Bmri2014 695281

Hindawi Publishing Corporation
BioMed Research International

Volume 2014, Article ID 695281, 16 pages
http://dx.doi.org/10.1155/2014/695281
Review Article
The Importance of the Ionic Product for Water to
Understand the Physiology of the Acid-Base Balance in Humans
María M. Adeva-Andany, Natalia Carneiro-Freire,

Cristóbal Donapetry-García, Eva Rañal-Muíño, and Yosua López-Pereiro
Hospital General Juan Cardona, C/ Pardo Bazán s/n, Ferrol, 15406 La Coruña, Spain
Correspondence should be addressed to Marı́a M. Adeva-Andany; madevaa@yahoo.com
Received 17 February 2014; Revised 31 March 2014; Accepted 4 April 2014; Published 30 April 2014
Academic Editor: George Seki
Copyright © 2014 Marı́a M. Adeva-Andany et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Human plasma is an aqueous solution that has to abide by chemical rules such as the principle of electrical neutrality and
the constancy of the ionic product for water. These rules define the acid-base balance in the human body. According to the
electroneutrality principle, plasma has to be electrically neutral and the sum of its cations equals the sum of its anions. In addition,
the ionic product for water has to be constant. Therefore, the plasma concentration of hydrogen ions depends on the plasma ionic
composition. Variations in the concentration of plasma ions that alter the relative proportion of anions and cations predictably lead
to a change in the plasma concentration of hydrogen ions by driving adaptive adjustments in water ionization that allow plasma
electroneutrality while maintaining constant the ionic product for water. The accumulation of plasma anions out of proportion of
cations induces an electrical imbalance compensated by a fall of hydroxide ions that brings about a rise in hydrogen ions (acidosis).
By contrast, the deficiency of chloride relative to sodium generates plasma alkalosis by increasing hydroxide ions. The adjustment
of plasma bicarbonate concentration to these changes is an important compensatory mechanism that protects plasma pH from
severe deviations.
1. Introduction 2. The Principle of Electrical Neutrality

Although invaluable contributions to the understanding of Electrolytes are molecules that dissociate in water forming
the acid-base balance in humans have been made, the phys- cations (positively charged ions) and anions (negatively
iological mechanisms that justify variations of plasma pH in charged ions). In humans, plasma cations include hydro-
different conditions are unclear and therefore the therapy of gen ion (H+ ), sodium, potassium, calcium, magnesium,
the acid-base disorders has remained elusive. and ammonium. Sodium ion contributes quantitatively the
The constancy of the ionic product for water is an principal positive charge to plasma, with a concentration of
essential missing piece of information that may contribute approximately 140 mmol/L (mM) (0.140 M), while normal
to elucidate the pathophysiology of the acid-base balance in plasma concentration of hydrogen ions is 0.00000004 mol/L
humans. (M) or 40 nanoM (nM). Plasma anions include hydroxide
Plasma and urine are aqueous solutions. As such, they ion (OH− , also termed hydroxyl ion), chloride, bicarbonate
have to comply with chemical rules that apply to aqueous (HCO3 − ), albumin, phosphate, lactate, 𝛽-hydroxybutyrate,
solutions, including the principle of electrical neutrality and acetoacetate, sulphate, urate, and other organic anions such as
the constancy of the ionic product for water. The state of pyruvate and propionate. The most abundant anion in human
ionization of plasma water varies according to the plasma plasma is chloride with a concentration of approximately
ionic composition to maintain these chemical rules. 100 mM. Plasma bicarbonate level is approximately 25 mM
2 BioMed Research International
and therefore also contributes significantly to the plasma In pure water, the concentration of water is 55.5 M and
negative charge in quantitative terms. the value for the equilibrium constant, 𝐾eq , determined by
In order to preserve normal plasma ionic composition, electrical conductivity measurements, is 1.8×10−16 M at 25∘ C
the kidneys produce urine with different concentration of (298 K) of temperature.
ions depending on body requirements. Urine cations include Substituting these values in the equilibrium constant
sodium, potassium, calcium, magnesium, ammonium, and expression,
hydrogen ions. Urine anions include chloride, bicarbonate,
phosphate, sulphate, citrate, oxalate, and hydroxide ions. 𝐾𝑤 = (1.8 × 10−16 ) × 55.5 = 99.9 × 10−16 ≈ 10−14 M2 . (6)
According to the electroneutrality principle, the sum of
all positively charged ions (cations) must be equal to the sum And therefore,
of all negatively charged ions (anions) in aqueous solutions.
Therefore, plasma and urine are electrically neutral and the 𝐾𝑤 = [H+ ] [OH− ] = 10−14 . (7)
sum of their anions (negative electrical charge) equals the
sum of their cations (positive electrical charge) [1–4]. The constant ionic product for water ([H+ ][OH− ]) is equal to
10−14 at 25∘ C.
In pure water, the concentration of hydrogen ions is equal
3. The Constancy of the Ionic to the concentration of hydroxide ions ([H+ ] = [OH− ]).
Product for Water At 25∘ C, both concentrations are equal to 10−7 M. Aqueous
The ionic product for water is a crucial piece to understand solutions are defined as acidic if there is an excess of hydrogen
acid-base balance physiology and to evaluate acid-base dis- ions over hydroxide ions ([H+ ] > [OH− ]) or alkaline
orders. In water, some water molecules accept a hydrogen when there is an excess of hydroxide ions over hydrogen
ion from a second water molecule, forming a hydronium ion ions ([H+ ] < [OH− ]), but the ionic product for water
(H3 O+ , also called hydroxonium ion or oxonium ion) and ([H+ ][OH− ]) is always constant in any aqueous solution,
a hydroxide ion (OH− ). Once generated, both ions react to regardless of the presence of dissolved solutes. If dissolved
produce water again, according to the following equilibrium substances alter the concentration of either hydrogen ions or
reaction: hydroxide ions, a concomitant change of the same magnitude
must occur in the other ion to maintain constant the ionic
H2 O + H2 O ←→ H3 O+ + OH− (1) product for water. Therefore, the concentration of hydrogen
ions rises whenever the concentration of hydroxide ions falls
By convenience, the hydronium ion (H3 O+ ) is usually and vice versa, the concentration of hydrogen ions decreases
identified as hydrogen ion (H+ ) and the equilibrium reaction when the level of hydroxide ions increases to maintain the
can be rewritten as constancy of the anion product for water in aqueous solutions
[1–4].
H2 O + H2 O ←→ H+ + OH− (2) Hence, aqueous solutions such as plasma and urine are
electrically neutral and maintain constant the ionic product
The law of mass action can be applied, defining the for water. Variations in the concentration of electrolytes in
equilibrium constant for the reversible ionization of water these solutions drive changes in the state of ionization of
(𝐾eq ): water molecules that alter the hydrogen ions concentration in
order to preserve electrical neutrality while keeping constant
[H+ ] [OH− ] the ionic product for water [1–4].
𝐾eq = . (3)
[H2 O]
4. Definition of pH
The concentration of each moiety is expressed in moles per
liter (M). The concentration of hydrogen ions (H+ ) may be expressed
The degree of ionization of water is very low and the num- in terms of pH, defined as the negative logarithm of the
ber of water molecules dissociated into ions is minuscule. At hydrogen ions concentration:
any given time, the amount of hydronium ions and hydroxide
1
ions present in water is extremely small and consequently the pH = − log [H+ ] = log . (8)
concentration of undissociated water molecules ([H2 O]) is [H+ ]
virtually unchanged by this minute ionization and may be
considered a constant. The normal plasma pH is 7.4 (7.35–7.45) [5].
𝐾eq × [H2 O] = [H+ ] [OH− ] . (4) 5. Definition of pK a

The product 𝐾eq × [H2 O] is a constant termed the ionic Acids may be defined as substances that increase the concen-
product for water (𝐾𝑤 ). tration of hydrogen ions when added to an aqueous solution,
Therefore, the ionic product for water (𝐾𝑤 ) is while bases are compounds that decrease the concentration
of hydrogen ions (and therefore increase hydroxyl anions
𝐾𝑤 = [H+ ] [OH− ] . (5) concentration) when dissolved in water or aqueous solutions.
BioMed Research International 3
For instance, hydrochloric acid (HCl) dissociates into H+ and value. The p𝐾𝑎 of a base gauges its tendency to join hydrogen
chloride (Cl− ) when dissolved in water, whereas ammonia ions. The stronger the base, the greater its tendency to bind
(NH3 ) becomes protonated when dissolved in water produc- protons and the higher its p𝐾𝑎 value.
ing ammonium ion (NH4 + ). When the concentration of the undissociated moiety
Each acid has a characteristic tendency to release hydro- (HA, NH4 + ) is equal to the concentration of the dissociated
gen ions in an aqueous solution, according to the reversible moiety (A− , NH3 ), pH equals p𝐾𝑎 , as log 1 = 0. Therefore, the
reaction: p𝐾𝑎 of an acid or a base is the pH at which the concentration
of dissociated and undissociated forms is the same.
HA ⇐⇒ H+ + A− (9)
Any reversible chemical reaction at a specified tem-

6. Strong Acids and Bases
perature has a specific equilibrium constant (𝐾𝑎 ), which
defines the final equilibrium concentrations of reactants and When the p𝐾𝑎 of an acid is lower than the pH of the
products (law of mass action): aqueous solution in which it is dissolved, the acid dissociates
releasing hydrogen ions, being transformed into an anion.
[H+ ] [A− ] Strong acids have low p𝐾𝑎 values and completely dissociate
𝐾𝑎 = . (10)
[HA] in aqueous solutions, yielding strong anions. Acids with
p𝐾𝑎 value of approximately 4 or less generate strong anions
The tendency of an acid to dissociate releasing anions at physiologic pH values. Many organic acids existing in
and hydrogen ions may be assessed from this equilibrium the human body possess p𝐾𝑎 values around 4 and there-
constant. The larger the value of the equilibrium constant, the fore appear predominantly in their anionic form, such as
greater the tendency of the acid to dissociate and the stronger bicarbonate, lactate, pyruvate, citrate, acetoacetate, and 𝛽-
the acid. hydroxybutyrate (Table 1).
Bases such as ammonia (NH3 ) attach hydrogen ions when When the pH of the aqueous solution is lower than the
they dissolved in aqueous solutions, to produce protonated p𝐾𝑎 value of a dissolved base, the base captures hydrogen ions
molecules such as ammonium ions (NH4 + ), according to the and becomes protonated. Strong bases have high p𝐾𝑎 values
reversible reaction: and therefore they remain protonated at physiologic plasma
pH. For instance, the p𝐾𝑎 value for the pair NH3 /NH4 + is 9.3,
NH4 + ⇐⇒ H+ + NH3 (11)
indicating that virtually only the protonated moiety (NH4 + )
The equilibrium constant for this reaction is is present in the human body.
Weak acids and bases are those with p𝐾𝑎 values closer
[H+ ] [NH3 ] to approximately 7. At physiological pH values, their degree
𝐾𝑎 = . (12) of dissociation or protonation, respectively, is variable. Weak
[NH4 + ]
anions in the human body include the pair dihydrogen phos-
The relative strength of a base can be assessed by its phate/monohydrogen phosphate (H2 PO4 − /HPO4 2− ) and
equilibrium constant. The lower the equilibrium constant urate (Table 1).
value, the higher the tendency of the base to capture protons
and the higher the concentration of the protonated moiety
(NH4 + ). 7. Physiological Relationship between Carbon
The Henderson-Hasselbalch equation is the logarithmic Dioxide and Plasma Bicarbonate
transformation of the equilibrium constant equation:
Plasma bicarbonate is a circulating anion that contributes
[A− ] substantially to the plasma negative charge in quantitative
pH = p𝐾𝑎 + log in the case of an acid, (13)
[HA] terms and therefore plays a role in defining plasma pH. Unlike
other plasma ions, bicarbonate concentration is determined
or by the lung ventilatory activity besides the kidney handling
[NH3 ] of bicarbonate. In addition, several isoenzymes of carbonic
pH = p𝐾𝑎 + log in the case of a base. (14) anhydrase are ubiquitously expressed in the human body
[NH4 + ]
and catalyze the reversible conversion of carbon dioxide into
The equilibrium constant may be conveniently stated in bicarbonate [6].
the form of p𝐾𝑎 , which is defined as the negative logarithm In humans, carbon dioxide (CO2 ) is an end product of
of 𝐾𝑎 : cell metabolism continuously incorporated into the tissue
capillaries and normally removed from the body by the
1 expired air [7].
p𝐾𝑎 = − log 𝐾𝑎 = log . (15) Carbon dioxide formed during cell metabolism diffuses
𝐾𝑎
across the plasma membrane into the tissue capillary net-
The p𝐾𝑎 reflects the relative strength of an acid. The work, being transported by blood in a number of ways.
stronger the acid, the greater its tendency to dissociate Approximately 5% of the carbon dioxide remains as a gas in
releasing anions and hydrogen ions and the lower its p𝐾𝑎 the aqueous phase of blood, being measured as the partial
Table 1: Some p𝐾𝑎 values. plasma bicarbonate is the principal way of transportation of
carbon dioxide in blood, plasma bicarbonate level increases
p𝐾𝑎 as carbon dioxide rises, while plasma bicarbonate concentra-
Phosphoric acid (H3 PO4 )/dihydrogen phosphate 1.97 tion falls as carbon dioxide declines. Both carbon dioxide and
(H2 PO4 − ) plasma bicarbonate reflect the ventilatory status. Hypoventi-
Dihydrogen phosphate (H2 PO4 − )/monohydrogen 6.86 lation results in hypercapnia and a rise in plasma bicarbonate
phosphate (HPO4 2− ) concentration, while hyperventilation leads to hypocapnia
Monohydrogen phosphate (HPO4 2− )/phosphate 12.35 and a subsequent reduction in the plasma bicarbonate level
(PO4 3− ) [11, 12].
Carbonic acid (H2 CO3 )/bicarbonate (HCO3 − ) 3.77 A quantitative relationship between carbon dioxide and
Citric acid/citrate 3.09 plasma bicarbonate has been demonstrated in a number of
Acetoacetic acid/acetoacetate 3.58 situations, further highlighting their physiological relation-
𝛽-hydroxybutyric acid/𝛽-hydroxybutyrate 4.39 ship.
In patients with chronic hypercapnic respiratory fail-
Lactic acid/lactate 3.86
ure, the plasma bicarbonate level increases by 5.1 mM for
Uric acid/urate 5.75 each 10 mmHg increase in the arterial pCO2 [13]. In panic
Ammonia (NH3 )/ammonium ion (NH4 + ) 9.3 disorder patients with hyperventilation attacks, for each
decrease of 1 mmHg in arterial pCO2 , plasma bicarbonate
level decreases by 0.41 mEq/L [14]. The same quantitative
pressure of carbon dioxide (pCO2 ). An even smaller propor- relationship between arterial pCO2 and plasma bicarbonate
tion of carbon dioxide binds to plasma proteins. Most of the concentration has been found in healthy volunteers under-
carbon dioxide (90–95%) arriving in capillary blood diffuses going simulated altitude: for each decrease of 1 mmHg in
into the red blood cells, where it is hydrated to bicarbonate the arterial pCO2 , the plasma bicarbonate concentration
(HCO3 − ) by the cytosolic enzyme carbonic anhydrase II, decreases by 0.41 mM [7]. A close linear relationship between
generating hydrogen ions that bind to oxyhemoglobin. As arterial pCO2 and plasma bicarbonate also exists in patients
a result, oxygen (O2 ) is released from oxyhemoglobin and with metabolic alkalosis due to diuretic use or vomiting, in
leaves the erythrocyte, reaching the tissue cells. Bicarbonate whom the arterial pCO2 increases 1.2 mmHg for each 1.0 mM
formed inside the red blood cells by carbonic anhydrase II increment in plasma bicarbonate level [15]. In patients with
leaves these cells towards the plasma in exchange for chloride metabolic acidosis, compensatory hyperventilation reduces
through the plasma membrane transporter anion exchanger- plasma carbon dioxide and consequently plasma bicarbonate.
1 (AE1). Erythrocytes with protonated deoxyhemoglobin In most of these patients, the decrease in plasma bicarbonate
formed in the tissue capillaries travel to the lungs, where concentration may be predicted from the arterial pCO2 by the
the uptake of oxygen transforms deoxyhemoglobin into Winter’s equation [16, 17].
oxyhemoglobin, releasing hydrogen ions that are combined A close linear relationship between arterial pCO2 and
with bicarbonate diffusing back from plasma by carbonic plasma bicarbonate also exists in patients with metabolic
anhydrase II, generating water and carbon dioxide, which is alkalosis due to diuretic use or vomiting, in whom the arterial
exhaled as a gas (Figure 1) [8, 9]. pCO2 increases 1.2 mmHg
Carbonic anhydrase is a zinc-containing enzyme that
catalyzes the reversible hydration of carbon dioxide (CO2 ) arterial pCO2 = 1.5 × [HCO3 − ] + 8. (17)
to bicarbonate (HCO3 − ) and a proton (H+ ). The molecule Furthermore, a correlation between end-tidal pCO2 and
of carbonic anhydrase contains a conic cavity at the bottom plasma bicarbonate concentration has been demonstrated in
of which is the zinc atom. The reaction catalyzed by the a number of studies. Capnometry is the measurement of the
enzyme involves two steps. First, carbon dioxide reacts with pCO2 at the end of an exhaled breath, which is termed end-
hydroxide ions (OH− ) from water leading to the formation of tidal carbon dioxide. In nonintubated patients presenting to
HCO3 − , which is displaced by a water molecule. The second an emergency department [18] and in patients with diabetic
step involves the transfer of an H+ from the water molecule ketoacidosis [19], end-tidal carbon dioxide correlates with
to one histidine residue, reforming OH− [6]. The net result of arterial pCO2 . Accordingly, end-tidal pCO2 monitoring may
the carbonic anhydrase II reaction is be used as surrogate for arterial pCO2 and prevent from
CO2 + H2 O ←→ HCO3 − + H+ (16) cumbersome arterial blood gases extraction [18]. In addition,
end-tidal pCO2 is correlated with serum bicarbonate level
In human erythrocytes, plasma membrane AE1 and and capnography has been used as noninvasive accurate
cytosolic carbonic anhydrase II form a functional complex estimate of plasma bicarbonate concentration in patients
[9, 10]. with diabetic ketoacidosis [17, 20], among children with
Blood carbon dioxide content is predominantly deter- gastroenteritis [21], and in patients presenting to the emer-
mined by pulmonary ventilatory activity. gency department [22]. In children with gastroenteritis, end-
An increment in the respiratory rate (hyperventilation) tidal pCO2 values greater than 34 mmHg ruled out plasma
results in carbon dioxide elimination leading to hypocapnia, bicarbonate concentration lower than 15 mmol/L [21].
whereas a reduction in the respiratory rate (hypoventilation) The relationship between carbon dioxide and bicarbonate
promotes carbon dioxide retention (hypercapnia) [7]. Since is additionally underlined by the fact that the infusion of
Red blood cell at tissue capillary Red blood cell at lung capillary
O2
CO2 + H2 O
Hemoglobin
H+ + HCO3 −
Cl− H+ + HCO3 −
Hemoglobin
CO2 + H2 O Cl−
O2
Figure 1: Carbon dioxide transport in blood.
sodium bicarbonate increases carbon dioxide production and In the early distal convoluted tubule, the sodium-chloride
arterial pCO2 , as it was first documented in 1956 [23, 24]. (Na+ -Cl− ) cotransporter is located at the apical membrane
In addition to pulmonary function, plasma bicarbonate and links sodium and chloride reabsorption. This cotrans-
concentration is determined by the kidney tubule, which porter is thiazide-sensitive, being inhibited by the admin-
may recover filtered bicarbonate or secrete bicarbonate into istration of hydrochlorothiazide. Blockade of the Na+ -Cl−
the urine depending on physiological requirements. Most cotransporter increases sodium delivery to the collecting duct
bicarbonate filtered at the glomerulus is normally reclaimed where uptake of sodium takes place without chloride by the
by the proximal convoluted tubule through mechanisms that ENaC [30, 32].
are being elucidated and involve both basolateral and apical In the collecting duct, the ENaC resides on the apical
ion transporters and isoenzymes of carbonic anhydrase. In membrane of principal cells and mediates sodium reabsorp-
addition to its ability to bicarbonate reabsorption by the tion without chloride, increasing the lumen electronegativity
proximal tubule, normal human kidney has a large capacity and creating an electrical gradient that promotes potassium
to excreting bicarbonate in more distal segments of the and hydrogen ions secretion into the urine. The H+ -ATPases
nephron. The collecting ducts possess at least two bicarbonate that secrete protons into the tubular lumen are functionally
transporters in humans, the kidney isoform of the AE1 coupled to the basolateral kidney isoform of the AE1 that
at the basolateral membrane and pendrin on the apical exchanges bicarbonate and chloride. The cytosolic enzyme
membrane. The enzyme carbonic anhydrase is also necessary carbonic anhydrase II provides the substrate for both trans-
to bicarbonate handling in this portion of the nephron. porters by catalyzing the hydration of carbon dioxide to
In the proximal tubule, the sodium-bicarbonate bicarbonate and hydrogen ions. Bicarbonate is reabsorbed
(Na+ -HCO3 − ) cotransporter NBCe1 mediates basolateral into the blood in exchange for chloride that is excreted into
electrogenic sodium-coupled bicarbonate transport and is the urine, while hydrogen ions are secreted into the tubular
required for bicarbonate (and sodium) recovery on this lumen by the H+ -ATPase. Therefore, sodium reabsorption by
segment of the nephron [25]. Additionally, sodium/proton the ENaC is linked to bicarbonate reclamation in exchange
exchangers (NHEs) that mediate exit of hydrogen ions for chloride [34–36].
from cells with uptake of sodium [26], vacuolar H+ -ATPase The ENaC is amiloride-sensitive and administration of
that mediates the ATP-dependent transport of protons this diuretic blocks the channel. As a consequence, sodium
[27], and Na+ -K+ ATPase [28] are involved in bicarbonate reabsorption with concomitant chloride excretion is sup-
reabsorption in the proximal tubule. Activity of the enzyme pressed and therefore sodium is lost in excess of chloride in
carbonic anhydrase II is also required to bicarbonate the urine resulting in plasma retention of chloride relative to
reabsorption in this portion of the nephron [29]. sodium [34–36].
In the ascending segment of the loop of Henle, the The ENaC is primarily regulated by flow rate and
sodium-potassium-chloride (Na+ -K+ -2Cl− ) cotransporter aldosterone. Blockade of sodium reabsorption earlier in the
located at the apical membrane drives the electroneutral nephron, either at the Na+ -K+ -2Cl− cotransporter on the
reabsorption of sodium, potassium, and chloride. This loop of Henle or the Na+ -Cl− cotransporter on the distal
cotransporter is furosemide-sensitive, being inhibited by the tubule, enhances urinary flow and sodium delivery to the
administration of this diuretic. Blockade of the Na+ -K+ -2Cl− collecting duct where uptake of sodium takes place via
cotransporter enhances sodium delivery to the collecting the ENaC, while bicarbonate is reabsorbed in exchange for
duct, where sodium is reabsorbed without chloride by the chloride. In addition, mineralocorticoids such as aldosterone
epithelial sodium channel (ENaC) [30, 31]. In addition, stimulate sodium reabsorption in the collecting duct through
dysfunction of the Na+ -K+ -2Cl− cotransporter induces activation of the ENaC and therefore allow bicarbonate
plasma volume contraction and subsequent activation of the recovery and chloride loss in urine. Aldosterone antagonists
renin-angiotensin-aldosterone (RAA) system that amplifies spironolactone and eplerenone inhibit aldosterone action and
sodium reabsorption without chloride through the ENaC therefore suppress ENaC activity, mimicking the effects of
[30, 32, 33]. amiloride. Sodium is wasted in urine in excess of chloride,
while the urinary excretion of potassium and hydrogen ions Quantitatively, the main anions normally circulating in
is inhibited [34–36]. human plasma are chloride and bicarbonate, while the most
Pendrin is a chloride/bicarbonate (Cl− /HCO3 − ) ex- abundant plasma cation is sodium. Alterations in the con-
changer positioned at the apical membrane of intercalated centration of these ions that modify their relative proportion
cells of the cortical collecting ducts that accounts for the inducing an electrical imbalance are the predominant cause
secretion of bicarbonate into the tubule lumen in exchange of acid-base disorders. Pulmonary function modifies carbon
for chloride reabsorption, modulating bicarbonate handling dioxide elimination and consequently plasma bicarbonate
by the kidney [37–40]. concentration, as this anion is the major way of carrying
carbon dioxide in blood. Therefore, respiratory acid-base
8. The Acid-Base Balance in Humans disorders are associated with primary changes in plasma
bicarbonate concentration, while metabolic acid-base disor-
In human beings, normal metabolism in tissue cells con- ders are caused by primary alterations in other plasma ions,
tinuously produces carbon dioxide, cations such as ammo- mainly chloride and sodium. In addition, modifications in
nium, and anions such as lactate (L-lactate and D-lactate), the pulmonary ventilatory rate are critical adaptive mech-
ketone bodies (acetoacetate and 𝛽-hydroxybutyrate), phos- anisms implemented to mitigate fluctuations in blood pH
phate (H2 PO4 − /HPO4 2− ), and sulphate (SO4 2− ). In addition, when plasma anions accumulate (acidosis) or are deficient
other charged molecules circulate in human plasma, includ- (alkalosis) relative to cations. Metabolic acidosis induces
ing negative charges such as albumin and positive charges hyperventilation in order to decrease the plasma concen-
such as immunoglobulins. Anomalous plasma ions may be tration of bicarbonate, whereas metabolic alkalosis induces
derived from exogenous substances, including cations such as hypoventilation to raise plasma bicarbonate concentration.
lithium and anions such as formate generated from methanol. Both compensatory mechanisms may be life-saving when
All of them may potentially change the plasma pH when severe deviations from normal pH take place [40].
modifications in their concentration alter the normal relative
proportion of plasma anions and cations. According to the 8.1. Metabolic Acidosis. Metabolic acidosis is caused by an
electroneutrality principle and the constancy of the ionic excess of plasma anions relative to cations that may be
product for water, the plasma concentration of hydrogen ions generated either by plasma accumulation of anions or by
depends on the plasma level of other ions and variations in marked reduction of plasma cations (sodium ion) which
the plasma ionic composition predictably lead to a change similarly leads to relative excess of negative ions. The elec-
in plasma pH. Plasma acidosis (plasma pH less than 7.35) trical imbalance driven by the accumulation of anions out of
is caused by an excess of plasma anions relative to cations, proportion of cations induces a fall in the hydroxide anions
which may be due to either an elevation of plasma anions concentration, which implies an increase in the hydrogen
out of proportion of cations (such as hyperchloremia with ions concentration, reducing the plasma pH. In addition,
no variation in plasma sodium) or a fall in plasma cations a compensatory increase in the ventilatory rate achieves
(such as hyponatremia with no change in plasma chloride). a reduction of the plasma bicarbonate concentration. The
The relative excess of anions over cations creates an electrical decline in plasma bicarbonate contributes to restricting the
imbalance that requires the implementation of adaptive fall in hydroxide anions, limiting the increase in hydrogen
mechanisms. To regain electrical neutrality, the remaining ions.
negative charge must be reduced and this is achieved by a fall The anions most frequently encountered in conditions
in the hydroxide anions concentration. In turn, the drop of leading to metabolic acidosis are chloride (hyperchloremic
hydroxide anions causes an increase in hydrogen ions of the acidosis), L-lactate (L-lactic acidosis), and the ketone bodies
same magnitude to maintain constant the ionic product for acetoacetate and 𝛽-hydroxybutyrate (ketoacidosis). D-lactate
water, decreasing plasma pH. By contrast, plasma alkalosis and other organic anions such as formate may also be a cause
(plasma pH greater than 7.45) is brought about by a relative of metabolic acidosis when their concentration is elevated.
reduction of plasma anions relative to cations, which may be The accumulation of anions other than chloride resulting
due to either a decrease in plasma anions out of proportion in plasma acidosis is called anion gap acidosis. Sometimes
of cations (such as hypochloremia with no change in plasma the same causative factor may produce acidosis by different
sodium) or an increase in plasma cations (hypernatremia mechanisms. For instance, toluene abuse has been associated
with no variation in plasma chloride). To comply with the with either hyperchloremic or anion gap acidosis [41, 42].
electroneutrality principle, the fall of plasma anions out of Distal renal tubular acidosis is the predominant cause of
proportion of cations is compensated by raising hydroxide hyperchloremic acidosis secondary to toluene poisoning [43],
anions. The increment of hydroxide ions implies a fall of while lactic acidosis [44] and ketoacidosis [45] have been
the same magnitude in plasma hydrogen ions to maintain found in cases of toluene intoxication with anion gap acidosis.
constant the ionic product for water, increasing plasma pH.
Therefore, modifications in the plasma ionic composition 8.1.1. Hyperchloremic (Nonanion Gap) Acidosis. An increase
that jeopardize electrical balance drive adjustments in water in the plasma concentration of chloride out of proportion of
dissociation in order to recover electrical neutrality and sodium causes hyperchloremic acidosis. The relative increase
maintain the constancy of the ionic product for water, which in plasma chloride may be due to either exogenous admin-
ultimately alter the plasma concentration of hydrogen ions istration of chloride in excess of sodium or a decrease in
[1–4]. the plasma sodium concentration with no change in the
chloride level. In addition, either intestinal or renal loss intact [46]. Proximal RTA may be isolated or a part of a
of fluid with low chloride concentration relative to sodium more generalized tubule defect, named Fanconi syndrome,
induces hyperchloremic acidosis, owing to plasma retention characterized by elevated urinary excretion of solutes like
of chloride in excess of sodium [46, 47]. The factor that phosphate, uric acid, potassium, glucose, amino acids, and
effectively modulates plasma pH is the relative proportion low-molecular-weight proteins [55].
between sodium and chloride concentrations. When an Distal RTA is a heterogeneous group of inherited and
elevation in plasma chloride occurs simultaneously with an acquired disorders characterized by the inability to acidify
increase in plasma sodium, hyperchloremia is not associated the urine in the collecting duct, where sodium reabsorption
with acidosis, as there is no electrical imbalance to com- through the amiloride-sensitive ENaC is linked to bicar-
pensate. By contrast, a patient with normal plasma chloride bonate recovery and chloride excretion in urine. Unlike
concentration and hyponatremia develops acidosis due to proximal RTA, patients with distal RTA maintain inappro-
relative hyperchloremia, as there is an increment in plasma priately alkaline urine in the presence of hyperchloremic
chloride relative to sodium [2–4]. acidosis [46, 56]. Tubulointerstitial nephropathies that injure
Causes of hyperchloremic acidosis include marked collecting ducts, hypoaldosteronism states, and the use of
hyponatremia with normochloremia, ureteral diversion into amiloride or aldosterone antagonists such as spironolactone
the intestinal tract, the administration of exogenous sub- and eplerenone induce urinary loss of sodium in excess of
stances that provide excess chloride relative to sodium, chloride that results in plasma chloride retention relative to
and loss of relatively chloride-free fluid, either intestinal sodium and hyperchloremic acidosis [35].
(diarrhea) or urinary (renal tubular acidosis). Congenital or acquired deficiency of carbonic anhydrase
Metabolic acidosis has been documented associated with II leads to RTA often combined proximal and distal, as the
a decrease in the plasma sodium concentration out of pro- enzyme is present in both segments of the kidney tubule.
portion of plasma chloride [48, 49]. Besides RTA, congenital deficiency of carbonic anhydrase II
Ureteral diversion into the intestinal tract (ureterosig- is characterized by cerebral calcification, osteopetrosis, men-
moidostomy) causes hyperchloremic acidosis due to intesti- tal retardation, and growth failure [29, 57]. The administra-
nal reabsorption of urinary chloride that leads to relative tion of carbonic anhydrase inhibitors such as acetazolamide
hyperchloremia [47]. induces hyperchloremic acidosis due to urinary excretion of
Plasma acidosis occurs after normal saline (0.9% sodium sodium without chloride [58].
chloride solution) infusion into the blood stream during fluid
resuscitation attempts [50]. The concentration of sodium ion
and chloride ion in normal saline is the same (154 mM), 8.1.2. Metabolic Acidosis Associated with Unmeasured Anions
while plasma sodium concentration is approximately 40 mM (Anion Gap Metabolic Acidosis). Anion gap metabolic aci-
greater than plasma chloride level. Therefore, the infusion of dosis is caused by accumulation of plasma anions other
normal saline into the blood stream increases proportionally than chloride. These anions are not usually measured in the
more the concentration of chloride than that of sodium, electrolyte panel, being called unmeasured anions. The most
resulting in an excess of plasma chloride relative to sodium. frequent unmeasured anions that cause metabolic acidosis
Similarly, hyperchloremic acidosis is produced in preterm are L-lactate (L-lactic acidosis), D-lactate (D-lactic acidosis),
infants fed with milk or parenteral nutrition providing excess 𝛽-hydroxybutyrate and acetoacetate (ketoacidosis), organic
chloride relative to sodium [51]. acids such as pyroglutamate from acetaminophen, anions
Diarrhea and pancreatic or biliary fistulas induces hyper- derived from metabolism of some alcohols, phosphate, and
chloremic acidosis due to the waste of intestinal fluid rich in sulphate derived from dietary animal protein.
sodium and relatively chloride-free, as both pancreatic and L-lactic acidosis may be secondary to congenital or
biliary secretions are rich in sodium bicarbonate [47, 52, 53]. acquired mitochondrial respiratory chain dysfunction,
Likewise, renal tubular acidosis (RTA) causes hyper- including tissue hypoxia [59], carbon monoxide poisoning
chloremic acidosis owing to the loss of urine containing low [60], cyanide poisoning [61] and drugs such as linezolid,
chloride concentration relative to sodium. Either proximal phenformin, and stavudine [62–64]. In addition, pyruvate
or distal dysfunction of the kidney tubule may be associated dehydrogenase deficiency [65], defective gluconeogenesis
with urinary loss of sodium bicarbonate in excess of chloride. pathway [66], thiamine (vitamin B1) deficiency [67],
Proximal RTA is caused by congenital or acquired dis- malignancy [68], liver disease [69], sepsis [70], asthma [71],
orders of the proximal convoluted tubule associated with fructose infusion [72], and ingestion of ethanol [73] may
defective sodium and bicarbonate reabsorption that cause produce L-lactic acidosis.
urinary loss of sodium out of proportion of chloride [54]. D-lactic acidosis occurs following small bowel resection
Among congenital disorders, mutations in SLC4A4, the gene (short bowel syndrome), intestinal bypass surgery for obesity
encoding the sodium-bicarbonate cotransporter NBCe1, [74], and administration of high doses of propylene glycol
cause proximal RTA [25]. Autoimmune diseases that dam- [75]. In addition, patients with diabetic ketoacidosis show
age the proximal convoluted tubule may produce acquired elevated plasma D-lactate level compared to diabetic patients
proximal RTA [55]. Patients with proximal RTA are able without ketoacidosis [76].
to reclaim filtered bicarbonate when the filtered load is A variety of conditions may increase the production of
low and therefore their urine may be acid in presence of ketone bodies (𝛽-hydroxybutyrate and acetoacetate), includ-
plasma acidosis, as distal acidification mechanisms remain ing a ketogenic diet [77], starvation or prolonged fasting
[78], uncontrolled type 1 and type 2 diabetes mellitus (dia- The normal value for the calculated serum anion gap is 8–
betic ketoacidosis) [79], and ethanol metabolism (alcoholic 16 mEq/L.
ketoacidosis) [80]. The anion gap provides an estimation of the unmeasured
Pyroglutamic acid or 5-oxoproline is an intermediary in anions in the plasma, including albumin and phosphate.
the 𝛾-glutamyl cycle, which facilitates the transport across As serum albumin is an unmeasured anion, a decrease in
cellular membranes of amino acids that participate in the plasma albumin concentration lowers the anion gap. It has
synthesis of glutathione. Pyroglutamic acidosis is an anion been estimated that each g/L decrease in serum albumin
gap metabolic acidosis that may be either congenital, due to diminishes the anion gap by 0.25 mEq/L (for each 1 g/dL
an autosomal recessive deficiency of glutathione synthetase descent in serum albumin, the anion gap would decrease
(5-oxoprolinase) or acquired, due to ingestion of paracetamol by 2.5 mEq/L). Failure to correct the calculated anion gap
and more rarely other medications, including vigabatrin, for the plasma albumin concentration may underestimate
netilmicin, and flucoxacillin [81]. Pyroglutamic acidosis is the true anion gap. A normal unadjusted anion gap does
characterized by elevated urinary excretion of 5-oxoproline not exclude the presence of unmeasured anions in patients
[82]. with hypoalbuminemia [88, 89]. Therefore, correction of
Intoxication by some alcohols, including ethanol [73, the calculated anion gap for serum albumin improves the
80], methanol, [83], and propylene glycol [75, 84] induces usefulness and accuracy of this parameter. The following
anion gap acidosis associated with L-lactic acidosis and equation may be used, expressing albumin level in g/L:
accumulation of anions derived from alcohol metabolism, adjusted serum anion gap = observed anion gap + 0.25 ×
including ketone bodies (ethanol), formate (methanol), D- ([normal alb]−[observed alb]). The factor is 2.5 if albumin
lactate (propylene glycol), and oxalate (ethylene glycol) [85, concentration is given in g/dL [87, 89].
86]. An increase in the albumin-adjusted anion gap denotes
The diagnosis of anion gap acidosis is not straightforward, the presence of unmeasured anions, such as phosphate, sul-
as the detection of anions not usually measured by the plasma phate, lactate, ketone bodies, formate, and oxalate, provided
chemical profile (unmeasured anions) has to be indirectly that the level of cations is not altered. A low anion gap occurs
performed via some equations, such as the anion gap, the when there is a significant increase in unmeasured cations, as
chloride/sodium ratio, and the strong ion gap [1, 87]. in lithium intoxication and multiple myeloma (accumulation
of cationic paraproteins). Bromide is identified as chloride
Serum Anion Gap. According to the electroneutrality princi- in some analyzers producing spurious hyperchloremia and a
ple, the sum of cations must be equal to the sum of anions in marked reduction in the anion gap [47, 90].
human plasma:
Chloride/Sodium Ratio. In response to metabolic acidosis due
[Na+ ] + [K+ ] + [unmeasured cations] to accumulation of unmeasured anions, plasma chloride level
(18) decreases relative to sodium, reducing the chloride/sodium
= [Cl− ] + [HCO3 − ] + [unmeasured anions] . ratio ([Cl− ]/[Na+ ]), although the absolute value of plasma
chloride may remain normal. The chloride/sodium ratio
Therefore,
may be used as surrogate to detect unmeasured anions in
[Na+ ] + [K+ ] − ([Cl− ] + [HCO3 − ]) patients with metabolic acidosis. A [Cl− ]/[Na+ ] ratio lower
(19) than 0.75 identifies the presence of unmeasured anions with
= [unmeasured anions] − [unmeasured cations] . a likelihood ratio similar to the anion gap. Conversely, a
high ratio (>0.79) excludes plasma unmeasured anions in
The serum anion gap can be calculated with the following patients with metabolic acidosis [91]. In critically ill neonates,
equation: the chloride/sodium ratio has been efficiently used as a tool
to evaluate raised unmeasured anions. In these patients, a
Serum anion gap (mEq/L)
(20) negative correlation between the chloride/sodium ratio and
= ([Na+ ] + [K+ ]) − ([Cl− ] + [HCO3 − ]) . corrected anion gap is observed [92].
The most commonly used formula for the calculation of the Apparent Strong Ion Difference. In normal human plasma,
serum anion gap excludes potassium concentration: the strong cations usually measured in chemical profiles
outnumber the usually measured strong anions and the
Serum anion gap (mEq/L) difference between them has been named apparent strong ion
(21) difference (SIDa) [1]. Consider
= [Na+ ] − ([Cl− ] + [HCO3 − ]) ,
SIDa (mEq/L) = [usually measured strong cations]
or
− [usually measured strong anions] ,
Serum aniongap (mEq/L)
(22) SIDa (mEq/L) = ([Na+ ] + [K+ ] + [Ca2+ ] + [Mg2+ ])
= [unmeasured anions] − [unmeasured cations] .
− ([Cl− ] + [lactate− ]) .
Normally, unmeasured anions outnumber unmeasured
cations in human plasma and the anion gap is positive. (23)
In normal plasma, the SIDa value is 38 to 42 mEq/L. The usually associated with substantial deviations of the plasma
increase of usually measured strong anions out of proportion pH and near-normal blood pH values have been repeatedly
of usually measured strong cations reduces the apparent observed, likely owing to the fact that the urinary chloride
strong ion difference, being a major cause of acidosis, termed excretion rises with increasing carbon dioxide retention,
SIDa acidosis. SIDa acidosis may be due to hyperchloremic leading to a fall in the plasma chloride concentration with
acidosis or lactic acidosis. If lactate concentration is normal, no variation in plasma sodium [11, 93]. In stable outpatients
SIDa acidosis is equivalent to hyperchloremic acidosis [1, 2, with chronic hypercapnic respiratory failure from COPD,
4]. the arterial pCO2 ranged from 45 to 77 mmHg, whereas the
pH ranged from 7.37 to 7.44. The overall average pH was
Plasma Sodium Concentration Minus Plasma Chloride Con- 7.40, while the overall mean pCO2 was 58 mmHg. The lowest
centration Difference (Sodium-Chloride Effect). As sodium observed pH was 7.37 and a pH lower than 7.38 was rarely
and chloride are the ions with the highest plasma concentra- encountered. Despite having arterial pCO2 levels as high as
tion, the difference between them ([Na+ ] − [Cl− ]) can be used 77 mmHg, all of the patients maintained their pH at 7.37 or
as surrogate for the apparent SID [2]. In critically ill patients, greater and more than 80% had a pH of 7.38 or greater. In
there is a positive correlation between the [Na+ ] − [Cl− ] dif- addition, an increase of 10 mmHg in the pCO2 was associated
ference and the SIDa and the [Na+ ] − [Cl− ] difference reveals with an increase of 5.1 mM in the plasma bicarbonate level
SIDa acidosis with high accuracy [3, 92]. As the [Na+ ] − [Cl− ] and a decrease of only 0.014 in the plasma pH. Therefore, in a
difference predicts the SIDa, the SIDa calculation may be stable patient with a pCO2 of 55 mmHg, the predicted plasma
substituted for the [Na+ ]−[Cl− ] effect in the diagnosis of acid- pH would be 7.40 with a bicarbonate level of 33 mM [13]. In
base disorders [4]. patients with COPD and chronic hypercapnia, the plasma
bicarbonate concentration is elevated and the blood pH is
Effective Strong Ion Difference. The apparent SID has to be only slightly reduced at 7.37. In these patients, a significant
counterbalanced by quantitatively equal negative charges to decrease in plasma chloride concentration is observed with
preserve plasma electroneutrality. The negative charges that no modification in plasma sodium [11]. Among hospitalized
offset the apparent SID are mostly contributed by albumin, hypercapnic patients, a normal arterial pH was seen in 87%
phosphate, and bicarbonate, and the sum of all of them has of the patients with pCO2 between 46 and 55 mmHg [12].
been called the effective strong ion difference (SIDe) [1, 87]: The arterial pH on admission to the hospital in patients with
SIDe (mEq/L) = [HCO3 − ] + [Alb− ] + [Pi− ] . (24) chronic respiratory failure was not significantly away from
normal with a range from 7.37 to 7.41 [94].
In stable patients with cystic fibrosis and severe pul-
monary involvement, the fall in plasma chloride concentra-
Strong Ion Gap. The difference between the apparent and the tion is more pronounced than in patients with COPD with
effective strong ion differences is termed the strong ion gap comparable airway obstruction. Accordingly, the frequency
(SIG): of metabolic alkalosis in patients with cystic fibrosis is signif-
SIG (mEq/L) = SIDa − SIDe. (25) icantly greater than the frequency of this acid-base disorder in
patients with COPD. The pathogenic mechanism that induces
In normal plasma with no excess unmeasured anions, hypochloremia and metabolic alkalosis in patients with cystic
apparent and effective strong ion differences are equal and fibrosis has not been elucidated, but defective cystic fibrosis
therefore the SIG is zero. The SIG becomes positive when transmembrane conductance regulator function with abnor-
there are unidentified anions in plasma, as the presence of mal electrolyte transport within the gastrointestinal tract or
unmeasured anions in plasma usually induces a decrease the kidney likely plays a role [95].
in the effective SID (due to a fall in plasma bicarbonate Patients with acute respiratory failure also show hyper-
concentration) and an increase in the apparent SID (due to capnia, elevated plasma bicarbonate concentration, and
a decrease in plasma chloride level), making positive the reduced plasma chloride concentration with no variation in
difference between SIDa and SIDe. Therefore, similarly to the plasma sodium. Unlike patients with chronic pulmonary dis-
anion gap, a positive SIG detects the presence of unmeasured orders, patients with acute respiratory failure tend to display
anions [1]. It has been shown that the anion gap corrected more acidic plasma pH in some studies [96], but plasma
for albumin and lactate can be used as surrogate for the SIG, acidosis in these patients is likely related to metabolic causes
avoiding its cumbersome calculation. An adjusted anion gap of acidosis, such as L-lactic acidosis due to 𝛽2 -adrenergic
greater than 8 mEq/L accurately predicts SIG acidosis [4]. agonists and the increasing rate and depth of breathing in
patients with acute respiratory failure may represent com-
8.2. Respiratory Acidosis. Neurological and respiratory disor- pensatory hyperventilation to metabolic acidosis rather than
ders, such as chronic obstructive pulmonary disease (COPD), worsening airway obstruction [97, 98].
may impair carbon dioxide elimination leading to carbon In patients with acute respiratory failure of neuromus-
dioxide retention and consequently to an increase in the cular cause, a wide range of plasma pH has been observed,
plasma bicarbonate level, as bicarbonate is the predominant from 7.13 to 7.51, with a mean value of 7.35 and a median
way in which carbon dioxide is transported in plasma [93]. value of 7.38. The average plasma bicarbonate concentration
In patients with chronic respiratory failure, carbon diox- in these patients is 29.8 mM (19–49) and the average pCO2 is
ide retention and raised plasma bicarbonate level are not 55 mmHg (26–100) [99].
8.3. Metabolic Alkalosis. Metabolic alkalosis is caused by a plasma volume contraction intensifies sodium reabsorption
reduction in the plasma chloride level out of proportion by the ENaC with chloride waste in the urine [30–33].
of plasma sodium that may occur either by loss of chlo- Furosemide administration induces acquired inhibition of
ride exceeding sodium or by a marked increase in plasma this cotransporter, whereas congenital blockade is due to
sodium with normochloremia which likewise results in a mutations in the gene encoding the transporter (Bartter
relative deficiency of chloride. The fall in the plasma chloride syndrome) [30, 31].
concentration relative to plasma sodium causes metabolic Similarly, blockade of the apical Na+ -Cl− cotransporter
alkalosis by driving adjustments in the state of dissociation in the distal tubule causes metabolic alkalosis by enhancing
of water to preserve both plasma electroneutrality and the sodium release to the collecting duct and inducing sec-
constancy of the ionic product for water. To maintain elec- ondary hyperaldosteronism. Hydrochlorothiazide use pro-
trical neutrality, the decline in plasma chloride induces an duces acquired inhibition of the Na+ -Cl− cotransporter, while
increase in hydroxide anions that in turn implies a drop Gitelman syndrome due to mutations in the gene coding the
in the hydrogen ions concentration of the same magnitude transporter causes congenital dysfunction [30, 32].
to ensure the constancy of the ionic product for water, In the collecting duct, the coordinated activity of cytosolic
increasing the pH. In addition, a compensatory decrease in carbonic anhydrase and both apical and basolateral ions
the ventilatory rate (hypoventilation) is a critical adaptive transporters including the ENaC, H+ -ATPases, and the kid-
mechanism that raises the plasma bicarbonate concentration, ney isoform of AE1 allow sodium recovery associated with
preventing the excessive increment of hydroxide anions that bicarbonate reabsorption in exchange for chloride that is
generate alkalosis [15, 40]. excreted into the urine. In addition, hydrogen ions and
The predominant cause of metabolic alkalosis is either potassium are secreted into the tubular lumen [34–36].
gastrointestinal or urinary loss of chloride that induces Mineralocorticoids such as aldosterone stimulate sodium
chloride depletion out of proportion of sodium, but a similar reabsorption in the collecting duct through activation of
relative descent in plasma chloride may be generated by the ENaC and therefore allow bicarbonate recovery and
an increment in plasma sodium without modification of chloride waste in urine [35]. Metabolic alkalosis occurs in
plasma anions. Indeed, metabolic alkalosis regularly occurs conditions associated with excess aldosterone activity, either
in critically ill patients developing hypernatremia without autonomous secretion of aldosterone (primary aldostero-
concomitant hyperchloremia [100, 101]. nism) or secondary activation of the RAA system owing to
Causes of metabolic alkalosis due to gastrointestinal renin-producing tumors, renal artery stenosis, and intravas-
loss of chloride exceeding sodium include vomiting, gastric cular volume contraction of any etiology [30, 32, 33, 52].
suction, and loss of intestinal fluid rich in chloride in rare
Metabolic alkalosis may also occur in Liddle syndrome
cases of congenital chloridorrhea, a chloride-rich diarrhea
and 11𝛽-hydroxysteroid dehydrogenase deficiency, condi-
caused by loss of function mutations in the downregulated
tions that cause apparent mineralcorticoid excess. Liddle
in adenoma gene leading to a defect in the apical membrane
syndrome is a congenital disease caused by mutations that
chloride/bicarbonate exchanger in the distal ileum and colon
inhibit the removal of the ENaC from the plasma membrane,
[31, 40, 52, 102].
resulting in permanent sodium reabsorption via this channel.
Metabolic alkalosis associated with chloride waste in the Similarly, excess cortisol levels owing to failure of inactivation
urine out of proportion of sodium is usually secondary to of cortisol by the enzyme 11𝛽-hydroxysteroid dehydrogenase
excess reabsorption of sodium by the ENaC (with attendant activate the mineralcortidoid receptor in the collecting duct
excessive chloride excretion), which may occur in a number and enhance sodium reclamation by the ENaC. Deficiency
of conditions, including furosemide use, Bartter syndrome, of the enzyme 11𝛽-hydroxysteroid dehydrogenase may be
administration of hydrochlorothiazide, Gitelman syndrome, congenital or acquired due to ingestion of carbenoxolone or
excess mineralocorticoid activity (primary or secondary licorice. Both Liddle syndrome and 11𝛽-hydroxysteroid dehy-
aldosteronism), and high dose glucocorticoids. Conditions drogenase deficiency simulate primary hyperaldosteronism,
that lead to apparent mineralcortidoid excess, such as Liddle including metabolic alkalosis, but the plasma concentrations
syndrome and deficiency of 11𝛽-hydroxysteroid dehydroge- of renin and aldosterone are low [33].
nase, also exhibit metabolic alkalosis. In addition, this acid- Pendred syndrome is a recessive autosomal disorder
base disorder may be a feature of Pendred syndrome. characterized by thyroid goiter and sensorineural hearing loss
Urinary chloride level is low (<10 mEq/L) in patients with due to mutations in the gene that encodes pendrin, which
gastrointestinal loss of chloride or prior diuretic use, while is an apical cortical collecting duct chloride/bicarbonate
a high concentration of chloride in the urine (>10 mEq/L) exchanger that manages the secretion of bicarbonate into the
suggests loss of chloride by the kidney including continued tubule lumen in exchange for chloride reabsorption [37–40].
diuretic use [30, 102]. Pendred syndrome (pendrin dysfunction) may be associated
Blockade of the apical membrane Na+ -K+ -2Cl− cotrans- with urinary chloride loss and secondary hypochloremic
porter located at the ascending limb of the Henle’s loop metabolic alkalosis, particularly during vomiting or thiazide
increases the amount of sodium that reaches the collecting therapy [37, 39].
duct, where sodium is reclaimed without chloride by the
ENaC, resulting in metabolic alkalosis. Secondary hyperal- 8.4. Respiratory Alkalosis. An increase in the ventilatory rate
dosteronism associated with activation of the RAA due to is usually secondary to tissue hypoxia or acidosis, although
primary hyperventilation occurs during voluntary forced concentration is sustained or increased further during the
breathing and panic disorder attacks [14, 103]. In addition, entire time at high altitude [107, 108]. Plasma chloride is also
hyperventilation typically precedes the encephalopathy asso- elevated in healthy volunteers experiencing simulated alti-
ciated with conditions featuring hyperammonemia and nor- tude of 3,100 m in a hypobaric chamber [114]. Unlike chloride,
mal human pregnancy is characterized by hyperventilation of no consistent changes in the plasma concentration of sodium
unclear cause [104]. have been detected upon altitude exposure in healthy humans
In healthy humans, voluntary hyperventilation induces [107, 116–120]. The increase in plasma chloride concentration
urine alkalinization to prevent the progression of plasma with no variation in plasma sodium limits the increase in
alkalinization, as it was first reported in 1919 [105]. The plasma pH that occurs upon high altitude exposure.
reabsorption of bicarbonate and sodium ions in the kidney In response to altitude, the kidney modifies the urinary
tubule is inhibited in response to hypocapnia, allowing the ionic composition, including the concentration of hydrogen
urinary excretion of sodium in excess of chloride with
ions. A rise in urine pH maintained during the duration
subsequent plasma chloride retention relative to sodium that
of the exposure is observed in healthy subjects undergoing
contributes to restrain the increase in plasma pH secondary
simulated altitude in hypobaric chambers [114, 121]. Similarly,
to forced breathing. The kidney compensatory response can
begin within minutes and takes effect over a period of hours the inhalation of 14% oxygen (normobaric hypoxia) induces
to days [103]. a fall in the urinary concentration of hydrogen ions and
therefore a shift of urinary pH to higher values [122].
In addition to tissue acidosis, adaptive hyperventilation is
Additionally, in response to acute exposure to high altitude,
physiologically induced by tissue hypoxia, which occurs upon
altitude exposure. A profound alteration in plasma and urine there is an increase in urinary sodium concentration [120,
ionic pattern takes place upon altitude exposure, intended to 123]. Simulated high altitude exposure [113, 114, 124] and
enhance the body capacity to uptake and transport oxygen normobaric hypoxia [122] elicit a similar response, enhancing
to tissue cells and to contain the progression of plasma sodium urinary excretion. After early acclimatization (four
alkalinization. weeks after arrival at 5,050 m altitude) the increase in sodium
At high altitude, the barometric pressure is progressively urinary excretion is less evident [123].
reduced and consequently the partial pressure of oxygen Hyperventilation typically precedes cerebral edema and
(pO2 ) in the inspired air is lower than at sea level. Sea level coma associated with metabolic decompensation in urea
barometric pressure of 760 mmHg drops to 253 mmHg on the cycle disorders and other diseases characterized by hyper-
8,848 meters summit of the Mount Everest and the pressure ammonemia. Indeed, blood ammonium should be deter-
of oxygen in the inspired air falls from 160 mmHg at sea level mined when consciousness deterioration is associated with
to approximately 43 mmHg at the summit of Mount Everest respiratory alkalosis [125]. Most conditions associated with
[106]. hyperammonemia and cerebral edema exhibit secondary
The decrease of the pO2 in the inspired air induces hyperventilation, including liver failure [126], urea cycle
hyperventilation immediately upon exposure to altitude in disorders [125], ornithine transcarbamylase deficiency [127],
order to maintain body oxygenation. The increase in pul- argininosuccinate lyase deficiency [128], lysinuric protein
monary ventilation leads to enhanced elimination of carbon intolerance [129], medium-chain acyl-CoA dehydrogenase
dioxide by the lungs and consequently to a reduction in the MCAD deficiency [130], propionic acidemia [131], valproate
arterial pCO2 [107–109]. In healthy subjects climbing Mount administration [132], Reye’s syndrome [133], urinary tract
Everest breathing ambient air, the mean arterial pCO2 values infections by urea-splitting organisms [134], and chemother-
fell with increasing altitude, while the pH values gradually apy for the treatment of hematologic malignancy [135]. The
increased, reaching mean values of 13.3 mmHg and 7.53 at pathogenic mechanisms that produce hyperventilation in
8,400 m, respectively [110]. The fall in the arterial pCO2 that severe hyperammonemia are unclear. Most disorders leading
occurs on acute arrival at altitude is maintained or further to acute metabolic decompensation with hyperammonemia
declined on prolonged exposure to altitude [107, 108, 111, 112]. and cerebral edema are associated with intracellular acidosis
Healthy subjects undergoing simulated exposure to altitude due to accumulation of different organic anions [136] and
in artificial hypobaric chambers show similar changes than hyperventilation may be a physiological response to intracel-
those that develop in natural high altitude sojourns [113, lular acidosis.
114]. Normobaric hypoxia also induces a fall in the arterial
pCO2 and a rise in the blood pH [115]. Plasma bicarbonate Conflict of Interests
concentration decreases as well on acute arrival at high
altitude and remains lower than at sea level during prolonged The authors declare that there is no conflict of interests
sojourns at altitude [107–109, 116]. An immediate reduction regarding the publication of this paper.
in the plasma bicarbonate concentration is also observed in
healthy subjects in a hypobaric chamber simulating 3,100 m Acknowledgment
altitude [114].
Plasma chloride concentration is elevated upon acute The authors would like to gratefully acknowledge the help
exposure to altitude [107]. The increase in plasma chloride received from Ms. Gema Souto in writing this paper.
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Hindawi Publishing Corporation

BioMed Research International

María M. Adeva-Andany, Natalia Carneiro-Freire,

Correspondence should be addressed to Marı́a M. Adeva-Andany; madevaa@yahoo.com

Academic Editor: George Seki

1. Introduction 2. The Principle of Electrical Neutrality

𝐾eq × [H2 O] = [H+ ] [OH− ] . (4) 5. Definition of pK a

Any reversible chemical reaction at a specified tem-

Figure 1: Carbon dioxide transport in blood.

References [16] M. Fulop, “A guide for predicting arterial CO2 tension in

[134] S. Sato, C. Yokota, K. Toyoda, M. Naganuma, and K. Minematsu,

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