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The Metabolic Alkaloses: Etiology on the Basis of ECF Volume Status
The generation, maintenance, and resolution of “classic” examples of metabolic alkalosis in each ECF volume status category are described below.
ECF Volume Contracted
Classic Example: Gastric Alkalosis.
Generation.
Gastric fluid osmolality is about 300 mosm/L with a [Cl−] of about 150 meq/L and total cations of about 150 meq/L. The [H+] typically varies between 40 and 140 meq/L, [K+] varies between 10 and 15 meq/L, and [Na+] makes up the balance (37). Secretion of HCl (via gastric type H+/K+ ATPase) into the gastric lumen generates equimolar addition of HCO3 to the ECF. Normally, gastric HCl secretion does not produce metabolic alkalosis because the acid is not lost from the body. The HCl leaves the stomach and enters the small bowel, where H+ is neutralized by HCO3− mainly secreted by the pancreas (with a smaller component from bile and intestinal epithelium). This generates CO2 and water. The secretion of HCO3− adds H+ to the body fluids. Because the quantity of HCO3− secreted into the small bowel equals the quantity of H+ delivered from the stomach, these two processes neutralize one another. However, removal of the gastric HCl from the body, by vomiting or tube suction, prevents the HCl from reaching the small bowel. Consequently, HCO3− is not secreted into the intestinal lumen so that a gastric-derived HCO3− bolus is added to the ECF and an equal quantity of Cl− is removed from the body. Later in the development of gastric alkalosis, a K+/H+ cell shift also generates additional HCO3− (described below).
Maintenance.
Initially, much of the HCO3− added to the ECF (after vomiting or gastric suction) is filtered and excreted by the kidneys largely as NaHCO3. The loss of gastric fluid combines with kidney loss of NaHCO3 and fluid to generate ECF volume contraction: GFR falls and kidney salt and fluid retention are stimulated. Distal delivery of Na+ and HCO3−, linked with secondary hyperaldosteronism, increases the fraction of HCO3− excreted as KHCO3 (40). Hypokalemia shifts K+ out of, and H+ into, cells generating ECF HCO3− (21,22). The resulting intracellular acidification of kidney tubule cells stimulates HCO3− reclamation and generation. Hypokalemia also reduces pendrin activity and type B intercalated cell density, which further limits HCO3− secretion (30,31).
ECF contraction generates proximal and distal Na+ reabsorption and HCO3− reclamation. Distally, Na+ reabsorption increases H+ and K+ secretion. K+ depletion also increases H+ secretion by type A intercalated cells via both H+ ATPase and H/K ATPase pumps (Figures 3 and 4), and increases kidney NH3 generation and excretion (38,39).
During the maintenance phase, the urine electrolyte pattern fluctuates. Generally, filtered Na+, K+, HCO3−, Cl−, and water are avidly reabsorbed, generating concentrated, electrolyte-poor, and relatively acid (denoted as “paradoxical aciduria” because metabolic alkalosis exists) urine. However, intermittently (for example, immediately after loss of a large bolus of gastric fluid), the serum [HCO3−] acutely increases, and for a period of time, the larger load of filtered HCO3− cannot be completely reclaimed despite the multiple stimulatory factors described previously. When this occurs, the urine [HCO3−], [Na+], [K+], and pH all temporarily increase. Subsequently, the serum [HCO3−] declines, the ECF volume contracts further, and filtered NaHCO3 is completely reclaimed. Urine electrolyte concentrations and pH again fall. However, it is important to note that throughout these cyclic variations, the urine [Cl−] remains low. Thus, a low urine [Cl−] (<20 meq/L) generally indicates the kidney’s ongoing response to reduced ECF volume or intra-arterial blood volume.
Resolution.
The factors responsible for kidney HCO3− retention are reversed by adequate ECF volume expansion (NaCl infusion) and KCl repletion. Adequate restoration of ECF volume is signified by rising urine [Cl−] and the development of a NaHCO3 diuresis. K+ replacement moves K+ into, and H+ out of, cells into the ECF, simultaneously reducing the [HCO3−] and increasing intracellular pH. The urine electrolyte profiles discussed above presume relatively intact kidney tubule function and the absence of diuretic activity.
The term “contraction alkalosis” has been used to describe several different disorders in which the ECF “contracts” around a relatively fixed quantity of HCO3−. Although gastric alkalosis is an ECF volume-“contracted” condition and the ECF contraction contributes importantly to both its pathogenesis and maintenance, the major cause of the blood [HCO3−] increase is not shrinkage of the ECF per se, but rather generation of HCO3− owing to gastric HCl loss and cellular H+-K+ shifts (21–23,40). Conversely, although expansion of the ECF with NaCl does dilute the ECF [HCO3−] to a small degree, its correcting action in these patients is mainly a result of kidney HCO3− excretion.
Reducing or stopping the loss of gastric HCl is of course critical for reversing the process at its initiation point. However, if the gastric fluid losses cannot be stopped, then reducing the gastric fluid [HCl] concentration with an H2 blocker or proton pump inhibitor can be helpful (41).
Table 2 lists the most common forms of ECF volume-contracted metabolic alkalosis. The urine [Cl−] is typically reduced to <20 meq/L.
ECF Volume Expanded
Classic Example: Primary Mineralocorticoid Excess Syndromes.
Primary hyperaldosteronism is a condition of autonomous, or inappropriately upregulated, aldosterone secretion. This generates ECF volume expansion, hypertension, hypokalemia, and metabolic alkalosis. A unilateral adrenal adenoma secreting aldosterone is the prototypical cause of this disorder, but many conditions can mimic the electrolyte and acid-base pathophysiology of primary hyperaldosteronism (Table 2).
ECF Volume Regulation of Renin and Aldosterone (Normal Physiology).
The reabsorption of Na+ in late distal tubules/collecting ducts is mainly accomplished by principal cells (Figure 4) through ENaC pores in the luminal membranes. When these pores are open, the electrochemical gradient favors reabsorption of Na+. This generates a lumen negative electrical potential (−40 mv) that drives both chloride reabsorption and secretion of K+ and H+.
ECF volume contraction in normal individuals reduces the GFR and sharply increases the reabsorption of NaCl and NaHCO3 in the proximal tubules. Volume contraction also generates secondary hyperaldosteronism (high aldosterone activity driven by high renin and angiotensin II activity). The result of these coordinated actions is that the potent aldosterone-driven stimulus to reabsorb Na+ in the distal/collecting tubules is coordinated with increased proximal reabsorption, which sharply reduces distal salt and water delivery. Consequently, reduced Na+ delivery to aldosterone-sensitive sites blunts the magnitude of Na+ reabsorption and the indirectly linked secretion of K+ and H+. The opposite occurs in response to ECF volume expansion in normal individuals—the GFR increases, proximal salt and water reabsorption fall, and generous distal salt and water delivery ensues. Simultaneously, renin angiotensin II and aldosterone levels fall. Now despite generous distal salt and water delivery, low aldosterone levels downmodulate distal Na+ reabsorption, and indirectly linked K+ and H+ secretion. This describes the normal reciprocal physiologic balance that exists between the magnitude of distal delivery of salt and water and neuro-hormonal stimulation of distal Na+ reabsorption and K+ and H+ secretion. This exquisite reciprocal balance is disrupted by autonomous aldosterone secretion (12,42).
Generation.
Autonomous hyperaldosteronism increases distal Na+ reabsorption, expanding the ECF. This expansion raises the GFR and reduces proximal tubule salt and water reabsorption. Generous distal salt and water delivery ensue. This results in inappropriately high aldosterone activity combining with generous distal tubule salt and water delivery. This combination represents pathophysiology and high rates of Na+ reabsorption, and indirectly linked K+ and H+ secretion ensue. Excretion of K+ and H+ exceeds physiologic requirements, generating hypokalemia and metabolic alkalosis. The development of hypokalemia and K+ depletion contribute importantly to HCO3− generation when K+ shifts out of cells in exchange for H+ (22), and kidney H+ secretion and ammonia excretion increases. Additionally, hypokalemia increases proximal tubule HCO3− reclaimation and H+/K+ ATPase activity in type A intercalated cells (25,27).
Maintenance Phase.
Usually, expansion of the ECF reduces proximal salt reabsorption and HCO3− reclamation and simultaneously reduces renin, angiotensin II, and aldosterone levels. Consequently, distal Na+ reabsorption and K+ and H+ secretion remain modest despite high delivery rates. However, when autonomous aldosterone secretion combines with generous distal salt delivery, inappropriately high levels of distal Na+ reabsorption and K+ and H+ excretion develop. As hypokalemia and K+ depletion ensue, they contribute importantly to both additional HCO3− generation and kidney HCO3− reclamation via systemic K+/H+ cell shifts and acidification of kidney tubule cells. Hypokalemia also increases H+/K+-ATPase activity in type A intercalated cells (Figures 4 and 5) (25,27). Furthermore, aldosterone also increases salt reabsorption via a sequence of pendrin-related events (Figure 5) (28). During the maintenance phase of autonomous hyperaldosteronism, the urine electrolytes reflect the patient’s salt intake. Thus, the urine [Cl−] will generally be >20 meq/L.
Recovery Phase.
Successful resection of an adrenal aldosterone secreting adenoma generally reverses the entire syndrome. However, if hypertension has existed for a long period of time, it may persist because of structural vascular pathology. In lieu of surgery, drugs that block the action of aldosterone can be very helpful. The physical and biochemical manifestations of primary hyperaldosteronism can also be ameliorated by ingestion of a very-low-salt diet, which reduces distal salt delivery, blunting H+ and K+ loss. Conversely, the physical findings and electrolyte abnormalities are exacerbated by a high-salt diet (42,43). Analagously, other mineralocorticoid excess syndromes and mineralocorticoid excess-like syndromes can sometimes be reversed or cured at their source and/or treated by blocking downstream pathophysiology.
ECF Volume Contracted: Diuretic and Diuretic-Like Etiologies
Classic Example: Thiazide and/or Loop Diuretics.
Thiazide and/or loop diuretics very frequently generate hypokalemia and metabolic alkalosis. Despite development of a relatively contracted ECF, or effective arterial blood volume, the generation and maintenance mechanisms of this condition has many similarities to the ECF volume-expanded condition of primary hyperaldosteronism (42). That is because increased distal salt and volume delivery (due to the diuretics) combine with activation of the renin angiotensin II-aldosterone axis.
Generation.
Inhibition of the Na/K/2Cl cotransporter (NKCC2) in the thick limb of Henle by loop diuretics and/or inhibition of the neutral Na/Cl cotransporter (NCC) in the diluting segment by thiazide diuretics increases NaCl and volume delivery to more distal sites. Diuretics also generally increase renin, angiotensin II, and aldosterone levels, generating a state of secondary hyperaldosteronism. In the absence of diuretics, secondary hyperaldosteronism is typically associated with reduced distal salt and volume delivery, which limits the magnitude of distal Na+ reabsorption (and thereby H+ and K+ secretion). However, diuretics generate a state of secondary hyperaldosteronism linked with generous distal tubule Na+ and volume delivery. Therefore, enhanced distal Na+ reabsorption via principal cell ENaCs occurs together with generous distal Na+ and volume delivery, accelerating distal H+ and K+ secretion and generating metabolic alkalosis and hypokalemia. Hypokalemia also generates additional ECF HCO3− via cellular H+/K+ exchange, which also stimulates distal H+ secretion. During periods of diuretic activity, urine [Na+] and [Cl−] are both high. However, diuretic action is generally intermittent, and periods of diuretic activity cycle with periods of inactivity and recovery. During the “off-diuretic” phases, avid kidney salt reabsorption markedly reduces distal NaCl delivery, limiting principal cell Na+ reabsorption and distal K+ and H+ secretion. Now, urine [Cl−] and [Na+] fall to low levels, reflecting the relative ECF-contracted state. Thus, the urine [Cl−] and [Na+] cycle up and down depending on the level of diuretic activity. In contrast, diuretic-mimicking disorders such as Bartter and Gitelman syndromes are characterized by persistent, high urine [Cl−] because they never develop an “off-diuretic-like” period.
Maintenance.
Again, many similarities to the maintenance mechanisms described for primary hyperaldosteronism exist. Hypokalemia increases both proximal and distal tubule H+ and NH4+ secretion. ECF and/or effective intra-arterial volume is reduced, generating a neurohormonal cascade that increases proximal tubule NaCl and HCO3− reclamation. Periods of diuretic activity deliver salt and volume to distal segments that are responding to hyperaldosteronism. These generation and maintenance phases cycle as diuretic activity waxes and wanes.
Recovery Phase.
Stopping the diuretic markedly reduces distal delivery of salt and volume so that HCO3− generation ceases. However, metabolic alkalosis will not resolve unless potent stimuli that accelerate proximal and distal salt reabsorption can be reduced or eliminated. Therefore, if diuretics were initiated to treat avid salt retention generated by heart failure or cirrhosis, the metabolic alkalosis generally persists until the underlying disorder can be ameliorated. Reversing hypokalemia and K+ depletion is also important. If the clinical situation mandates continuing diuretics despite severe metabolic alkalosis, the addition of potassium sparing (triamterene, spironolactone, etc.) or “acidifying” (acetazolamide) diuretics can be helpful. Note, however, that acetazolamide often generates marked K+ wasting, so aggressive K+ supplementation is generally required (44).
All three types of intercalated cells located in the distal tubule/collecting ducts not only play a major role in acid/base regulation, but also participate in volume regulation and NaCl balance (32,33). These cells may be especially important in moderating the development of metabolic alkalosis in patients receiving thiazide diuretics (34) (Figure 5).
Diagnostic Approach.
When the cause of metabolic alkalosis is not readily apparent from the history and physical examination, then it is very helpful to categorize the disorder on the basis of the patient’s kidney function and volume status. If the GFR is markedly reduced and major acidic gastrointestinal fluid losses do not exist, a source of exogenous bicarbonate loading should be sought. If the GFR is not markedly reduced, then carefully assess volume status with history, physical examination, and a spot urine [Cl−] measurement. A urine [Cl−] <20 meq/L is consistent with a reduced ECF or effective intra-arterial volume, whereas a urine [Cl−] >20 meq/L suggests an expanded state. Consider the diagnoses in Table 2. However, recognize that diuretic-generated metabolic alkaloses are characterized by cyclic changes in urine [Cl−] as the diuretic effect waxes and wanes. In general, widely varying urine [Cl−] changes indicate diuretic use (which some patients may deny).
Metabolic alkalosis is a very common disorder. This brief review provides a diagnostic and therapeutic framework using an ECF volume-oriented physiologic approach to the generation, maintenance, and resolution of this disorder. Space limitations preclude in-depth discussion of many fascinating clinical metabolic alkalosis syndromes and a number of recent physiologic and pathophysiologic discoveries that enhance our understanding of this disorder.