Alkalosis




(1)
Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

 



Keywords

Generation phaseMaintenance phaseRecovery phaseRenal transport mechanismsGenetic mechanismsGI mechanisms


Metabolic alkalosis is defined as a primary increase in serum [HCO3 −] >32 mEq/L with pH >7.45. Hypoventilation with an increase in arterial pCO2 is an appropriate respiratory response for an increase in serum [HCO3 −]. Thus, metabolic alkalosis is characterized by elevations in pH, [HCO3 −] and pCO2.


Metabolic alkalosis occurs very commonly in hospitalized patients. It accounts for about 50% of all acid–base disorders. Mortality rates approach 85% in patients with pH >7.65. pH of this extent occurs in combined metabolic and respiratory alkalosis, and recognition of this mixed acid–base disorder is extremely important to prevent morbidity and mortality in any patient.


Course of Metabolic Alkalosis


The course of metabolic alkalosis is divided into three phases: generation phase, maintenance phase, and recovery phase.


Generation Phase


Generation occurs either by loss of H+ from the body or addition of alkali by any one of the causes shown in Table 11.1.


Table 11.1

Causes of 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


Cl− -depletion alkalosis

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

  

Maintenance Phase


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


Cl− depletion sustains metabolic alkalosis by the following mechanisms (Fig. 11.1):


  1. 1.

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


     

  2. 2.

    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


     

  3. 3.

    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


     

../images/480755_1_En_11_Chapter/480755_1_En_11_Fig1_HTML.png

Fig. 11.1

Factors that generate and maintain metabolic alkalosis


K+ depletion maintains metabolic alkalosis by the following mechanisms (Fig. 11.1):


  1. 1.

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


     

  2. 2.

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


     

  3. 3.

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


     

  4. 4.

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


     

  5. 5.

    Reduction of GFR by both K+ and Cl− depletion


     


Recovery Phase


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


Figure 11.1 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 aldosteronism 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



$$ {\displaystyle \begin{array}{cccc}& \underline{pH}& \underline {{HCO_3}^{-}}& \underline {pCO_2}\\ {}\mathrm{Normal}:& 7.40& 24\kern0.5em \mathrm{mEq}/\mathrm{L}& 40\kern0.5em \mathrm{mmHg}\\ {}\mathrm{Patient}:& 7.47& 34\ \mathrm{mEq}/\mathrm{L}& ?\end{array}} $$




$$ {\displaystyle \begin{array}{l}\Delta {HCO_3}^{-}=34-24=10\\ {}\mathrm{Expected}\kern0.5em {pCO}_2=10\times 0.7=7\\ {}40+7=47\ \end{array}} $$

Classification


Clinically, metabolic alkalosis is divided into:


  1. 1.

    Chloride (saline)-responsive alkalosis


     

  2. 2.

    Chloride (saline)-resistant alkalosis


     

Causes


The most important causes of metabolic alkalosis are shown in Table 11.1.


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. Disturbances in these transport mechanisms cause metabolic alkalosis by retention of HCO3 − and secretion of H+. Table 11.2 summarizes the transport mechanisms and their modifiers for HCO3 − reabsorption and sustenance of metabolic alkalosis. Figure 11.2 shows mutations of some of the transporters that result in genetic diseases and metabolic alkalosis.


Table 11.2

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. Hypokalemia downregulates pendrin, resulting in maintenance of metabolic alkalosis


2. Loss-of-function mutation of gene encoding 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


../images/480755_1_En_11_Chapter/480755_1_En_11_Fig2_HTML.png

Fig. 11.2

Mutations of transporters in various segments of the nephron. TALH thick ascending limb of Henle’s loop; DCT distal convoluted tubule; CCD cortical collecting duct


Genetic Mechanisms



Bartter syndrome


It is caused by genetic defects in the apical or basolateral membrane transport mechanisms of the thick ascending limb of Henle’s loop. Various types of Bartter syndrome are shown in Table 11.3.



  • In general, patients with Bartter syndrome behave similar to patients 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.




Table 11.3

Inherited disorders of NaCl transport mechanisms in various segments of the nephron
























































Segment and involved transporter

Disease

Some clinical features

Inheritance

Thick ascending limb


Apical Na/K/2Cl cotransporter

Neonatal Bartter syndrome type 1

Hypokalemia, metabolic alkalosis, hypercalciuria, hypotension

AR


Apical K channel (ROMK)

Neonatal Bartter syndrome type 2

Hypokalemia, metabolic alkalosis, hypotension

AR


Basolateral Cl channel (ClC-kb)

Classic Bartter syndrome type 3 (infantile)

Hypokalemia, metabolic alkalosis, hypotension or normal BP

AR


Basolateral Cl channel (ClC-kb/barttin)

Bartter syndrome type 4

Hypokalemia, metabolic alkalosis, hypotension, sensorineural deafness

AR


Activation of basolateral Ca2 +-sensing receptor

Bartter syndrome type 5

Salt wasting, hypokalemia, metabolic alkalosis, hypercalciuria

AD


Distal convoluted tubule


Apical Na/Cl cotransporter

Gitelman syndrome

Hypokalemia, metabolic alkalosis, hypocalciuria, normal to low BP

AR


Cortical collecting duct


Apical epithelial Na+ channel (ENaC)

Liddle syndrome

Hypokalemia, metabolic alkalosis, low rennin and aldosterone levels, hypertension (responsive to amiloride)

AD



↑ increase, ↓ decrease, AD autosomal dominant, AR autosomal recessive, ROMK renal outer medullary potassium channel



Gitelman syndrome


It is caused by mutations in distal tubule Na/Cl cotransporter.



  • Behaves similar to a patient on thiazide diuretic.



  • Characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and normal or low blood pressure. Although these manifestations are similar to Bartter syndrome, Gitelman syndrome occurs at any age (1–70 years) but is diagnosed in young adults.



  • Generation and maintenance phases are similar to those of Bartter syndrome.



  • The only way one can distinguish Gitelman syndrome from Bartter syndrome is urinary Ca2+ excretion. In Gitelman syndrome, urinary excretion of Ca2+ is low (hypocalciuria), whereas in Bartter syndrome it is normal or high (hypercalciuria).



  • Hypocalciuria is due to proximal tubule reabsorption of Ca2+, and hypomagnesemia is probably related to downregulation of Mg2+ channel in the distal collecting tubule.



  • Treatment includes lifelong liberal salt intake, K+, and Mg2+ supplementation (KCl, MgCl2) as well as K+-sparing diuretics (spironolactone, amiloride, spironolactone-receptor blocker).



Liddle syndrome


An autosomal dominant disorder is 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)


It is 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


It is 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 (1667 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. 1.

      Relative volume depletion by loss of NaCl


       

    2. 2.

      Hypokalemia


       

    3. 3.

      Hypochloremia


       

    4. 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. 1.

      Increase pCO2


       

    2. 2.

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


       

    3. 3.

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


       


Milk (calcium)–alkali syndrome


This syndrome was initially described in patients with peptic ulcer disease who consumed calcium salts and milk for many years. With the introduction of new drugs for peptic ulcer disease, the use of calcium salts and milk has decreased substantially. However, calcium salts alone or in combination with vitamin D are being used to prevent and/or treat osteoporosis. Thus, the incidence of milk–alkali syndrome is increasing recently.



  • Since milk is not consumed to prevent peptic ulcer or bone disease, and calcium supplements are recommended, the preferable term may be calcium–alkali syndrome.



  • Calcium–alkali syndrome is characterized by the triad of hypercalcemia, metabolic alkalosis, and some degree of renal insufficiency. Hypercalcemia impairs PTH secretion, which subsequently enhances proximal tubular HCO3 − reabsorption. Also, hypercalcemia has effects similar to loop diuretics in the thick ascending limb of Henle’s loop by activating basolateral Ca2+-sensing receptor. This activation causes loss of Na+, K+, and Cl− with resultant volume contraction. Both development and maintenance of metabolic alkalosis occur because of continued intake of alkali and its limited excretion due to volume depletion.



  • Hydration with normal saline initially will improve both calcium and metabolic alkalosis, but elevated creatinine may persist. Discontinuation of alkali and calcium will also improve metabolic alkalosis.



Hypercalcemia


Hypercalcemia due to increased bone resorption, as in malignancy or other conditions, may cause metabolic alkalosis. Increased bone resorption releases alkali (calcium carbonate), which is reabsorbed by the proximal tubule by hypercalcemia-suppressed PTH action. Also, HCO3 − excretion is reduced due to volume contraction. Also, hypercalcemia can directly stimulate H+ secretion with resultant increase in net acid excretion. As mentioned above, hypercalcemia has loop diuretic-like effect. Thus, hypercalcemia per se can cause metabolic alkalosis.



Cystic fibrosis


Metabolic alkalosis develops in patients with cystic fibrosis due to volume depletion and hypokalemia. Loss of Na+ and Cl− in sweat causes volume depletion and hypochloremia. Hyperaldosteronism due to volume depletion results in hypokalemia. H+ secretion also increases. All these changes generate and maintain metabolic alkalosis.


Table 11.4 summarizes various laboratory tests that are useful in the differential diagnosis of metabolic alkalosis.


Table 11.4

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

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Oct 20, 2020 | Posted by in NEPHROLOGY | Comments Off on Alkalosis

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