolic or respiratory acidosis results in an elevated serum chloride concentration. Hyperchloremic metabolic acidosis may occur when the kidneys are unable to conserve bicarbonate, as in interstitial renal disease (eg, obstruction, pyelonephritis, and analgesic nephropathy), GI bicarbonate loss from diarrhea, and acetazolamide-induced carbonic anhydrase inhibition.31 One of the most common causes of hyperchloremia in hospitalized patients is excessive use of IV saline solution.29 Falsely elevated chloride is rare but may occur with bromide toxicity due to an inability to distinguish between these two halogens by the laboratory’s chemical analyzer. Because the signs and symptoms associated with hyperchloremia and hypochloremia are related to fluid status or a patient’s acid–base status and its underlying causes, rather than to chloride itself, the reader is referred to discussions in Chapter 13.
Normal range: 1.7 to 2.4 mg/dL (0.7 to 1 mmol/L) or 1.4 to 2 mEq/L
Magnesium has a widespread physiologic role in maintaining neuromuscular functions and enzymatic functions. Magnesium acts as a cofactor for phosphorylation of ATPs from adenosine phosphates. Magnesium also is vital for binding macromolecules to organelles (eg, messenger ribonucleic acid to ribosomes).
The average adult body contains 21 to 29 g (1,750 to 2,400 mEq) of magnesium with the following distribution:
Approximately 50% in bone (about 30% or less of this pool is slowly exchangeable with extracellular fluid)
20% in muscle
Approximately 10% in nonmuscle soft tissues
1% to 2% in extracellular fluid (for plasma magnesium, about 50% is free; about 15% is complexed to anions; and 30% is bound to protein, primarily albumin)
Approximately 30% to 40% of the ingested magnesium is absorbed from the jejunum and ileum through transcellular and paracellular mechanisms. The regulation of oral magnesium absorption is by both passive diffusion down an electrochemical gradient and active transport process. TRPM6 is the transport protein that is highly expressed along the brush border membrane of the enterocytes and plays a key role in regulating the absorption of magnesium. The extent of magnesium absorption may be affected by dietary magnesium intake, calcium intake, vitamin D, and PTH. However, conflicting data are available, and the extent to which these parameters affect absorption is unresolved. Certain medications (eg, cyclosporine, tacrolimus, cisplatin, amphotericin B) can significantly increase renal magnesium loss, predisposing the patient to hypomagnesemia.32,33
Urinary magnesium accounts for one-third of the total daily magnesium output, whereas the other two-thirds are in the GI tract (eg, stool). Unbound serum magnesium is freely filtered at the glomerulus. All but 3% to 5% of filtered magnesium is normally reabsorbed (100 mg/day). In other words, 95% to 97% of the filtered magnesium is reabsorbed under normal physiology. Reabsorption is primarily through the ascending limb of the loop of Henle (50% to 60%). About 30% is reabsorbed in the proximal tubule and 7% from the distal tubule. This explains why loop diuretics have a profound effect on renal magnesium wasting. The drive of magnesium reabsorption is mediated by the charge difference generated by the sodium–potassium–chloride cotransport system in the lumen.
The regulation of magnesium is primarily driven by the serum magnesium concentration. Changes in serum magnesium concentrations have potent effects on renal reabsorption and stool losses. These effects are seen over 3 to 5 days and may persist for a long time. Hormonal regulation of magnesium seems to be much less critical for its homeostasis.
Factors affecting calcium homeostasis also affect magnesium homeostasis.17,32 A decline in serum magnesium concentration stimulates the release of PTH, which increases serum magnesium by promoting its release from the bone store and enhancing renal reabsorption. Hyperaldosteronism causes increased magnesium renal excretion. Insulin by itself does not alter the serum magnesium concentration, but in a hyperglycemic state, insulin causes rapid intracellular uptake of glucose. This process causes an increase in the phosphorylation by sodium–potassium ATPase on the cell membrane. Because magnesium is used as a cofactor for sodium potassium ATPase, serum magnesium concentration declines, resulting in hypomagnesemia. Excretion of magnesium is influenced by serum calcium and phosphorus concentrations. Magnesium movement generally follows that of phosphorus (ie, if phosphorus declines, magnesium also declines) and is the opposite of calcium.32,34,35 Other factors that increase magnesium reabsorption include acute metabolic acidosis, hyperthyroidism, and chronic alcohol use.
Magnesium also regulates neuromuscular function. Magnesium depletion results in neuromuscular weakness as the release of acetylcholine to motor endplates is enhanced by the presence of magnesium. Motor endplate sensitivity to acetylcholine also is affected. When serum magnesium decreases, acetylcholine release increases, resulting in increased muscle excitation, which may lead to increased deep tendon reflexes. Common symptoms associated with hypomagnesemia include weakness, muscle fasciculation with tremor, tetany, and increased deep tendon reflexes. In addition, vasodilation may occur by a direct effect on blood vessels and ganglionic blockade due to hypomagnesemia.
Hypomagnesemia is loosely defined as a serum magnesium concentration <1.7 mg/dL (<0.7 mmol/L). The common causes of hypomagnesemia include renal wasting, chronic alcohol use, diabetes mellitus, protein-calorie malnutrition, refeeding syndrome, GI losses from chronic diarrhea or high ileostomy output, and postparathyroidectomy. Because serum magnesium deficiency can be offset by magnesium release from bone, muscle, and the heart, the serum value may not be a useful indicator of cellular depletion and complications (eg, arrhythmias). However, low serum magnesium usually indicates low cellular magnesium as long as the patient has a normal extracellular fluid volume.34
Magnesium deficiency is more common than magnesium excess. Depletion usually results from excessive loss from the GI tract or kidneys (eg, use of loop diuretics). Magnesium depletion is not commonly the result of decreased intake because the kidneys can cease magnesium elimination in four to seven days to conserve the ion. However, with chronic alcohol consumption, deficiency can occur from a combination of poor intake, poor GI absorption (eg, vomiting or diarrhea), and increased renal elimination. Depletion also can occur from poor intestinal absorption (eg, small-bowel resection). Diarrhea can be a source of magnesium loss because diarrhea stools may contain as much as 14 mEq/L (7 mmol/L) of magnesium. Chronic use of proton-pump inhibitors also has been associated with hypomagnesemia.
Urinary magnesium loss may result from diuresis or tubular defects, such as the diuretic phase of acute tubular injuries. Some patients with hypoparathyroidism may exhibit low magnesium serum concentrations from renal loss and, possibly, decreased intestinal absorption. Other conditions associated with magnesium deficiency include hyperthyroidism, primary aldosteronism, diabetic ketoacidosis, and pancreatitis. Magnesium deficiency associated with these conditions may be particularly dangerous because often there are concurrent potassium and calcium deficiencies. Although loop diuretics lead to significant magnesium depletion, thiazide diuretics alone rarely cause hypomagnesemia, especially at lower doses (hydrochlorothiazide <50 mg/day). Furthermore, potassium-sparing diuretics (eg, spironolactone, triamterene, and amiloride) have some magnesium-sparing effect and, therefore, play a limited clinical role in preserving body magnesium and preventing hypomagnesemia.
Magnesium affects the central nervous system (CNS). Magnesium depletion can cause personality changes, disorientation, convulsions, psychosis, stupor, and coma.32,34 Severe hypomagnesemia may result in hypocalcemia due to intracellular cationic shifts. Many symptoms of magnesium deficiency result from concurrent hypocalcemia.
Perhaps the most important effects of magnesium imbalance are on the heart. Decreased magnesium in cardiac cells may manifest as a prolonged QT interval, which is associated with an increased risk of arrhythmias, especially torsades de pointes, which can be effectively treated by IV magnesium.17,36,37 Moderately decreased concentrations can cause electrocardiogram (EKG) abnormalities similar to those observed with hypokalemia.
Hypermagnesemia is defined as a serum magnesium concentration >2.4 mg/dL (>1 mmol/L).
Besides magnesium overload (eg, overreplacement of magnesium, treatment for preeclampsia, and antacid/laxative overuse), the most important risk factor for hypermagnesemia is renal dysfunction, especially CKD. Rapid infusions of IV solutions containing large amounts of magnesium may result in transient hypermagnesemia.
Serum magnesium concentrations <6 mg/dL (<2.5 mmol/L) rarely cause serious symptoms. Nonspecific symptoms, such as muscle weakness, decrease in deep tendon reflexes, or fatigue, may be present. As magnesium concentration rises above 6 mg/dL, more notable symptoms such as lethargy, mental confusion, and hypotension may be observed (Table 11-9).35,38 In severe hypermagnesemia (12 mg/dL), life-threatening symptoms, including coma, paralysis, or cardiac arrest, can be observed and urgent therapy is indicated.
Signs and Symptoms of Hypermagnesemia
SERUM MAGNESIUM CONCENTRATION
MAJOR CLINICAL SIGNS AND SYMPTOMS
Bradycardia, flushing, sweating, sensation of warmth, fatigue, drowsiness
Hypotension, decreased deep tendon reflexes, altered mental status possible
Flaccid paralysis and increased PR and QRS intervals, severe mental confusion, coma, respiratory distress, and asystole
Treatment for severe or symptomatic hypermagnesemia may include IV calcium gluconate 1 to 2 g over 30 minutes to reverse the neuromuscular and cardiovascular blockade of magnesium. Increased renal elimination of magnesium can be achieved by forced diuresis with IV saline hydration and a loop diuretic agent. Hemodialysis should be reserved as a last resort.
Normal range: 9.2 to 11 mg/dL (2.3 to 2.8 mmol/L) for adults
Calcium plays an important role in the propagation of neuromuscular activity, regulation of endocrine functions (eg, pancreatic insulin release and gastric hydrogen secretion), blood coagulation including platelet aggregation, and bone and tooth metabolism.17,35,39
The serum calcium concentration is closely regulated by complex interactions among PTH, serum phosphorus, vitamin D system, and the target organ (Figure 11-4). About one-third of the ingested calcium is actively absorbed from the proximal area of the small intestine, facilitated by 1,25-dihydroxycholecalciferol (1,25-DHCC or calcitriol, the most active form of vitamin D). Passive intestinal absorption is negligible with intake of <2 g/day. The average daily calcium intake is 2 to 2.5 g/day.
The normal adult body contains approximately 1,000 g of calcium, with only 0.5% found in the extracellular fluid; 99.5% is integrated into bones. Therefore, the tissue concentration of calcium is small. Because bone is constantly remodeled by osteoblasts and osteoclasts, a small quantity of bone calcium is in equilibrium with extracellular fluid. Extracellular calcium exists in three forms:
Complexed to bicarbonate, citrates, and phosphates (6%)
Protein bound, mostly to albumin (40%)
Ionized or free fraction (54%)
The imbalance of body calcium results in disturbances in neuromuscular actions. Within the cells, calcium maintains a low concentration. The calcium that is attracted into the negatively charged cell is either actively effluxed out of the cells or sequestered by mitochondria or the endoplasmic reticulum. Such differences in concentrations allow calcium to be used for transmembrane signaling. In response to stimuli, calcium ions either enter a cell or are released from internal cellular stores where they interact with specific intracellular proteins to regulate cellular functions or metabolic processes.17,39,40 Calcium enters cells through one of the three types of calcium channels: T (transient or fast), N (neuronal), and L (long-lasting or slow).
In the muscle, calcium is released from the intracellular sarcoplasmic reticulum. The released calcium binds to troponin and stops troponin from inhibiting the interaction of actin and myosin. This interaction results in muscle contraction. Conversely, muscle relaxation occurs when calcium is pumped back into the sarcoplasmic reticulum. In cardiac tissue, calcium becomes important during phase 2 of the action potential. During this phase, fast entry of sodium stops and calcium entry through the slow channels begins (Figure 11-5), resulting in contraction. During repolarization, calcium is actively pumped out of the cell.17
Calcium channel blockers (eg, nifedipine, diltiazem, and verapamil) inhibit the movement of calcium into muscle cells, thus decreasing the strength of contraction. They primarily affect the l-channels. The areas that are most sensitive to these effects appear to be the sinoatrial and atrioventricular nodes and vascular smooth muscles, which explains the hypotensive effects of nifedipine.
Complexed calcium usually accounts for <1 mg/dL (<0.25 mmol/L) of blood calcium. The calcium complex usually is formed with bicarbonate, citrate, or phosphate. In patients with CKD, calcium also may be bound with sulfate because of the decreased renal elimination of sulfate ions. Phosphorus plays an important role in calcium homeostasis. Under normal physiologic conditions, the product of total serum calcium concentration and serum phosphorus concentration (calcium–phosphate product) is relatively constant: an increase in one ion necessitates a corresponding decline in the other. In addition, many homeostatic mechanisms that control calcium also regulate phosphate. This relationship is particularly important in renal failure; the decreased phosphate excretion associated with CKD may ultimately lead to hypocalcemia, if hyperphosphatemia is untreated.17,40
Calcium also binds to serum proteins such as albumin (80%) and globulins (20%). Protein-bound calcium is in equilibrium with ionized calcium, which is affected by the serum anion concentration and blood pH. This equilibrium is important because ionized calcium is the physiologically active moiety. Alkalemia increases protein binding of calcium, resulting in a lower free fraction, whereas acidemia has the opposite effect. In patients with uncompensated respiratory or metabolic alkalosis, the signs and symptoms of hypocalcemia may become more pronounced due to increased binding. Conversely, signs and symptoms of hypercalcemia become more apparent in patients with uncompensated metabolic or respiratory acidosis. Therefore, total serum calcium concentration, which is commonly reported by clinical laboratories, is not as clinically significant as the quantity of available ionized calcium. In fact, it is the free calcium concentration that is closely regulated by the different homeostatic mechanisms.
Clinically, serum protein concentrations, especially albumin, have an important influence on regulating the amount of physiologically active calcium in the serum. The normal serum calcium range is 9.2 to 11 mg/dL (2.3 to 2.8 mmol/L) for a patient with a serum albumin of 4 g/dL. In normal healthy adults, only 40% to 50% of the total serum calcium is free from protein-binding and thus considered physiologically active. In patients with hypoalbuminemia (eg, due to acute illnesses, severe malnutrition), the free concentration of calcium is elevated despite a “normal” total serum calcium concentration. Therefore, it is a common practice either to measure ionized calcium or correct the total serum calcium concentration based on the measured albumin concentration. The following formula is commonly used in an attempt to “correct” total serum calcium concentration:
where Cacorr is the corrected serum calcium concentration and Cauncorr is the uncorrected (or measured total) serum calcium concentration. For example, a clinician may be asked to write parenteral nutrition orders for an emaciated cancer patient with a GI obstruction. The serum albumin is 1.9 g/dL (19 g/L), and the total serum calcium concentration is 7.7 mg/dL (1.9 mmol/L). At first glance, one might consider the calcium to be low; however, with the reduced serum albumin concentration, more ionized calcium is available to cells.
The corrected serum calcium concentration is, thus, within the normal range. More importantly, the patient does not exhibit any signs and symptoms of hypocalcemia; thus, calcium supplementation is not indicated. In the presence of severe hypoalbuminemia, as in critically ill patients, an apparently low total serum calcium may in fact be sufficient or, in some instances, excessive.
Although this serum calcium correction method may be useful, the clinician must be aware of its limitations and potential for inaccuracy. The correction factor of 0.8 represents an average fraction of calcium bound to albumin under normal physiology. To have an accurate determination of the free concentration, a direct measurement of serum ionized calcium concentration is preferred (normal range: 4 to 4.8 mg/dL or 1 to 1.2 mmol/L). Ultimately, a patient’s clinical presentation is the most important factor to determine if immediate treatment for a calcium disorder is indicated.
Although calcium absorption takes place throughout the entire small intestine, the proximal regions of the small intestine (jejunum and proximal ileum) are the most active and regulated areas. Calcium absorption from the human GI tract is mediated by two processes: (1) transcellular active transport, a saturable, vitamin D–responsive process mediated by specific calcium-binding proteins primarily in the upper GI tract, particularly in the distal duodenum and upper jejunum; and (2) paracellular process, a nonsaturable linear transfer via diffusion that occurs throughout the entire length of the intestine. Under normal physiology, the total calcium absorptive capacity is the highest in the ileum because of longer residence time. The rate of paracellular calcium absorption remains stable regardless of calcium intake. However, when dietary calcium intake is relatively limited, the efficiency of transcellular calcium transport becomes higher and accounts for a significant fraction of the absorbed calcium. Transcellular calcium transport is closely regulated by vitamin D, although other mechanisms also may be involved.43,44 Specifically, 1,25-DHCC induces the intestinal expressions of transcellular calcium transporters through its binding with the vitamin D receptors in the intestinal epithelial cells.
Effect of vitamin D
A small amount of calcium is excreted daily into the GI tract through saliva, bile, and pancreatic and intestinal secretions. However, the primary route of elimination is filtration by the kidneys. Calcium is freely filtered at the glomeruli, where approximately 65% is reabsorbed at the proximal tubules under partial control by calcitonin and 1,25-DHCC. Roughly 25% is reabsorbed in the loop of Henle, and another 10% is reabsorbed at the distal tubules under the influence of PTH.41,45
Despite being classified as a vitamin, the physiologic functions of vitamin D more closely resemble a hormone. Vitamin D is important for the following functions:
Intestinal absorption of calcium
PTH-induced mobilization of calcium from bone
Calcium reabsorption in the proximal renal tubules
Vitamin D is absorbed by the intestines in two forms, 7-dehydrocholesterol and cholecalciferol. 7-dehydrocholesterol is also converted into cholecalciferol in the skin by ultraviolet-B radiation from the sun. Hepatic and intestinal enzymes, including CYP27A1, CYP2J2, and CYP3A4, convert cholecalciferol to 25-hydroxycholecalciferol (25-HCC or calcidiol or calcifediol), which is then further converted by CYP27B1 in the kidneys to form 1,25-DHCC or calcitriol. This last conversion step is regulated by PTH and serum calcium concentration.43,46 When PTH is increased during hypocalcemia, renal production of calcitriol increases, which increases intestinal absorption of calcium. Although calcitriol is the most active form of vitamin D in regulating calcium homeostasis, its short serum half-life and tight regulation of serum and tissue concentrations under normal physiology make it an inaccurate marker for assessing total body vitamin D status. Calcidiol has a serum half-life of 14 days, and its serum concentration does not fluctuate significantly in response to serum calcium concentration. It is also the main circulating form of vitamin D with high concentration in the plasma. Therefore, it is the preferred laboratory test when vitamin D status is being evaluated. Note that in most laboratories, the calcidiol assay measures the total concentration of 25-hydroxy-ergocalciferol (D2) and 25-hydroxycholecalciferol (D3).47
Influence of calcitonin
Calcitonin is a hormone secreted by specialized C cells of the thyroid gland in response to a high level of circulating ionized calcium. Calcitonin lowers serum calcium levels in part by inhibiting osteoclastic activity, thereby inhibiting bone resorption. It also decreases calcium reabsorption in the renal proximal tubules, resulting in increased renal calcium clearance. Calcitonin is used for the treatment of acute hypercalcemia; several different forms of the hormone are available.
Influence of parathyroid hormone
PTH is an important hormone involved in calcium homeostasis. It is secreted by the parathyroid glands, which are embedded in the thyroid, in direct response to low circulating ionized calcium. PTH closely regulates, and is regulated by, the vitamin D system to maintain serum ionized calcium concentration within a narrow range. Generally, PTH increases the serum calcium concentration and stimulates the enzymatic activity of CYP27B1 to promote renal conversion of calcidiol to calcitriol, which enhances intestinal calcium absorption. Elevated calcitriol concentration also serves as a potent suppressor of PTH synthesis via a negative feedback mechanism that is independent of the serum calcium concentration.41,43 The normal reference range for serum PTH concentrations is 10 to 65 pg/mL (10 to 65 ng/L).
Tubular reabsorption of calcium and phosphate at the nephron is controlled by PTH; it increases renal reabsorption of calcium and decreases the reabsorption of phosphate, resulting in lower serum phosphorus and higher serum calcium concentrations. Perhaps the most important effect of PTH is on the bone. In the presence of PTH, osteoblastic activity is diminished and bone resorption processes of osteoclasts are increased. These effects increase serum ionized calcium, which feeds back to the parathyroid glands to decrease PTH output.
The suppressive effect of calcitriol on PTH secretion is used clinically in patients with CKD who have excessively high serum PTH concentrations caused by secondary hyperparathyroidism. PTH is a known uremic toxin, and its presence in supraphysiological concentrations has many adverse effects (eg, suppression of bone marrow erythropoiesis and increased osteoclastic bone resorption with replacement by fibrous tissue).41Figure 11-6 depicts the relationship between serum PTH and serum calcium concentrations.
True abnormal serum concentrations of calcium may result from an abnormality in any of the previously mentioned mechanisms, such as
Altered intestinal absorption
Altered number or activity of osteoclast and osteoblast cells in bone
Changes in renal reabsorption of calcium
Calcium or phosphate IV infusions
Patients with CKD have increased serum phosphorus and decreased serum calcium concentrations as a result of the following factors that interact via a complex mechanism: decreased phosphate clearance by the kidneys, decreased renal production of calcitriol, and skeletal resistance to the calcemic action of PTH. This interaction is further complicated by the metabolic acidosis of renal failure, which can increase bone resorption to result in decreased bone integrity.
Hypocalcemia is defined as a total serum calcium concentration of <9.2 mg/dL (<2.3 mmol/L). The most common cause of hypocalcemia is low serum proteins. As discussed previously, decreased serum proteins leads to an increased free fraction of ionized calcium despite a mild reduction of total serum calcium concentration. If there is no other coexisting factor that could impair or alter calcium homeostasis, this should not be associated with a functional calcium deficit and clinical symptoms. Therefore, serum protein concentrations should always be taken into consideration when interpreting total serum calcium concentration. Even in the case of true, mild hypocalcemia, the patient may remain asymptomatic and often no treatment is required.
The most common causes of a true reduction in total serum calcium are disorders of vitamin D metabolism or impaired PTH production (Table 11-10). Osteomalacia (in adults) and rickets (in children) can result from severe deficiency in dietary calcium or vitamin D, diminished synthesis of vitamin D3 from insufficient sunlight exposure, or resistance of the intestinal wall to the action of vitamin D. The reduction in serum calcium leads to secondary hyperparathyroidism, which increases bone resorption. Over a long period of time, bones lose their structural integrity and become more susceptible to fracture. The diminished serum calcium concentration, if significant, may result in tetany. Other notable findings may include EKG changes (QT prolongation) and arrhythmias.
Common Etiologies of Hypocalcemia
Decreased nutrient intake
Medications (see text)
Insufficient daily intake
Although uncommon, diminished intake of calcium is an important cause of hypocalcemia, especially in patients receiving long-term parental nutrition solutions.48,49
Excessive use of certain drugs to lower serum calcium by either increasing bone deposition or decreasing renal reabsorption of calcium may lead to hypocalcemia. These drugs include calcitonin, corticosteroids, loop diuretics, pamidronate, alendronate, zoledronic acid, cinacalcet, and denosumab.50
Intravenous bicarbonate administration and hyperventilation can lead to alkalemia, resulting in decreased serum ionized calcium. This decrease is usually important only in patients who already have low total serum calcium concentrations. Drugs such as phenytoin, phenobarbital, carbamazepine, dexamethasone, and rifampin activate pregnane X receptor and thereby increase the metabolism of vitamin D. Over time, it may lead to mild hypocalcemia if chronic hypovitaminosis D is present. Calcium absorption may be impaired by aluminum-containing antacids.
Rapid IV administration of phosphate salts, especially at high doses, can also precipitate acute hypocalcemia. Phosphate can bind calcium ions and form an insoluble complex that can deposit into soft tissues and clog the microcirculation, causing metastatic calcification, hardening of normally pliable tissues, or blockage of capillary blood flow.37,38 Soft-tissue deposition of the calcium–phosphate complex in lungs and blood vessels occurs when the serum solubility product of calcium times phosphorus is high. The product of total serum calcium and phosphorus concentrations (both expressed in milligrams/deciliter) is often calculated, especially in patients with CKD, to minimize the risk for tissue calcification. An increased risk of deposition is likely in patients with a calcium–phosphate product that exceeds 50 mg2/dL2 or in patients with alkalemia.
Hypoparathyroidism can reduce serum calcium concentrations. The most common cause of hypoparathyroidism is thyroidectomy, in which the parathyroid glands are removed along with the thyroid glands. Because PTH is the major hormone regulating calcium balance, its absence significantly reduces serum calcium.41
Hypocalcemia is commonly seen in patients with secondary hyperparathyroidism resulting from CKD (Figure 11-6). The mechanism is complex and involves elevated serum phosphorus concentrations and reduced activation of vitamin D. PTH acts on bone to increase calcium and phosphate resorption. Because renal phosphate elimination is reduced because of renal failure, the serum phosphorus concentration is often high and depresses the serum calcium level. Because of the high phosphate concentrations in the intestinal lumen, dietary calcium is bound and absorption is impaired, while phosphate absorption continues.
Common in CKD, metabolic acidosis further enhances bone resorption. With prolonged severe hyperparathyroidism, excessive osteoclastic resorption of bones results in replacement of bone material with fibrous tissues. This condition is termed osteitis fibrosa cystica.40 Such diminution of bone density may result in pathologic fractures. Although total serum calcium concentrations are low, patients may not show symptoms of hypocalcemia because the accompanying acidosis helps to maintain serum ionized calcium through the reduction in protein binding.
Similar to potassium, calcium balance is affected by magnesium homeostasis. Therefore, if a patient develops concurrent hypocalcemia and hypomagnesemia as a result of loop diuretic therapy, calcium replacement therapy may not be effective until magnesium balance is restored.
As with any electrolyte disorder, the severity of the clinical manifestations of hypocalcemia depends on the acuteness of onset. Hypocalcemia can, at times, be a medical emergency, with symptoms primarily in the neuromuscular system, including fatigue, depression, memory loss, hallucinations, and, in severe cases, seizures and tetany. The early signs of hypocalcemia are finger numbness, tingling and burning of extremities, and paresthesia. Mental instability and confusion may be seen in some patients as the primary manifestation.
Tetany is the hallmark of severe hypocalcemia. The mechanism of muscle fasciculation during tetany is the loss of the inhibitory effect of ionized calcium on muscle proteins. In extreme cases, this loss leads to increased neuromuscular excitability that can progress to laryngospasm and tonic-clonic seizures. Chvostek and Trousseau signs are hallmarks of hypocalcemia. The Chvostek sign is a unilateral spasm induced by a slight tap over the facial nerve. The Trousseau sign is a carpal spasm elicited when the upper arm is compressed by an inflated BP cuff.48,49
As hypocalcemia worsens, the cardiovascular system may be affected, as evidenced by myocardial failure, cardiac arrhythmias, and hypotension. Special attention should be paid to serum calcium concentrations in patients receiving diuretics, corticosteroids, digoxin, antacids, lithium, and parenteral nutrition and in patients with renal disease, because they may be more susceptible to symptomatic hypocalcemia.
Hypercalcemia indicates a total serum calcium concentration >11 mg/dL (>2.8 mmol/L).
The most common causes of hypercalcemia are malignancy and primary hyperparathyroidism (Figure 11-6). Malignancies can increase serum calcium by several mechanisms. Osteolytic metastases can arise from breast, lung, thyroid, kidney, or bladder cancer. These tumor cells invade bone and produce substances that directly dissolve bone matrix and mineral content. Some malignancies, such as multiple myeloma, can produce factors that stimulate osteoclast proliferation and activity. Another mechanism is the ectopic production of PTH or PTH-like substances by tumor cells, resulting in a pseudohyperparathyroid state.50,51
In primary hyperparathyroidism, inappropriate secretion of PTH from the parathyroid gland, usually due to an adenoma, increases serum calcium concentrations. The other major cause of hypercalcemia in hyperparathyroidism is the increased renal conversion of calcidiol to calcitriol. As the serum calcium concentration rises, the renal ability to reabsorb calcium may be exceeded, leading to an increased urinary calcium concentration and the subsequent formation of calcium–phosphate and calcium–oxalate renal stones. Typically, this condition results from parathyroid adenomas but also may be caused by primary parathyroid hyperplasia of chief cells or parathyroid carcinomas.50
Approximately 2% of patients treated with thiazide diuretics may develop hypercalcemia. Patients at risk are those with hyperparathyroidism. The mechanism appears to be multifactorial and includes enhanced renal reabsorption of calcium and decreased plasma volume.
The milk-alkali syndrome (Burnett syndrome), rarely observed today, is another drug-related cause of hypercalcemia.52 This syndrome occurs from a chronic high intake of milk or calcium products combined with an absorbable antacid (eg, calcium carbonate, sodium bicarbonate, or magnesium hydroxide). This syndrome was more common in the past when milk or cream was used to treat gastric ulcers and before the advent of nonabsorbable antacids. Renal failure can occur as a result of calcium deposition in soft tissues.
Hypercalcemia also can result from the following conditions2:
Excessive administration of IV calcium salts
Chronic high-dose oral or enteral calcium supplements
Acute adrenal insufficiency
Lithium-induced renal calcium reabsorption
Excessive intake of vitamin D, vitamin A, or thyroid hormone
Similar to hypocalcemia and other electrolyte disorders, the severity of the clinical manifestations of hypercalcemia depends on the acuteness of onset. Hypercalcemia can be a medical emergency, especially when serum concentrations rise above 14 mg/dL (>3.5 mmol/L). Symptoms associated with this condition often consist of vague GI complaints, such as nausea, vomiting, abdominal pain, dyspepsia, and anorexia. More severe GI complications include peptic ulcer disease, possibly due to increased gastrin release and acute pancreatitis.50,51
Severe hypercalcemic symptoms primarily involve the neuromuscular system (eg, lethargy, obtundation, psychosis, cerebellar ataxia, and, in severe cases, coma and death). However, EKG changes and spontaneous ventricular arrhythmias also may be seen. Hypercalcemia also may enhance the inotropic effects of digoxin, increasing the likelihood of cardiac arrhythmias.
Renal function may be affected by hypercalcemia through the ability of calcium to inhibit the adenyl cyclase–cyclic adenosine monophosphate system that mediates ADH effects on the collecting ducts. This inhibition results in diminished conservation of water by the kidneys. The renal effect is further compounded by diminished solute transport in the loop of Henle, leading to polyuria, nocturia, and polydipsia. Other chronic renal manifestations include nephrolithiasis, nephrocalcinosis, chronic interstitial nephritis, and renal tubular acidosis.
In addition, hypercalcemia can cause vasoconstriction of the renal vasculature, resulting in a decrease in renal blood flow and GFR. If hypercalcemia is allowed to progress, oliguric acute renal failure may ensue. In the presence of high calcium–phosphate product, soft-tissue calcification by the calcium–phosphate complex may occur. The signs and symptoms described previously are mostly seen in patients with severe hypercalcemia. With serum concentrations <13 mg/dL (3.2 mmol/L), most patients should be asymptomatic.
Causes of spurious laboratory results
False hypercalcemia can occur if the tourniquet is left in place too long when the blood specimen is drawn. This results from increased plasma-protein pooling in the phlebotomized arm. Falsely elevated calcium should be suspected if serum albumin is >5 g/dL. Table 11-11 contains the normal range values for tests related to calcium metabolism.
Normal Ranges for Tests Related to Calcium Metabolism in Adults
<250 mg/day in men
<200 mg/day in women
1 g/day (average)
Normal range: 2.3 to 4.7 mg/dL (0.74 to 1.52 mmol/L) for adults
Many of the factors that influence serum calcium concentrations also affect serum phosphorus, either directly or indirectly. Laboratory values for calcium and phosphorus should, therefore, be interpreted together. Because phosphate exists as several organic and inorganic moieties in the body, some clinical laboratories simply report the phosphate value as phosphorus.
Phosphate is a major intracellular anion with several functions. It is important for intracellular metabolism of proteins, lipids, and carbohydrates, and it is a major component in phospholipid membranes, ribonucleic acids, nicotinamide diphosphate (an enzyme cofactor), cyclic adenine and guanine nucleotides (second messengers), and phosphoproteins. Another important function of phosphate is in the formation of high-energy bonds for the production of ATP, which is a source of energy for many cellular reactions. Phosphate is a component of 2,3-diphosphoglycerate (2,3-DPG), which regulates the release of oxygen from Hgb to tissues. In addition, phosphate has a regulatory role in the glycolysis and hydroxylation of cholecalciferol. It is also an important acid–base buffer.17,40
A balanced diet for adults usually contains 800 to 1,500 mg/day of phosphate. About two-thirds is actively absorbed from the small intestine. Some of the phosphate is absorbed passively with calcium, and some is absorbed under the influence of calcitriol, which also increases the intestinal absorption of calcium. However, phosphate is the first of the two to be absorbed.42
Phosphate absorption is diminished when a large amount of calcium or aluminum is present in the intestine due to the formation of insoluble phosphate compounds. Such large amounts of calcium and aluminum may result from the consumption of antacids. In fact, for patients with CKD who have high serum phosphorus concentrations, calcium- and aluminum-containing antacids may be given with meals as phosphate binders to reduce intestinal phosphate absorption.42 It should be noted that due to concerns of detrimental accumulation of aluminum in the CNS as well as the ability to worsen anemia and bone disease, chronic use of aluminum-containing antacids should be avoided.
Phosphate is widely distributed in the body throughout the plasma, extracellular fluid, cell membrane structures, intracellular fluid, collagen, and bone. Bone contains 85% of the phosphate in the body. About 90% of serum phosphorus is filtered at the glomeruli, and most is actively reabsorbed at the proximal tubule. Some reabsorption also takes place in the loop of Henle, distal tubules, and possibly the collecting ducts.17,40,53 The amount of renal phosphate excretion is, therefore, the amount filtered minus the amount reabsorbed. Increased urinary phosphate excretion can result from an increase in plasma volume and the action of PTH, which can block phosphate reabsorption throughout the nephron. In contrast, vitamin D3 and its metabolites can directly stimulate proximal tubular phosphate reabsorption. In all, 90% of eliminated phosphate is excreted renally, while the remainder is secreted into the intestine. Renal handling of phosphate, especially the proximal tubules, therefore, plays an important role in maintaining the homeostatic balance of phosphate. Renal phosphate transport is active, saturable, and dependent on pH and sodium ions. However, fluctuation in serum phosphorus mostly results from changes in either the GFR or the rate of tubular reabsorption.
Serum phosphorus and calcium concentrations as well as PTH and vitamin D levels are intimately related to each other. Serum phosphorus indirectly controls PTH secretion via a negative feedback mechanism. With a decrease in serum phosphorus concentration, the conversion of calcidiol to calcitriol increases (which increases serum concentrations of both phosphorus and calcium). Both the intestinal absorption and renal reabsorption of phosphate are increased. The concomitant increase in serum calcium then directly decreases PTH secretion. This decrease in serum PTH concentration permits a further increase in renal phosphate reabsorption.53
A true phosphate imbalance may result from an abnormality in any of the previously discussed mechanisms and hormones for maintaining calcium and phosphate homeostasis. They may include altered intestinal absorption, altered number or activity of osteoclast and osteoblast cells in bone, changes in renal calcium and phosphate reabsorption, and IV infusions of calcium or phosphate salts.
Hypophosphatemia indicates a serum phosphate concentration of <2.3 mg/dL (<0.74 mmol/L). The following three mechanisms commonly contribute to decreased serum phosphorus concentrations:
Increased renal excretion
Decreased phosphate or vitamin D intake
To identify the etiology of hypophosphatemia, the serum and urine phosphate concentrations should be evaluated simultaneously. Low urine and serum phosphates indicate either a diminished phosphate intake or excessive use of phosphate-binders. An increased urine phosphate suggests either hyperparathyroidism or renal tubular dysfunction. If the increased urine phosphate is accompanied by elevated total serum calcium, the presence of primary hyperparathyroidism or decreased vitamin D metabolism must be considered.
Hypophosphatemia commonly results from decreased renal reabsorption or increased GFR, a shift of phosphate from extracellular to intracellular fluid, alcoholism, or malnutrition. Phosphate is added to parenteral nutrition solutions for muscle growth and replenishment of hepatic glycogen storage in malnourished patients. The infusion of concentrated dextrose (eg, ≥5%) solution increases insulin secretion from the pancreas, which facilitates glucose and phosphate cell entry. Phosphate is used to form phosphorylated hexose intermediates during cellular utilization of glucose. An inadequate phosphate content in these nutritional fluids can decrease anabolism, glycolysis, and ATP and 2,3-DPG production.
Infusion of concentrated dextrose solutions or feeding can produce hypophosphatemia through intracellular phosphate shifting. Refeeding syndrome is a classic example of this presentation. This risk of hypophosphatemia is higher in patients who have chronic malnutrition or insufficient nutrient intake. Patients with cancer, chronic alcoholism, and anorexia nervosa and older adults are at risk for developing refeeding syndrome. Hypophosphatemia also can occur during treatment of hyperkalemia with IV regular insulin and dextrose. In addition, aluminum- and calcium-containing antacids, as well as magnesium hydroxide, are potent binders of intestinal phosphate and reduce its absorption. Their chronic use can lead to hypophosphatemia. Moreover, calcitonin, glucagon, and β-adrenergic agonists can decrease serum phosphorus concentrations. Thiazide and loop diuretics can increase renal phosphate excretion; however, this effect is often mild at typical doses for treating hypertension.
Other conditions known to cause hypophosphatemia include treatment of diabetic ketoacidosis, decreased absorption or increased intestinal loss, alcohol withdrawal, the diuretic phase of acute tubular necrosis, and prolonged respiratory alkalosis. To compensate for respiratory alkalosis, carbon dioxide shifts from intracellular to extracellular fluid. This shift increases the intracellular fluid pH, which activates glycolysis and intracellular phosphate trapping. Metabolic acidosis, in contrast, produces a minimal change in serum phosphorus.
Burn patients often retain a great amount of sodium and water. During wound healing, diuresis often ensues, which results in a substantial loss of phosphate. Because anabolism also occurs during recovery, hypophosphatemia may be inevitable without proper replacement. A moderate reduction in serum phosphorus can occur from prolonged nasogastric suctioning, gastrectomy, small bowel or pancreatic disease resulting in malabsorption, and impaired renal phosphate reabsorption in patients with multiple myeloma, Fanconi syndrome, heavy-metal poisoning, amyloidosis, and nephrotic syndrome.53,54
Severe phosphate depletion (<1 mg/dL or <0.32 mmol/L) can occur during insulin infusion in the management of diabetic ketoacidosis. Acidemia causes bone mineral mobilization, promotes intracellular organic substrate metabolism, and releases phosphate into the extracellular fluid. The glycosuria and ketonuria caused by diabetic ketoacidosis result in an osmotic diuresis that increases urinary phosphate excretion. The combined effects of these events may produce a normal serum phosphorus concentration but a severe intracellular deficiency. When diabetic ketoacidosis is corrected with insulin, phosphate accompanies glucose to move intracellularly. Serum phosphorus is usually reduced within 24 hours of treatment. As the acidosis is corrected, there is further intracellular shifting of phosphate to result in profound hypophosphatemia. The accompanying volume repletion may exacerbate the hypophosphatemia further.
Patients with a moderate reduction in serum phosphorus (2 to 2.3 mg/dL or 0.64 to 0.74 mmol/L) are often asymptomatic. Neurologic irritability may occur as the serum phosphorus concentration drops below 2 mg/dL (<0.64 mmol/L). Severe hypophosphatemia is often associated with muscle weakness, rhabdomyolysis, paresthesia, hemolysis, platelet dysfunction, and cardiac and respiratory failure.
Central nervous system effects may include encephalopathy, confusion, obtundation, seizures, and, ultimately, coma. The mechanism for these effects may involve decreased glucose use by the brain, decreased brain cell ATP, or cerebral hypoxia from increased oxygen-Hgb affinity, secondary to diminished erythrocyte 2,3-DPG content. This decreased content results in decreased glycolysis, which leads to decreased 2,3-DPG and ATP production. The decreased contents of 2,3-DPG and ATP result in an increased affinity of Hgb for oxygen, eventually leading to decreased tissue oxygenation. The ensuing cerebral hypoxia may explain the persistent coma often seen in patients with diabetic ketoacidosis. Hemolysis may occur, but it is rarely seen at serum phosphorus concentrations >0.5 mg/dL (>0.16 mmol/L).
Hyperphosphatemia occurs when a serum phosphorus concentration is >4.7 mg/dL (>1.52 mmol/L). There are three basic causes for elevated serum phosphorus concentrations:
Decreased renal phosphate excretion
Shift of phosphate from intracellular to extracellular fluid
Increased intake of vitamin D or phosphate-containing products
Elevated phosphate concentrations also may result from reduced PTH secretion, increased body catabolism, and certain malignant conditions (eg, leukemias and lymphomas).
The most common cause of hyperphosphatemia is renal dysfunction, which commonly occurs as the GFR falls below 25 mL/min. CKD results in secondary hyperparathyroidism, which can further reduce renal phosphate elimination. Elevated serum phosphorus concentration increases the risk for deposition of insoluble calcium–phosphate complex in soft tissues (ie, metastatic calcification). This complexation may further reduce the serum concentration of ionized calcium and stimulate a further increase in PTH production and release. A sustained period of high PTH levels leads to excessive bone resorption, which increases the risk of bone fracture.53-57
Hyperphosphatemia can be caused by a shift of phosphate from intracellular to extracellular fluid. This shift of phosphate can result from massive cell break down after administering chemotherapy for leukemia or lymphoma and during rhabdomyolysis and septic shock. In addition, hyperthyroidism can elevate serum phosphorus by directly increasing renal tubular phosphate reabsorption.
Signs and symptoms of hyperphosphatemia commonly result from accompanying hypocalcemia and hyperparathyroidism (see Hypocalcemia section). Renal function may diminish if hyperphosphatemia is left untreated. In the presence of renal dysfunction, phosphate excretion is further reduced, which causes an even greater increase of serum phosphorus concentration and a further decline in serum calcium concentration56,57 (Minicase 4).
A Case of Calcium and Phosphate Disorders in a Patient With Chronic Renal Failure
Michael S., a 72-year-old man, had a 1-week history of nausea, vomiting, and general malaise. His appetite has severely decreased over the past 2 months. He has a longstanding history of uncontrolled hypertension and type 2 diabetes mellitus as well as diabetic nephropathy, retinopathy, and neuropathy.
His physical examination reveals a BP of 160/99 mm Hg, diabetic retinopathic changes with laser scars bilaterally, and diminished sensation bilaterally below the knees. His laboratory values include the following results:
Serum sodium, 146 mEq/L
Potassium, 4.7 mEq/L
Chloride, 104 mEq/L
Total CO2 content, 15 mEq/L
SCr, 3.2 mg/dL (3.1 mg/dL from 1 month ago)
BUN, 92 mg/dL
Random blood glucose, 181 mg/dL
Because of his renal failure, additional laboratory tests were obtained:
Calcium, 7.5 mg/dL
Phosphorus, 9.1 mg/dL
Albumin, 3.3 g/dL
Over the next several days, he reports finger numbness, tingling, and burning of extremities. He also has experienced increasing confusion and fatigue. A neurologic examination is positive for both Chvostek and Trousseau signs. Repeated laboratory tests show substantial changes in serum calcium (6.1 mg/dL) and phosphorus (10.4 mg/dL). His intact serum PTH is 280 pg/mL (10 to 65 pg/mL).
QUESTION: How would you characterize this patient’s calcium and phosphorus disorders?
DISCUSSION: He has three laboratory abnormalities that are related specifically to calcium–phosphate metabolism: (1) hypocalcemia, (2) hyperphosphatemia, and (3) secondary hyperparathyroidism. He is exhibiting classic signs and symptoms of hypocalcemia, such as finger numbness, tingling, burning of extremities, confusion, fatigue, and positive Chvostek and Trousseau signs.
Chronic kidney disease, as seen in this patient, is commonly associated with hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism, and vitamin D deficiency. These calcium–phosphate abnormalities are responsible for the development of renal osteodystrophy. During the early stages of renal failure, renal phosphate excretion begins to decrease. His serum phosphorus concentration was increased, and the total serum calcium concentration became reduced, which stimulated the release of PTH and resulted in secondary hyperparathyroidism. The higher concentration of PTH reduced his renal tubular phosphate reabsorption, thereby increasing its excretion. The hyperparathyroidism helped to maintain his serum phosphorus and calcium concentrations within normal ranges during the early stage of renal failure (Figure 11-3).
As renal function continues to deteriorate (eGFR <30 mL/min), renal tubules cease to respond adequately to the high serum PTH concentration, resulting in hyperphosphatemia. In response to the hypocalcemia that followed, calcium was mobilized from the bone through the action of PTH. However, such a compensatory response was not sufficient because hypocalcemia and hyperphosphatemia continued. The persistent hyperphosphatemia could inhibit the conversion of calcidiol to calcitriol and further reduce the intestinal calcium absorption capacity. Therefore, hypocalcemia was worsened by the presence of hypovitaminosis D, which subsequently stimulated PTH secretion increasing mobilization of calcium from bone. The metabolic acidosis that is common in renal failure also may have contributed to the negative calcium balance in the bone.
This patient was relatively asymptomatic up to this point, primarily because these laboratory abnormalities developed over a long period of time and allowed the body to compensate. In the presence of nausea and vomiting and the lack of appetite, his oral calcium intake was probably reduced substantially, which may have enhanced his malaise. Because calcium is commonly reported as total calcium and not as the free or ionized fraction, his total serum calcium concentration must be corrected for his low serum albumin value. For every 1 g/dL reduction in serum albumin <4 g/dL, 0.8 mg/dL should be added to his serum calcium concentration. Therefore, with his serum albumin concentration of 3.3 g/dL, his initial serum calcium value of 7.5 mg/dL is equivalent to a total calcium concentration of 8.1 mg/dL. He does have true hypocalcemia, although the deficit is mild. It is important to note that his calcium and phosphorus derangements are severe. This patient has demonstrated neurologic signs of hypocalcemia. His EKG should be checked to determine if his cardiac rhythm is affected by hypocalcemia.
Causes of spurious laboratory results
Hemolysis can occur during phlebotomy, which may lead to a falsely elevated serum phosphorus concentration. If the serum is not separated soon after phlebotomy, phosphate may be falsely decreased as it is taken up by the cellular components of blood.
Similar to what may occur to specimens for potassium concentration determination, when blood is allowed to clot with the use of nonheparinized tubes, phosphate may leach out of platelets and result in a falsely elevated concentration. In patients with thrombocytosis, phosphate concentrations should, therefore, be obtained from plasma (ie, heparinized tube) rather than serum (ie, nonheparinized tube) samples.
Serum phosphorus may vary by 1 to 2 mg/dL (0.32 to 0.64 mmol/L) after meals. Meals rich in carbohydrates can reduce serum phosphorus; meals with high phosphate contents, such as dairy products, can increase serum phosphorus. If accurate assessment of the phosphate concentration is necessary, the blood specimen should be obtained from the patient after fasting.
Normal range: 70 to 140 mcg/dL (11 to 22 mmol/L) (men); 80 to 155 mcg/dL (13 to 24 mmol/L) (women) for serum or plasma copper; 20-50 mg/dL for serum ceruloplasmin depending on age and assay used
The relationship between copper homeostasis and human diseases was uncovered in 1912 shortly after Wilson disease was described. In the early 1930s, a link between copper deficiency and anemia was suspected, although the hypothesis was not proven at that time. In the 1970s, the physiologic functions of copper were better understood and its link to various disease states was better appreciated. An official dietary copper recommendation and adequate daily dietary intake was introduced for the first time in 1979. Copper deficiency is now a recognized concern in patients with bariatric surgery and small bowel resection.
Copper plays an integral part in the synthesis and functions of many circulating proteins and enzymes. In addition, copper is an essential factor for the formation of connective tissues, such as the cross-linking of collagen and elastin. Copper also regulates the cellular uptake and physiologic functions with iron.58 In the CNS, copper is necessary for the formation or maintenance of myelin and other phospholipids. Cuproenzymes (copper-dependent enzymes) are crucial in the metabolism of catecholamines. For example, the functions of dopamine hydroxylase and monoamine oxidase are impaired by copper deficiency. Copper also affects the function of tyrosinase in melanin synthesis, which is responsible for the pigmentation of skin, hair, and eyes. Deficiency of tyrosinase results in albinism. Other physiologic functions of copper include thermal regulation, glucose metabolism, blood clotting (eg, factor V function), and protection of cells against oxidative damage.58
The normal adult daily intake of copper, based on a typical American diet, is about 2 to 3 mg. Plant copper is in the inorganic (free ionic) form, whereas meat (animal) copper is in the form of cuproproteins (copper–protein complex). Inorganic copper is absorbed in the upper GI tract (stomach and proximal duodenum) under acidic conditions. Cuproprotein copper is absorbed in the jejunum and ileum. Absorption of copper from the GI tract is a saturable process. The oral bioavailability of copper ranges from 15% to 97% and shows a negative correlation with the amount of copper present in the diet and total body copper status.
Once absorbed, copper is bound to a mucosal copper-binding protein called metallothionein (a sulfur-rich, metal-binding protein present in intestinal mucosa). From this protein, copper is slowly released into the circulation, where it is taken up by the liver and other tissues.58-60 Animal data suggest that the liver serves as the ultimate depot for copper storage. Copper absorption may be reduced by a high intake of zinc (>50 mg elemental zinc/day), ascorbic acid, and dietary fiber. Oral zinc supplementation may induce the synthesis of intestinal metallothionein and form a barrier to copper ion absorption by trapping copper ions in the enterocytes and decreases their oral bioavailability. IV zinc supplementation is not expected to decrease oral copper absorption.
The normal adult body contains approximately 110 mg of copper. The highest tissue copper concentration is found in the muscle and skeletal tissues, followed by liver and brain. Copper in the muscle and skeletal tissues account for about 50% of the total body copper. The rest is distributed in the heart, spleen, kidneys, and blood (erythrocytes and neutrophils).59,60
In the plasma, copper is highly bound (95%) to ceruloplasmin (also known as ferroxidase I), a blue copper protein. This protein contains six to seven copper atoms per molecule. The fraction of plasma copper associated with ceruloplasmin seems to be relatively constant for the same individual. However, a significant interindividual variation exists. The remainder of the plasma copper is bound to albumin and amino acids or is free.58 Copper is eliminated mainly by biliary excretion (average 25 mcg/kg/day), with only 0.5% to 3% of the daily intake in the urine.59
Ceruloplasmin is considered the most reliable indicator of copper status because of its large and relatively stable binding capacity with serum copper. Therefore, when evaluating copper status in the body, it is highly recommended that serum ceruloplasmin concentration should be assessed together with serum copper concentration.60
Although it was thought that copper deficiency is relatively uncommon in humans, more cases have been reported recently in patients after bariatric surgery. Copper deficiency is also an increasingly recognized concern in patients with Crohn disease or short bowel syndrome.61;62Hypocupremia usually occurs with chronic diarrhea or malabsorption syndrome, such as after Roux-en-Y gastric bypass surgery, duodenal switch, and major resection of the small intestine or in low-birth-weight infants fed with cow’s milk (rather than formulas).61-63 Premature infants, who typically have low copper stores, are at a higher risk for developing copper deficiency under these circumstances.
Copper deficiency may occur in patients receiving long-term parenteral nutrition with insufficient trace element supplementation (eg, product shortages). Chronic malabsorption syndromes (eg, celiac disease and ulcerative colitis), protein-wasting enteropathies, short bowel syndrome, and the presence of significant bowel resection or bypass (eg, malabsorptive bariatric surgical procedures such as long-limb Roux-en-Y or jejunoileal bypass) are all potential risk factors resulting in copper deficiency. Individuals on a vegan diet may also be at risk because (1) meat is a major food source of copper and (2) plant sources often have high-fiber content that may interfere with copper absorption.59
Prolonged hypocupremia leads to a syndrome of neutropenia and iron-deficiency anemia, which is correctable with copper.62 The anemia can be normocytic or microcytic and hypochromic. It results mainly from poor iron absorption and ineffective heme incorporation of iron. Neurologic symptoms are another common presentation of copper deficiency and may include gait ataxia, numbness, peripheral neuropathy, and psychosis.62 Copper deficiency can affect any system or organs whose enzymes require copper for proper functioning. As such, copper deficiency may lead to abnormal glucose tolerance, arrhythmias, hypercholesterolemia, atherosclerosis, depressed immune function, defective connective tissue formation, demineralization of bones, and pathologic fractures.
Two well-known genetic defects are associated with impaired copper metabolism in humans. Menkes syndrome (also called kinky-hair syndrome/steely-hair syndrome) is an X-linked disorder that occurs in 1 out of every 50,000 to 100,000 live births. These patients have defective copper absorption and are commonly deceased by the age of 4 years. They have reduced copper concentrations in the blood, liver, and brain.64,65 Most of them are children suffering from slow growth and retardation, defective keratinization and pigmentation of hair, hypothermia, and degenerative changes in the aortic elastin and neurons. Progressive nerve degeneration in the brain results in intellectual deterioration, hypotonia, and seizures. However, anemia and neutropenia, hallmark symptoms of nutritional copper deficiency, are not found in persons with Menkes syndrome. Administration of parenteral copper increases serum copper and ceruloplasmin concentrations but does not have any apparent effect on slowing disease progression.
Wilson disease is an autosomal recessive disease of copper storage. Its frequency is uncertain, but it is believed to be not as common as Menkes syndrome. Wilson disease appears to be associated with altered copper catabolism and excretion of ceruloplasmin copper into the bile. It is associated with elevated urinary copper loss and low plasma ceruloplasmin and low plasma copper concentrations. However, copper deposition occurs in the liver, brain, and cornea. If untreated, significant copper accumulation in these organs eventually leads to irreversible damage such as cirrhosis and neurologic impairment.66
Copper excess, or hypercupremia, is not common in humans and usually occurs with a deliberate attempt to ingest large quantities of copper. The exact amount of copper that results in toxicity is unknown. Acute or long-term ingestion of >15 mg of elemental copper may lead to symptomatic copper poisoning.67 Also, it has been reported that drinking water with 2 to 3 mg/L of copper is associated with hepatotoxicity in infants. Similar to other metallic poisonings, acute copper poisoning leads to nausea, vomiting, intestinal cramps, and diarrhea.67 A larger ingestion can result in shock, hepatic necrosis, intravascular hemolysis, renal impairment, coma, and death. Elevated intrahepatic copper concentrations may be present in patients with primary biliary cirrhosis and biliary atresia.68 Long-term parenteral nutrition (PN) use is also a risk factor for hepatic copper overload due to chronic, unregulated exposure of IV copper through the multitrace element mixture. For patients receiving chronic home parenteral nutrition, it is recommended that serum copper concentration is monitored to prevent copper toxicity.69,70 Chronic cholestasis secondary to parenteral nutrition–associated liver disease has been suggested as the primary cause. Because copper plays an important role in the neurologic system, it has been suggested that copper-induced free radical–induced neurodegeneration may be a contributing factor for Alzheimer disease. At present, there is no known treatment for hypercupremia.
Normal range: 50 to 150 mcg/dL (7.7 to 23 micromol/L) serum or plasma
Next to iron, zinc is the most abundant trace element in the body. It is an essential nutrient that is a constituent of, or a cofactor to, many enzymes. These metalloenzymes participate in the metabolism of carbohydrates, proteins, lipids, and nucleic acids. As such, zinc influences the following processes71:
Tissue growth and repair
Cell membrane stabilization
Bone collagenase activity and collagen turnover
Immune response, especially T-cell–mediated response
Sensory control of food intake
Spermatogenesis and gonadal maturation
Normal testicular function
The normal adult body contains 1.5 to 2.5 g of zinc. Aside from supplementation with zinc capsules, dietary intake is the only source of zinc for humans. Food sources of zinc include meat products, oysters, and legumes. Food-based zinc is largely bound to proteins and released by gastric acid and pancreatic enzymes. Ionic zinc found in zinc supplements is absorbed in the duodenum directly. Foods rich in calcium, dietary fiber, or phytate may interfere with zinc absorption, as can folic acid supplements.
After absorption, zinc is transported from the small intestine to the portal circulation where it binds to proteins such as albumin, transferrin, and other globulins. Circulating zinc is bound mostly to serum proteins; two-thirds are loosely bound to albumin and transthyretin, while one-third is bound tightly to α-2 macroglobulin.53 Only 2% to 3% (3 mg) of zinc is either in free ionic form or bound to amino acids.72,73
Zinc can be found in many organs. Tissues high in zinc include liver, pancreas, spleen, lungs, eyes (retina, iris, cornea, and lens), prostate, skeletal muscle, and bone. Because of their mass, skeletal muscle (60% to 62%) and bone (20% to 28%) have the highest zinc contents among the body tissues.71 Only 2% to 4% of total body zinc is found in the liver. In blood, 85% is in erythrocytes, although each leukocyte contains 25 times the zinc content of an erythrocyte.71
Plasma or serum zinc concentration is a poor indicator of total body zinc store. Because 98% of the total body zinc is present in tissues and end organs, the plasma zinc concentration tends to reflect the continuous shifting from intracellular sources (ie, zinc trafficking). Additionally, metabolic stress, such as infection, acute myocardial infarction, and critical illnesses increase intracellular shifting of zinc to the liver and lower serum zinc concentrations, even when total body zinc is normal. Conversely, plasma zinc concentrations may be normal during starvation or wasting syndromes due to release of zinc from tissues and cells.71 Therefore, serum/plasma zinc concentration alone has little meaning clinically in patients with acute illnesses. It has been suggested that the rate of zinc turnover in the plasma provides better assessment of the body zinc status. This may be achieved by measuring 24-hour zinc loss in body fluids (eg, urine and stool). However, this approach is rarely practical for critically ill patients as renal failure is often present. Alternatively, zinc turnover and mobilization may be determined by adjusting plasma zinc concentrations with serum α-2 macroglobulin and albumin concentrations.72,73 To more accurately assess the body zinc status, others have suggested monitoring the functional indices of zinc, such as erythrocyte alkaline phosphatase, serum superoxide dismutase, and lymphocyte 5′ nucleotidase. However, the clinical validity of these tests remains to be substantiated, especially in patients who are acutely ill.
Zinc undergoes substantial enteropancreatic recirculation and is excreted primarily in pancreatic and intestinal secretions. Diarrhea significantly increases zinc loss. Zinc is also lost dermally through sweat, hair and nail growth, and skin shedding. Except in certain disease states, only 2% of zinc is lost in the urine.
In Western countries, zinc deficiency is rare from dietary insufficiency. Individuals with no acute illnesses whose serum zinc concentrations are <50 mcg/dL (<7.6 μmol/L) are at an increased risk for developing symptomatic zinc deficiency. It also must be emphasized that serum zinc exhibits a negative acute phase response. The presence of proinflammatory cytokines causes an intracellular and intrahepatic influx of zinc from the serum, which would lead to transient hypozincemia. Therefore, serum or plasma zinc concentration alone should not be used to assess zinc status in patients with acute illnesses or any acute inflammatory response. Given the caveats of measuring serum zinc concentrations in certain disease states, response to empirical zinc supplementation may be the only way of diagnosing this deficiency. In the presence of chronic diseases, it is difficult to determine if zinc deficiency is clinical or subclinical because of the reduced protein binding. Conditions leading to deficiency may be divided into five classes (Table 11-12):
Etiologies of Zinc Deficiency
Certain vegetarian diets
Exclusion of trace elements in parenteral nutrition
Short bowel syndrome
Enterocutaneous fistula drainage
Exercise (long-term, strenuous)
Impaired enteropancreatic recycling
Sickle cell disease
Arthritis and other inflammatory diseases
Zinc deficiency is commonly caused by diarrhea and insufficient intake. Patients with increased ostomy output due to GI tract surgery are especially at risk for zinc deficiency. Acrodermatitis enteropathica is an autosomal, recessive disorder involving zinc malabsorption that occurs in infants of Italian, Armenian, and Iranian heritage. It is characterized by severe dermatitis, chronic diarrhea, emotional disturbances, and growth retardation.71 Examples of malabsorption syndromes that may lead to zinc deficiency include Crohn disease, celiac disease, and short bowel syndrome.
Excessive zinc may be lost in the urine (hyperzincuria), as occurs in alcoholism, beta thalassemia, diabetes mellitus, diuretic therapy, nephrotic syndrome, sickle cell anemia, and treatment with parenteral nutrition. Severe or prolonged diarrhea (eg, inflammatory bowel diseases and GI graft versus host disease) may lead to significant zinc loss in the stool. Patients with end-stage liver disease frequently have depleted zinc storage due to decreased functional hepatic cell mass.
Because zinc is involved in a diverse group of enzymes, its deficiency manifests in numerous organs and physiologic systems (Table 11-13). Dysgeusia (lack of taste) and hyposmia (diminished smell acuity) are common. Pica is a pathologic craving for specific food or nonfood substances (eg, geophagia). Chronic zinc deficiency, as occurs in acrodermatitis enteropathica, leads to growth retardation, anemia, hypogonadism, hepatosplenomegaly, and impaired wound healing. Additional signs and symptoms of acrodermatitis enteropathica include diarrhea; vomiting; alopecia; skin lesions in oral, anal, and genital areas; paronychia; nail deformity; emotional lability; photophobia; blepharitis; conjunctivitis; and corneal opacities.
Signs and Symptoms of Zinc Deficiency
Anergy to skin test antigens
Premature or stillborn birth
Decreased basal metabolic rate
Decreased circulating T4 concentration
Decreased lymphocyte count and function
Effect on fetus, infant, or child
Congenital defects of skeleton, lungs, and CNS
Impaired neutrophil function
Impairment and delaying of platelet aggregation
Increased susceptibility to dental caries
Increased susceptibility to infections
Poor wound healing
Short stature in children
Acne and recurrent furunculosis
Defective night vision
T4 = thyroxine.
Zinc is one of the least toxic trace elements. Clinical manifestations of excess zinc, hyperzincemia, occur with chronic, high doses of a zinc supplement. However, patients with Wilson disease who commonly take high doses of zinc rarely show signs of toxicity. This may be explained by the stabilization of serum zinc concentrations during high-dose administration. As much as 12 g of zinc sulfate (>2,700 mg of elemental zinc) taken over 2 days has caused drowsiness, lethargy, and increased serum lipase and amylase concentrations. Nausea, vomiting, and diarrhea also may occur.71
Normal range: Varies depending on assay method, sample (whole blood versus serum), and age. Whole blood method is preferred to detect toxicity. Normal whole blood manganese concentrations range from 4 to 15 mcg/L (72 to 270 nmol/L)
Manganese is an essential trace element that serves as a cofactor for numerous diverse enzymes involved in carbohydrate, protein, and lipid metabolism; protection of cells from free radicals; steroid biosynthesis; and metabolism of biogenic amines.74 Interestingly, manganese deficiency does not affect the functions of most of these enzymes, presumably because magnesium may substitute for manganese in most instances.74 In animals, manganese is required for normal bone growth, lipid metabolism, reproduction, and CNS regulation.75,76
Manganese plays an important role in the normal function of the brain, primarily through its effect on biogenic amine metabolism. This effect may be responsible for the relationship between brain concentrations of manganese and catecholamines.74,75
The manganese content of the adult body is 10 to 20 mg. Manganese homeostasis is regulated through control of its absorption and excretion. Plants are the primary source of food manganese because animal tissues have low contents. Manganese is absorbed from the small intestine by a mechanism similar to that of iron. However, only 3% to 4% of the ingested manganese is absorbed. Dietary iron and phytate may affect manganese absorption.77
Human and animal tissues have low manganese content. Tissues relatively high in manganese are the bone, liver, pancreas, and pituitary gland. Most circulating manganese is loosely bound to the β-1 globulin transmanganin, a transport protein similar to transferrin. With overexposure, excess manganese accumulates in the liver and brain, causing severe neuromuscular signs and symptoms.
Manganese is excreted primarily in biliary and pancreatic secretions. In manganese overload, other GI routes of elimination also may be used. Little manganese is lost in urine.
Because of its relative abundance in plant sources, manganese deficiency is rare among the general population. Deficiency normally occurs after several months of deliberate manganese omission from the diet. Little is known regarding serum manganese concentrations and the accompanying disease states in humans.78 Limited evidence suggests that manganese deficiency may be associated with bone demineralization and poor growth in children, skin rashes, hair depigmentation, decreased serum lipids, depression, and increased premenstrual pain in women.79,80
Manganese is one of the least toxic trace elements. Overexposure primarily occurs from inhalation of manganese compounds (eg, manganese mines).77 Long-term use of parenteral nutrition is a risk factor for hypermanganesemia caused by continued and unregulated exposure. The excess amount accumulates in the liver and brain, resulting in severe neuromuscular manifestations. Patients receiving home parenteral nutrition with trace elements daily for >6 months should have serum manganese concentration monitored.69,70,81-83 Symptoms include encephalopathy and profound neurologic disturbances that mimic Parkinson disease.84-86 These manifestations are not surprising because metabolism of biogenic amines is altered in both manganese excess and Parkinson disease. Other signs and symptoms include anorexia, apathy, headache, erectile dysfunction, and speech disturbances. Inhalation of manganese products may cause manganese pneumonitis.77
Average range: Varies depending on assay method, sample (whole blood versus serum), and age. Concentrations in blood and urine reflect recent selenium intake. Normal whole blood selenium concentrations are typically between 150 and 240 ng/mL, typical normal serum selenium concentration is usually between 70 and 150 ng/mL for patients >1 year
Selenium is a trace element that is naturally present in many foods and available as a dietary supplement. The primary physiologic role of selenium is to serve as an antioxidant, especially via the selenoprotein, glutathione peroxidase, to help protect cells from oxidative damage. In most cases, selenoprotein and glutathione work along with other cellular antioxidant defense mechanisms, such as ascorbate, tocopherol, and superoxide dismutase. Glutathione peroxidase activity is decreased in patients with selenium deficiency. Upon repletion of selenium, glutathione activity is restored.87
Selenium exists in the inorganic form (selenite) and organic form (selenomethionine and selenocysteine). The most common form of selenium in the active site of glutathione peroxidase is selenocysteine, which has independent activity that does not allow it to use hydrogen peroxide as a substrate. Selenomethionine is another common form of selenium in human cells.
The estimated dietary intake of selenium varies geographically due to dietary variance and characteristics of the soil. Food sources of selenium include Brazil nuts, seafoods, organ meats, breads, grains, poultry, and eggs. About 90% of selenium is absorbed as the organic form of selenomethionine in the human body and is available in that form in most dietary supplements. The injectable forms of selenium are selenious acid and sodium selenite.79,88
Dietary selenium deficiency is rare in the United States and Canada and in isolation rarely causes illness. Patients with acute inflammation or uncontrolled chronic illnesses have lower selenium concentrations, likely due to increased oxidative stress associated with their diseases. Critically ill patients have low serum selenium concentration, and the magnitude of deficiency correlates with the severity of illness. Supplementation with large doses of antioxidant cocktail containing selenium has not been shown to improve survival or decreased ICU or hospital length of stay.89,90 Patients undergoing long-term hemodialysis and patients living with human immunodeficiency virus (HIV) are also likely to develop selenium deficiency. For patients undergoing hemodialysis, selenium is removed from the blood. Due to uremia and dietary restrictions, patients may have low dietary intakes that may be supplemented. However, little evidence suggests that supplementation is beneficial in this patient population.91 Patients living with HIV have low levels of selenium due to insufficient intake and malabsorption due to GI symptoms (ie, diarrhea). More evidence is needed to determine whether selenium supplementation can reduce the risk of mortality, hospitalization, and HIV transmission.92
Selenoproteins may help prevent oxidative modification of lipids, thus reducing inflammation and preventing platelet aggregation. However, it is yet to be determined if patients should supplement with selenium as a primary prevention or if it should be used as a tertiary prevention for patients who already have cardiovascular disease. There are some conflicting reports on whether selenium supplementation may increase the risk of advanced prostate cancer and skin cancer in men.93
Inorganic and organic forms of selenium can have similar toxic effects. Tolerable upper intake levels for selenium vary based on age and geographic location. Common symptoms of acute selenium excess include garlic breath odor and a metallic taste in the mouth. For adults, serum selenium concentration >400 mcg could produce symptoms such as hair and nail loss, GI and neurologic symptoms, acute respiratory distress syndrome, tremors, kidney failure, and cardiac failure. Death from selenium toxicity is rare but can occur with excessive intake.88,92 A case report of fatality was associated with a single oral ingestion of 10 g of sodium selenite (96% purity) in a 75-year-old man. The patient presented with cardiovascular collapse, hypoxemic respiratory failure, mild hypokalemia (3.4 mEq/L), and a serum selenium concentration of 5,370 ng/mL.93
Average range: serum chromium 0.3 to 0.9 ng/mL; sample contamination (eg, use of regular blood collection tubes not designed for trace elements) may result in ranges from 2 to 5 ng/mL
The main physiologic role of chromium is as a cofactor for insulin.94 In its organic form, chromium potentiates the action of endogenous and exogenous insulin, presumably by augmenting its adherence to cell membranes.49 The organic form is in the dinicotinic acid–glutathione complex or glucose tolerance factor (GTF).79 Chromium is the metal portion of GTF; with insulin, GTF affects the metabolism of glucose, cholesterol, and triglycerides.94 Therefore, chromium is important for glucose tolerance, glycogen synthesis, amino acid transport, and protein synthesis. Chromium also is involved in the activation of several enzymes
The adult body contains an average of 5 mg of chromium.95 Food sources of chromium include brewer’s yeast, spices, vegetable oils, unrefined sugar, liver, kidneys, beer, meat, dairy products, and wheat germ.95 GTF is present in the diet and can be synthesized from inorganic trivalent chromium (Cr+3) available in food and dietary supplements.50 Chromium is absorbed via a common pathway with zinc; its degree of absorption is inversely related to dietary intake, varying from 0.5% to 2%.79,94
Chromium circulates as free Cr3+, bound to transferrin and other proteins, and as the GTF complex. GTF is the biologically active moiety and is more important than total serum chromium concentration. Trivalent chromium accumulates in the hair, kidneys, skeleton, liver, spleen, lungs, testes, and large intestine. GTF concentrates in insulin-responsive tissues such as the liver.79,94
The metabolism of chromium is not well-understood for several reasons:
Low concentrations in tissues
Difficulty in analyzing chromium in biological fluids and tissue samples
Presence of different chromium forms in food
Homeostasis is controlled by release of chromium from GTF and by dietary absorption. The kidneys are the main site of elimination, where urinary excretion is constant despite variability in the fraction absorbed.94
It is important to stress that the body store of chromium cannot be reliably assessed. Serum or plasma chromium may not be in equilibrium with other pools. As with other trace elements, the risk for developing chromium deficiency increases over time with lack of oral intake and insufficient supply from other sources, such as a trace element-free parenteral nutrition solution.69,70 Marginal deficiencies or defects in use of chromium may be present in elderly patients, patients with diabetes, or patients with atherosclerotic coronary artery disease.95
Hyperglycemia increases urinary losses of chromium. Coupled with marginal intake, a patient with type II diabetes is predisposed to chromium deficiency, which can further impair glucose tolerance.94,96 Finally, multiparous women are at a higher risk than nulliparous women for becoming chromium deficient because, over time, chromium intake may not be adequate to meet fetal needs and maintain the mother’s body store.
The manifestations of chromium deficiency may involve insulin resistance and impaired glucose metabolism. Such manifestations may present clinically in three stages as the deficiency progresses:
Glucose intolerance is present but is masked by a compensatory increase in insulin release.
Impaired glucose tolerance and lipid metabolism are clinically evident.
Marked insulin resistance and symptoms associated with hyperglycemia are evident.
Chromium supplementation has been shown in patients with diabetes to increase insulin sensitivity, improve glucose control, and shorten the QTc interval, suggesting a potential favorable effect on cardiovascular risk. However, currently, no conclusive support demonstrates the benefit of chromium supplementation in patients with diabetes or persons with impaired glucose metabolism.
Chromium deficiency may lead to hypercholesterolemia and become a risk factor for developing atherosclerotic disease. Low chromium tissue concentrations have been associated with increased risk for myocardial infarction and coronary artery disease in both healthy subjects and patients with diabetes, although a cause-and-effect relationship has not been established.96
Chromium has low toxicity with no established specific clinical symptoms or presentations. The clinical significance of a high body store of chromium is unknown. Patients receiving long-term home parenteral nutrition with a standard daily amount of chromium from the multitrace element admixture may have an increase serum chromium concentration; however, the clinical risk is unknown at this point.69 Serum chromium concentrations may be increased in asymptomatic patients with metal-on-metal prosthetics.
Hyponatremia and hypernatremia may be associated with high, normal, or low total body sodium. Hyponatremia may result from abnormal water accumulation in the intravascular space (dilutional hyponatremia), a decline in both extracellular water and sodium, or a reduction in total body sodium with normal water balance. Hypernatremia is most common in patients with either an impaired thirst mechanism (eg, neurohypophyseal or pituitary lesion) or an inability to replace water depleted through normal insensible loss or from renal or GI loss. Neurologic manifestations are signs and symptoms often associated with sodium and water imbalance. The most common symptom of hyponatremia is confusion. However, if sodium continues to fall, seizures, coma, and death may result. Thirst is a common symptom of hypernatremia; decreased urine specific gravity, suggesting less concentrated urine, is often observed.
Hypokalemia and hyperkalemia may indicate either a true or an apparent (due to transcellular shifting) potassium imbalance. Hypokalemia can occur because of excessive loss from the kidneys (diuretics) or GI tract (vomiting or diarrhea). The most serious manifestation involves the cardiovascular system (ie, cardiac arrhythmias). Renal impairment, usually in the presence of high intake, commonly causes hyperkalemia. Like hypokalemia, the most serious clinical manifestations of hyperkalemia involve the cardiovascular system.
Serum chloride concentration may be used as a confirmatory test to identify abnormalities in fluid and acid–base balance. Hypochloremia may be diuretic induced and results from the concurrent loss of sodium and also contraction alkalosis. Signs and symptoms associated with these conditions are related to the abnormalities in fluid or acid–base balance and underlying causes rather than to chloride itself.
Hypomagnesemia usually results from excessive loss from the GI tract (eg, nasogastric suction, biliary loss, ileostomy or chronic diarrhea) or the kidneys (eg, diuresis). Magnesium depletion is usually associated with neuromuscular symptoms such as weakness, muscle fasciculation with tremor, tetany, and increased reflexes. Increased magnesium intake in the presence of renal dysfunction commonly causes hypermagnesemia. Neuromuscular signs and symptoms that are opposite to those caused by hypomagnesemia may be observed.
The most common causes of true hypocalcemia are disorders of vitamin D metabolism and PTH production. Severe hypocalcemia can be a medical emergency and lead to cardiac arrhythmias and tetany, with symptoms primarily involving the neuromuscular system.
The most common causes of hypercalcemia are malignancy and primary hyperparathyroidism. Symptoms often consist of vague GI reports such as nausea, vomiting, abdominal pain, anorexia, constipation, and diarrhea. Severe hypercalcemia can cause acute neurologic changes and possibly cardiac arrhythmias, which can be a medical emergency.
The most common causes of hypophosphatemia are decreased intake and increased renal loss. Although mild hypophosphatemia is usually asymptomatic, severe depletion (<1 mg/dL or <0.32 mmol/L) is typically associated with muscle weakness, rhabdomyolysis, paresthesia, hemolysis, platelet dysfunction, and cardiac and respiratory failure. The most common cause of hyperphosphatemia is renal dysfunction, often with a GFR <25 mL/min. Signs and symptoms, if present, primarily result from the ensuing hypocalcemia and hyperparathyroidism.
Hypocupremia is uncommon in adults but can occur in infants, especially those born prematurely. Also susceptible are infants who have chronic diarrhea or malabsorption syndrome or whose diet consists mostly of milk. Prolonged hypocupremia results in neutropenia and iron-deficiency anemia that is correctable with copper.
Copper excess is not common and may result from a deliberate attempt to ingest large quantities. Similar to other metallic poisonings, acute copper poisoning leads to nausea and vomiting, intestinal cramps, and diarrhea.
Likely candidates for zinc deficiency are infants; rapidly growing adolescents; menstruating, lactating, or pregnant women; persons with low meat intake; institutionalized patients; and patients receiving parenteral nutrition solutions without trace elements for prolonged periods. Because zinc is involved with a diverse group of enzymes, its deficiency manifests in different organs and physiologic systems. Zinc excess develops from chronic, high-dose zinc supplementation. Signs and symptoms include nausea, vomiting, diarrhea, drowsiness, lethargy, and increases in serum lipase and amylase concentrations.
Manganese deficiency can occur after several months of deliberate omission from the diet. Signs and symptoms include weight loss, slow hair and nail growth, color change in hair and beard, transient dermatitis, hypocholesterolemia, and hypotriglyceridemia. Manganese excess primarily occurs through inhalation of manganese compounds (eg, manganese mines). As a result of manganese accumulation, severe neuromuscular manifestations occur, including encephalopathy and profound neurologic disturbances, which mimic Parkinson disease. Inhalation of manganese products may cause manganese pneumonitis.
Chromium deficiency may be found in patients receiving prescribed chronic nutrition regimens that are low in chromium content. Insulin resistance and impaired glucose metabolism are the main manifestations.
1. What does an abnormal serum electrolyte concentration mean?
ANSWER: An isolated abnormal serum electrolyte concentration may not always necessitate immediate treatment because it can be the result of a poor sample (hemolyzed blood sample), wrong timing (during an IV infusion or immediately after hemodialysis), or other confounding factors. Careful assessment of the patient’s existing risk factors, history of illness, and clinical symptoms should be made to correctly interpret a specific laboratory result. Patients with abnormal serum electrolyte concentrations who are also symptomatic, especially with potentially life-threatening clinical presentations such as EKG changes, should be treated promptly. The cause or precipitating factor of the electrolyte abnormality should be identified and corrected, if possible.
2. How should we approach a patient who has an abnormal serum sodium concentration?
ANSWER: Alteration of serum sodium concentration can be precipitated by sodium alone (either excess or deficiency) or abnormal water regulation. It is important to fully assess the patient’s sodium and fluid status, symptoms, physical exam findings, and medical, surgical, and medication history for factors that may precipitate sodium disorders. Because the homeostasis of sodium and water is closely regulated by the kidney, it may be useful to check urine electrolytes and osmolality to help establish the diagnosis and guide clinical management.
3. What are the most common risk factors that can lead to hyperkalemia?
ANSWER: The leading cause of hyperkalemia is renal function impairment, especially acute renal insufficiency and associated metabolic acidosis common in severe acute kidney injury. Two other important causes are drug-induced hyperkalemia (eg, ACE inhibitors, potassium-sparing diuretic) and high dietary intake (especially with CKD).
4. What is the clinical significance of abnormal serum calcium and phosphorus concentrations?
ANSWER: Severe hypocalcemia and hypercalcemia can result in neuromuscular problems. In addition, significant hypercalcemia may cause EKG changes and arrhythmias. Although hyperphosphatemia is not expected to cause any acute problems, severe hypophosphatemia can result in neurologic and CNS manifestations. In the presence of chronic hyperphosphatemia, especially in patients with CKD, the risk is increased for phosphorus to bind with calcium to form insoluble complexes that will result in soft tissue and vascular calcification. There is an increasing amount of evidence to show that such vascular calcification can increase the mortality and morbidity of CKD patients. Concurrent hypercalcemia further increases the serum calcium–phosphate product and exacerbates the calcification process.
5. What is the most common clinical presentation of hypocupremia and what are the causes of copper deficiency?
ANSWER: The most common clinical symptoms associated with hypocupremia are neurologic symptoms, which may present as ataxia, spasticity, muscle weakness, peripheral neuropathy, loss of vision, anemia, and leukopenia. The most common causes include intestinal malabsorption, post-bariatric surgery status, and decreased nutrient consumption.
KanbayM, YilmazS, DincerN, et al.Antidiuretic hormone and serum osmolarity physiology and related outcomes: what is old, what is new, and what is unknown?J Clin Endocrinol Metab. 2019;104(11):5406-5420.PubMed
KanbayM, YilmazS, DincerN, et al.Antidiuretic hormone and serum osmolarity physiology and related outcomes: what is old, what is new, and what is unknown? J Clin Endocrinol Metab. 2019;104(11):5406-5420.PubMed)| false
WiigH, LuftFC, TitzeJM. The interstitium conducts extrarenal storage of sodium and represents a third compartment essential for extracellular volume and blood pressure homeostasis. Acta Physiol (Oxf). 2018;222(3).PubMed
WiigH, LuftFC, TitzeJM. The interstitium conducts extrarenal storage of sodium and represents a third compartment essential for extracellular volume and blood pressure homeostasis. Acta Physiol (Oxf). 2018;222(3).PubMed)| false
DickTB, RainesAA, StinsonJB, et al.Fludrocortisone is effective in the management of tacrolimus-induced hyperkalemia in liver transplant recipients. Transplant Proc. 2011;43(7):2664-2668.PubMed
DickTB, RainesAA, StinsonJB, et al.Fludrocortisone is effective in the management of tacrolimus-induced hyperkalemia in liver transplant recipients. Transplant Proc. 2011;43(7):2664-2668.PubMed)| false
HruskaKA, SlatopolskyE.Disorders of phosphorus, calcium, and magnesium metabolism. In: SchrierRW, GottschalkCW, eds. Diseases of the Kidney. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2607-2660.
HruskaKA, SlatopolskyE.Disorders of phosphorus, calcium, and magnesium metabolism. In: SchrierRW, GottschalkCW, eds. Diseases of the Kidney. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2607-2660.)| false
SatoC, KoyamaH, SatohH, et al.Concentrations of copper and zinc in liver and serum samples in biliary atresia patients at different stages of traditional surgeries. Tohoku J Exp Med. 2005;207(4):271-277.PubMed
SatoC, KoyamaH, SatohH, et al.Concentrations of copper and zinc in liver and serum samples in biliary atresia patients at different stages of traditional surgeries. Tohoku J Exp Med. 2005;207(4):271-277.PubMed)| false
HowardL, AshleyC, LyonD, ShenkinA.Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. Food and Drug Administration formulation. JPEN J Parenter Enteral Nutr. 2007;31(5):388-396.PubMed
HowardL, AshleyC, LyonD, ShenkinA.Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. Food and Drug Administration formulation. JPEN J Parenter Enteral Nutr. 2007;31(5):388-396.PubMed)| false
de HaanKE, de GoeijJJ, van den HamerCJ, et al.Changes in zinc metabolism after burns: observations, explanations, clinical implications. J Trace Elem Electrolytes Health Dis. 1992;6(3):195-201.PubMed
de HaanKE, de GoeijJJ, van den HamerCJ, et al.Changes in zinc metabolism after burns: observations, explanations, clinical implications. J Trace Elem Electrolytes Health Dis. 1992;6(3):195-201.PubMed)| false
HurleyLS. Clinical and experimental aspect of manganese in nutrition. In: PrasadAR, ed. Clinical, Biochemical, and Nutritional Aspects of Trace Elements. New York, NY: Alan R Liss; 1982:369-378.
HurleyLS. Clinical and experimental aspect of manganese in nutrition. In: PrasadAR, ed. Clinical, Biochemical, and Nutritional Aspects of Trace Elements. New York, NY: Alan R Liss; 1982:369-378.)| false
NakamuraM, MiuraA, NagahataT, et al.Low zinc, copper, and manganese intake is associated with depression and anxiety symptoms in the Japanese working population: findings from the Eating Habit and Well-Being Study. Nutrients. 2019;11(4):847.PubMed
NakamuraM, MiuraA, NagahataT, et al.Low zinc, copper, and manganese intake is associated with depression and anxiety symptoms in the Japanese working population: findings from the Eating Habit and Well-Being Study. Nutrients. 2019;11(4):847.PubMed)| false
AbdalianR, SaquiO, FernandesG, AllardJP. Effects of manganese from a commercial multi-trace element supplement in a population sample of Canadian patients on long-term parenteral nutrition. JPEN J Parenter Enteral Nutr. 2013;37(4):538-543.PubMed
AbdalianR, SaquiO, FernandesG, AllardJP. Effects of manganese from a commercial multi-trace element supplement in a population sample of Canadian patients on long-term parenteral nutrition. JPEN J Parenter Enteral Nutr. 2013;37(4):538-543.PubMed)| false
ManzanaresW, LemieuxM, ElkeG, et al.High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis. Crit Care. 2016;20(1):356.PubMed
ManzanaresW, LemieuxM, ElkeG, et al.High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis. Crit Care. 2016;20(1):356.PubMed)| false
GudivadaKK, KumarA, ShariffM, et al.Antioxidant micronutrient supplementation in critically ill adults: a systematic review with meta-analysis and trial sequential analysis. Clin Nutr. 2020:S0261-5614(20)30348-4.
GudivadaKK, KumarA, ShariffM, et al.Antioxidant micronutrient supplementation in critically ill adults: a systematic review with meta-analysis and trial sequential analysis. Clin Nutr. 2020:S0261-5614(20)30348-4.)| false
Companion to iron enzyme cofactor, Hgb synthesis, collagen and elastin synthesis, metabolism of many neurotransmitters, energy generation, regulation of plasma lipid levels, cell protection against oxidative damage
One-third in liver and brain; one-third in muscles; one-third in heart, spleen, kidneys, and blood (erythrocytes and neutrophils)
95% of circulating copper is protein bound as ceruloplasmin
Mainly by biliary excretion; only 0.5%–3% of daily intake found in urine
Major causes of…
Deliberate ingestion of large amounts (>15 mg of elemental copper); Wilson disease
Uncommon in humans
Associated signs and symptoms
Nausea, vomiting, intestinal cramps, diarrhea
Larger ingestions lead to shock, hepatic necrosis, intravascular hemolysis, renal impairment, coma, and death