Metabolic Alkalosis

Chloride-responsive alkalosis

Chloride-resistant alkalosis

Gastrointestinal (GI)and renal-associated

Hypertension-associated

Vomiting

Primary aldosteronism

Nasogastric suction

11β-hydroxysteroid dehydrogenase type 2 deficiency

Congenital chloride diarrhea

Licorice, chewing tobacco, carbenoxolone

Villous adenoma

Fludrocortisone administration

Posthypercapnia

Cushing syndrome

Contraction alkalosis^a

Glucocorticoid-remediable aldosteronism

Cystic fibrosis

Hyperreninism and hyperaldosteronism (malignant and renovascular hypertension, renin-secreting tumors)

Severe K⁺ deficiency

Liddle syndrome

Milk-alkali syndrome

Normotension-associated

Gastrocystoplasty

Bartter syndrome

Zollinger–Ellison syndrome

Gitelman syndrome

Drug-associated

Others

Loop diuretics

Hypercalcemia

Thiazide diuretics

Hypoparathyroidism

Poorly reabsorbable anions (carbenicillin, penicillin, phosphate, sulfate)

Post-feeding alkalosis

NaHCO₃ (baking soda)

Sodium citrate, lactate, gluconate, acetate

Antacids

Transfusions

^aThe term contraction alkalosis should not be used routinely since it implies that serum [HCO₃ ⁻] increases because of loss of water. This increase in serum [HCO₃ ⁻] alone does not generate metabolic alkalosis, but contraction (volume depletion) does maintain alkalosis

Maintenance Phase

Following generation, persistence of metabolic alkalosis is maintained by volume depletion (Cl⁻-responsive), Cl⁻ deficiency, K⁺ deficiency, low glomerular filtration rate (GFR), or excess mineralocorticoid activity.

Cl⁻ depletion sustains metabolic alkalosis by the following mechanisms (Fig. 31.1):

Fig. 31.1

Factors that generate and maintain metabolic alkalosis

Cl⁻ depletion inhibits K⁺ reabsorption in the thick ascending limb of Henle’s loop (TALH) via Na/K/2Cl cotransporter

Along with K⁺, Na⁺ reabsorption is also impaired in the TALH. This causes more delivery of Na⁺ to the cortical collecting duct (CCD), where it is reabsorbed via the luminal epithelial Na⁺ channel (ENaC). Reabsorption of Na creates a negative lumen potential, resulting in K⁺ and H⁺ secretion

Cl⁻ depletion causes decreased delivery of Cl⁻ to the CCD where HCO₃ ⁻ secretion is reduced via apical Cl/HCO₃ exchanger located in the intercalated type B cell. Thus, Cl⁻ depletion maintains metabolic alkalosis by causing hypokalemia and hyperbicarbonatemia

K⁺ depletion maintains metabolic alkalosis by the following mechanisms (Fig. 31.1):

A decrease in intracellular pH due to movement of H⁺ into the cell to replace K⁺ loss

An increase in HCO₃ ⁻ reabsorption by enhanced activities of luminal Na/H-ATPase and basolateral Na/HCO₃ cotransporters in the proximal tubule

An increase in distal tubule acidification by activating H-ATPase in response to increased production of NH₃

A decrease in Na/K/2Cl cotransporter activity due to Cl⁻ depletion in the TALH

Reduction of GFR by both K⁺ and Cl⁻ depletion

Recovery Phase

Correction of Cl⁻, K⁺, and treatment of underlying cause improves metabolic alkalosis.

Figure 31.1 summarizes the mechanisms for generation and maintenance of metabolic alkalosis. Cl⁻ loss with Na⁺ induces volume contraction. Also, Cl⁻ depletion causes K⁺ loss. Therefore, NaCl administration corrects certain cases of metabolic alkalosis. Mineralocorticoid excess stimulates Na⁺ reabsorption and, in turn, promotes K⁺ and H⁺ secretion. Volume status is variable (↑ in primary aldosteronisma, and ↓ in Gitelman syndrome).

Respiratory Response to Metabolic Alkalosis

An increase in pCO₂ due to hypoventilation is a normal response to metabolic alkalosis, so that extremely dangerous levels of blood pH are avoided. On average, pCO₂ increases by 0.7 mmHg (above normal pCO₂ of 40 mmHg) for each mEq/L increase in serum [HCO₃ ⁻] (above normal [HCO₃ ⁻] of 24 mEq/L). The following example shows the appropriate respiratory response to an increase in pCO₂ in metabolic alkalosis.

Example

$\begin{matrix} {} & \underline{\text{pH}} & [\underline{\text{HC}{{\text{O}}_{\text{3}}}^{-}}] & \underline{\text{pC}{{\text{O}}_{\text{2}}}}\\ \text{Normal}: & \text{7}.\text{4}0 & \text{24}\ \text{mEq/L} & \text{4}0\ \text{mmHg}\\ \text{Patient}: & \text{7}.\text{47} & \text{34 mEq/L} & ?\\\end{matrix}$

$\begin{aligned}& \Delta \text{HC}{{\text{O}}_{\text{3}}}^{-}=\text{34}-\text{24}=\text{1}0 \\& \text{Expected}\ \text{pC}{{\text{O}}_{\text{2}}}=\text{1}0\times 0.\text{7}=\text{7} \\& \text{4}0+\text{7}=\text{47} \\ \end{aligned}$

Classification

Clinically, metabolic alkalosis is divided into:

Chloride (saline)-responsive alkalosis

Chloride (saline)-resistant alkalosis

Causes

The most important causes of metabolic alkalosis are shown in Table 31.1.

Pathophysiology

For simplicity, the pathophysiology of metabolic alkalosis is discussed in selective conditions and under two major mechanisms: renal and gastrointestinal (GI).

Renal Mechanisms

Renal Transport Mechanisms

Since retention of HCO₃ ⁻ and secretion of H⁺ are responsible for development of metabolic alkalosis, it is important to recall the normal cellular mechanisms involved in their renal handling (Chap. 26). Disturbances in these transport mechanisms cause metabolic alkalosis by retention of HCO₃ ⁻ and secretion of H⁺. Table 31.2 summarizes the transport mechanisms and their modifiers for HCO₃ ⁻ reabsorption and sustenance of metabolic alkalosis.

Table 31.2

Renal mechanisms for increased HCO₃ ⁻ reabsorption

Tubule	Transporter	Mechanism for HCO₃ ⁻ reabsorption
PT	Na/H-ATPase	↓ K⁺ stimulates H⁺ secretion
	H-ATPase	↓ K⁺ stimulates H⁺ secretion
TALH	Na/K/2Cl cotransporter	(1) ↑ Delivery of NaCl to CCD, resulting in ↑ Na⁺ reabsorption with subsequent ↑ K⁺ and H⁺ secretion due to loop diuretic-inhibition of cotransporter
		(2) Bartter syndrome due to mutation in cotransporter
		(3) ↓ K⁺ inhibition of cotransporter
		(4) Cl⁻ depletion by above mechanisms
DCT	Na/Cl cotransporter	(1) ↑ Delivery of NaCl to CCD, resulting in ↑ Na⁺ reabsorption with subsequent ↑ K⁺ and H⁺ secretion due to thiazide diuretic-inhibition of cotransporter
		(2) ↓ K⁺ inhibition of cotransporter
		(3) Gitelman syndrome due to mutation in cotransporter
CCD
Principal cell	ENaC	Liddle syndrome due to mutation in ENaC
β-intercalated cell	Pendrin (Cl/HCO₃ exchanger)	(1) ↓ K⁺ upregulates pendrin in metabolic alkalosis
		(2) Loss-of-function mutation of pendrin aggravates metabolic alkalosis
		(3) Thiazide therapy aggravates metabolic alkalosis in pendred syndrome
α-intercalated cell	H-ATPase	↑ H⁺ secretion in response to ↑ Na⁺ delivery to ENaC due to loop diuretics, Bartter syndrome, and Gitelman syndrome
	H/K-ATPase	Same as above

PT proximal tubule, TALH thick ascending limb of Henle’s loop, DCT distal convoluted tubule, CCD cortical collecting duct, ↑ increase, ↓ decrease

Genetic Mechanisms (See Chap. 15 for Details)

Bartter syndrome: Caused by genetic defects in the apical or basolateral membrane transport mechanisms of the thick ascending limb of Henle’s loop
Behaves similar to a patient on loop diuretics
Generation phase is due to increased loss of H⁺ in the urine
Maintenance phase is due to K⁺ and Cl⁻ loss, volume depletion, and secondary hyperaldosteronism
Characterized by hypokalemia, metabolic alkalosis, and normal blood pressure or at times hypotension
Treatment includes chronic supplementation of K⁺. Spironolactone, amiloride, ACE-inhibitors, and nonsteroidal anti-inflammatory drugs have been tried with variable results
Gitelman syndrome: Caused by mutations in distal tubule Na/Cl cotransporter
Behaves similar to a patient on thiazide diuretics
Generation and maintenance phases are similar to those of Bartter syndrome
Characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and normal blood pressure
Treatment includes lifelong liberal salt intake, K⁺ and Mg²⁺ supplementation (KCl, MgCl₂) as well as K⁺-sparing diuretics (spironolactone, amiloride, aldosterone-receptor blocker)
Liddle syndrome: An autosomal dominant disorder, caused by mutations in the subunits of ENaC
Generation of metabolic alkalosis is caused by increased K⁺ and H⁺ loss, and maintenance is due to hypokalemia and hypochloremia
Aldosterone levels are low because of Na⁺ reabsorption and volume expansion
Characterized by hypokalemia, metabolic alkalosis, and hypertension
Hypertension does not respond to spironolactone. Amiloride is the drug of choice
Glucocorticoid-remediable hyperaldosteronism (GRA): Also called familial hyperaldosteronism type 1
Caused by fusion of two enzymes: aldosterone synthase and 11β-hydroxylase
Patients present with hypokalemia, metabolic alkalosis, and hypertension
Administration of glucocorticoid improves hypokalemia, metabolic alkalosis, and hypertension
Apparent mineralocorticoid excess syndrome (AME): Cortisol is not converted into inactive cortisone by the mutated enzyme 11β-hydroxysteroid dehydrogenase type 2
Patients present with hypokalemia, metabolic alkalosis, and hypertension
Treatment with spironolactone or amiloride improves hypokalemia, alkalosis, and hypertension
AME can also be acquired. Ingestion of licorice, chewing tobacco, bioflavonoids, or carbenoxolone can cause AME. These agents contain glycyrrhetinic acid, which is a competitive inhibitor of 11β-hydroxysteroid dehydrogenase type 2
Clinical manifestations are similar to the genetic type of AME

Acquired Causes

Primary aldosteronism: Caused by autonomous secretion of aldosterone by adrenal adenoma or hyperplasia of the adrenal gland
Alkalosis is generated by K⁺ and H⁺ loss due to increased delivery of NaCl to the distal nephron
Hypokalemia, hypochloremia, and persistent aldosterone activity maintain metabolic alkalosis
Characterized by hypokalemia, hypertension, and metabolic alkalosis
Removal of adenoma or treatment with K⁺-sparing diuretics (spironolactone) corrects metabolic abnormalities and hypertension
Malignant hypertension: A disorder of high renin-AII-aldosterone activity
Characterized by hypertension, hypokalemia, and metabolic alkalosis
Renal artery stenosis: Clinically similar to malignant hypertension with high renin-AII-aldosterone activity
Patients present with severe hypokalemia, hypertension, and metabolic alkalosis
Removal of stenosis by stents or surgery improves hypokalemia, metabolic alkalosis, and hypertension
Drugs other than diuretics: Exogenous alkali causes metabolic alkalosis only when the subject is hypovolemic with compromised renal function. Dialysis patients develop metabolic alkalosis due to the use of HCO₃ ⁻ in the dialysate bath
One study showed that daily ingestion of 140 g (1,667 mEq) of baking soda (NaHCO₃) for up to 3 weeks raises serum [HCO₃ ⁻] and causes metabolic alkalosis
Metabolic alkalosis resolves following discontinuation of NaHCO₃ ⁻ provided hypokalemia and volume depletion are absent; however, it continues once renal failure develops
Delivery of nonreabsorbable anions such as sodium penicillin to the distal tubule promotes K⁺ secretion, resulting in hypokalemia and metabolic alkalosis
Diuretics: Diuretics other than acetazolamide and K⁺-sparing diuretics generate metabolic alkalosis
Mechanisms include:

1.

Relative volume depletion by loss of NaCl

2.

Hypokalemia

3.

Hypochloremia

4.

Increased net acid secretion due to hyperaldosteronism (most important)
Note that urine Cl⁻ may be variable; high when diuretic action is maximum and low after 24 h of diuretic ingestion
Posthypercapnic metabolic alkalosis: This condition results in patients with chronic respiratory acidosis with high HCO₃ ⁻ and pCO₂
When such patients require intubation, and pCO₂ is acutely lowered, blood pH goes up without a change in serum [HCO₃ ⁻]
Since the kidneys cannot excrete HCO₃ ⁻ immediately, the pH should be corrected by any one or all of the following treatments:

1.

Increase pCO₂

2.

Lower serum [HCO₃ ⁻] by administration of normal saline and/or acetazolamide

3.

To lower pH acutely, some physicians use HCl administration, but this option is rarely required

Table 31.3 summarizes various laboratory tests that are useful in the differential diagnosis of metabolic alkalosis.

Table 31.3

Serum renin, aldosterone (Aldo), urine electrolytes, and pH in metabolic alkalosis

Condition	Renin	Aldo	Na⁺ (mEq/L)	K⁺ (mEq/L)	Cl⁻ (mEq/L)	HCO₃ ⁻ (mEq/L)	pH	Volume status
Bartter syndrome	↑	↑	↑	↑	↑	↓	↓ (acid)	↓
Gitelman syndrome	↑	↑	↑	↑	↑	↓	↓	↓
Liddle syndrome	↓	↓	N↑	↑	↑	↑	↓	↑
Licorice	↓	↓	↑	↑	↑	↓	↓	↑
AME	↓	↓	↑	↑	↑	↓	↓	↑
GRA	↓	↑	↑	↑	↑	↓	↓	↑
Primary aldosteronism	↓	↑	↑	↑	↑	↓	↓	↑
Malignant and renovascular HTN	↑	↑	↑	↑	↑	↓	↓	↓
Diuretics (loop and thiazide)	↑	↑	↓↑^a	↑	↑	↓	↓	↓

AME apparent mineralocorticoid excess syndrome, GRA glucocorticoid-remediable hyperaldosteronism, N normal, ↑ increase, ↓ decrease

^aVariable

GI Mechanisms

Vomiting and Nasogastric Suction

This is one of the most common causes of metabolic alkalosis besides diuretic use.

On average, gastric fluid contains the following electrolytes in mEq/L:

$\begin{aligned}& {{\text{H}}^{+}}\,=\text{1}00 \\& \text{C}{{\text{l}}^{-}}=\text{12}0 \\& \text{N}{{\text{a}}^{+}}=\text{15} \\& {{\text{K}}^{+}}=\text{1}0 \\& \text{Volume}=\text{1L} \\ \end{aligned}$

Generation of alkalosis starts with loss of HCl, resulting in addition of HCO₃ ⁻ and loss of Cl⁻
Glomerular filtration of Cl⁻ is reduced
Initially, the kidney gets rid of HCO₃ ⁻, which obligates Na⁺ and K⁺ excretion
Because of bicarbonaturia, the urine pH is alkaline (> 6.5)
If vomiting or gastric suction continues, loss of Na⁺ and water results in volume depletion. Na⁺ and HCO₃ ⁻ reabsorption increases, and their excretion is decreased
Na⁺ reabsorption is accompanied by secretion of H⁺ and K⁺, resulting in net acid excretion, and urine pH becomes acidic (Table 31.4)

Table 31.4

Urinary electrolyte (mEq/L) pattern and pH in vomiting

Vomiting

Na⁺

K⁺

Cl⁻

HCO₃ ⁻

pH

Early (1–2 days)

↑

↑

↓

↑

↑

Late (> 2 days)

↓

↑

↓

↓

↓
Metabolic alkalosis is, therefore, maintained by hypokalemia and volume depletion
Table 31.4 shows urinary electrolyte pattern in early (1–2 days) and late (> 2 days) vomiting
Treatment: Both volume repletion with normal saline and correction of hypokalemia with KCl improve metabolic alkalosis

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