View source for Acid–base homeostasis

{{Short description|Process by which the human body regulates pH}}
{{Acids and bases}}
'''Acid–base homeostasis''' is the [[homeostasis|homeostatic]] regulation of the [[pH]] of the [[Body fluid|body's]] [[extracellular fluid]] (ECF).<ref name="CJASN">{{Cite journal |vauthors=Hamm LL, Nakhoul N, Hering-Smith KS |date=December 2015 |title=Acid-Base Homeostasis |journal=Clinical Journal of the American Society of Nephrology |volume=10 |issue=12 |pages=2232–2242 |doi=10.2215/CJN.07400715 |pmc=4670772 |pmid=26597304}}</ref> The proper [[#Acid–base balance|balance]] between the [[acid]]s and [[Base (chemistry)|bases]] (i.e. the pH) in the ECF is crucial for the normal [[physiology]] of the body—and for [[Cell (biology)|cellular]] [[metabolism]].<ref name="CJASN" /> The pH of the [[intracellular fluid]] and the extracellular fluid need to be maintained at a constant level.<ref>{{Cite book |title=Principles of anatomy & physiology. |vauthors=Tortora GJ, Derrickson B |date=2012 |publisher=Wiley |others=Derrickson, Bryan. |isbn=9780470646083 |edition=13th |location=Hoboken, NJ |pages=42–43 |oclc=698163931}}</ref>

The [[tertiary structure|three dimensional structures]] of many extracellular proteins, such as the [[plasma proteins]] and [[membrane protein]]s of the body's [[Cell (biology)|cells]], are very sensitive to the extracellular pH.<ref name="macefield">{{Cite journal |vauthors=Macefield G, Burke D |date=February 1991 |title=Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons |journal=Brain |volume=114 ( Pt 1B) |issue=1 |pages=527–540 |doi=10.1093/brain/114.1.527 |pmid=2004255 |doi-access=free}}</ref><ref>{{Cite book |title=Biochemistry |vauthors=Stryer L |date=1995 |publisher=W.H. Freeman and Company |isbn=0-7167-2009-4 |edition=4th |location=New York |pages=347, 348}}</ref> Stringent mechanisms therefore exist to maintain the pH within very narrow limits. Outside the acceptable range of pH, [[protein]]s are [[denaturation (biochemistry)|denatured]] (i.e. their 3D structure is disrupted), causing [[enzyme]]s and [[ion channels]] (among others) to malfunction.

An [[acid–base imbalance]] is known as acidemia when the pH is acidic, or alkalemia when the pH is alkaline.

== Lines of defense ==
In humans and many other animals, acid–base homeostasis is maintained by multiple mechanisms involved in three lines of defense:<ref name="silverthorn">{{Cite book |title=Human physiology. An integrated approach |vauthors=Silverthorn DU |publisher=Pearson |year=2016 |isbn=978-1-292-09493-9 |edition=7th, Global |location=Harlow, England |pages=607–608, 666–673}}</ref><ref>{{Cite journal |vauthors=Adrogué HE, Adrogué HJ |date=April 2001 |title=Acid-base physiology |journal=Respiratory Care |volume=46 |issue=4 |pages=328–341 |pmid=11345941}}</ref>

# Chemical: The first lines of defense are immediate, consisting of the various chemical [[Buffer solution|buffers]] which minimize pH changes that would otherwise occur in their absence. These buffers include the [[bicarbonate buffer system]], the [[phosphate buffer system]], and the [[protein buffer system]].<ref>{{Cite web |title=184 26.4 Acid-Base Balance {{!}} Anatomy and Physiology {{!}} OpenStax |url=https://opentextbc.ca/anatomyandphysiology/chapter/26-4-acid-base-balance/ |url-status=dead |archive-url=https://web.archive.org/web/20200917014006/https://opentextbc.ca/anatomyandphysiology/chapter/26-4-acid-base-balance/ |archive-date=2020-09-17 |access-date=2020-07-01 |website=openstax.org |language=en}}</ref>
# Respiratory component: The second line of defense is rapid consisting of the control the [[carbonic acid]] (H<sub>2</sub>CO<sub>3</sub>) concentration in the ECF by changing the rate and depth of [[breathing]] by [[hyperventilation]] or [[hypoventilation]]. This blows off or retains [[carbon dioxide]] (and thus carbonic acid) in the blood plasma as required.<ref name="silverthorn" /><ref name="medline" />
# Metabolic component: The third line of defense is slow, best measured by the [[base excess]],<ref name="Base Excess">{{Cite web |title=Terminology |url=https://acid-base.com/terminology#BE2 |access-date=9 April 2021 |website=Acid Base Tutorial |publisher=Grog LLC |vauthors=Grogono A}}</ref> and mostly depends on the [[Renal System|renal system]] which can add or remove [[bicarbonate]] ions ({{chem|HCO|3|-}}) to or from the ECF.<ref name="silverthorn" /> Bicarbonate ions are derived from [[Metabolism|metabolic]] carbon dioxide which is enzymatically converted to carbonic acid in the [[Renal tubule|renal tubular cells]].<ref name="silverthorn" /><ref name="tortora2" /><ref name="stryer" /> There, carbonic acid spontaneously [[Dissociation (chemistry)|dissociates]] into hydrogen ions and bicarbonate ions.<ref name="silverthorn" /> When the pH in the ECF falls, hydrogen ions are excreted into urine, while bicarbonate ions are secreted into blood plasma, causing the plasma pH to rise.<ref name="tortora1" /> The converse happens if the pH in the ECF tends to rise: bicarbonate ions are then excreted into the urine and hydrogen ions into the blood plasma.

The second and third lines of defense operate by making changes to the buffers, each of which consists of two components: a weak acid and its [[Conjugate acid|conjugate base]].<ref name="silverthorn" /><ref name="tortora" /> It is the ratio concentration of the weak acid to its conjugate base that determines the pH of the solution.<ref name="Bray1999" /> Thus, by manipulating firstly the concentration of the weak acid, and secondly that of its conjugate base, the pH of the [[extracellular fluid]] (ECF) can be adjusted very accurately to the correct value. The bicarbonate buffer, consisting of a mixture of carbonic acid (H<sub>2</sub>CO<sub>3</sub>) and a bicarbonate ({{chem|HCO|3|-}}) salt in solution, is the most abundant buffer in the extracellular fluid, and it is also the buffer whose acid-to-base ratio can be changed very easily and rapidly.<ref name="garrett" />

==Acid–base balance==
The [[pH#Living systems|pH]] of the extracellular fluid, including the [[blood plasma]], is normally tightly regulated between 7.32 and 7.42 by the [[chemical buffers]], the [[respiratory system]], and the [[renal system]].<ref name="tortora">{{Cite book |url=https://archive.org/details/principlesofan1987tort |title=Principles of anatomy and physiology |vauthors=Tortora GJ, Derrickson BH |date=1987 |publisher=Harper & Row, Publishers |isbn=0-06-350729-3 |edition=Fifth |location=New York |pages=[https://archive.org/details/principlesofan1987tort/page/698 698–700] |url-access=registration}}</ref><ref name="ciba">{{Cite book |title=in: Scientific Tables |vauthors=Diem K, Lentner C |date=1970 |publisher=CIBA-GEIGY Ltd. |edition=Seventh |location=Basle, Switzerland |page=527 |chapter=Blood – Inorganic substances}}</ref><ref>{{MedlinePlusEncyclopedia|003855|Blood gases}}</ref><ref>{{Cite book |title=Nancy Caroline's Emergency care in the streets |vauthors=Caroline N |publisher=Jones & Bartlett Learning |year=2013 |isbn=978-1449645861 |edition=7th |location=Buffer systems |pages=347–349}}</ref><ref name=CJASN/> The normal pH in the [[fetus]] differs from that in the adult. In the fetus, the pH in the [[umbilical vein]] pH is normally 7.25 to 7.45 and that in the [[umbilical artery]] is normally 7.18 to 7.38.<ref name="Yeomans">{{Cite journal |vauthors=Yeomans ER, Hauth JC, Gilstrap LC, Strickland DM |date=March 1985 |title=Umbilical cord pH, PCO2, and bicarbonate following uncomplicated term vaginal deliveries |journal=American Journal of Obstetrics and Gynecology |volume=151 |issue=6 |pages=798–800 |doi=10.1016/0002-9378(85)90523-x |pmid=3919587}}</ref>

[[Aqueous solution|Aqueous]] [[buffer solution]]s will react with [[strong acids]] or [[strong base]]s by absorbing excess {{chem|H|+}} ions, or {{chem|OH|-}} ions, replacing the strong acids and bases with [[Acid strength#Weak acids in water|weak acids]] and [[weak base]]s.<ref name="tortora" /> This has the effect of damping the effect of pH changes, or reducing the pH change that would otherwise have occurred. But buffers cannot correct abnormal pH levels in a solution, be that solution in a test tube or in the extracellular fluid. Buffers typically consist of a pair of compounds in solution, one of which is a weak acid and the other a weak base.<ref name="tortora" /> The most abundant buffer in the ECF consists of a solution of carbonic acid (H<sub>2</sub>CO<sub>3</sub>), and the bicarbonate ({{chem|HCO|3|-}}) salt of, usually, sodium (Na<sup>+</sup>).<ref name="silverthorn" /> Thus, when there is an excess of {{chem|OH|-}} ions in the solution carbonic acid ''partially'' neutralizes them by forming H<sub>2</sub>O and bicarbonate ({{chem|HCO|3|-}}) ions.<ref name="silverthorn" /><ref name="garrett">{{Cite book |url=https://books.google.com/books?id=iGPsen3fSOIC&pg=PA43 |title=Biochemistry |vauthors=Garrett RH, Grisham CM |publisher=Cengage Learning |year=2010 |isbn=978-0-495-10935-8 |page=43}}</ref> Similarly an excess of H<sup>+</sup> ions is ''partially'' neutralized by the bicarbonate component of the buffer solution to form carbonic acid (H<sub>2</sub>CO<sub>3</sub>), which, because it is a weak acid, remains largely in the undissociated form, releasing far fewer H<sup>+</sup> ions into the solution than the original strong acid would have done.<ref name="silverthorn" />

The pH of a buffer solution depends solely on the ''ratio'' of the [[Molar mass|molar]] concentrations of the weak acid to the weak base. The higher the concentration of the weak acid in the solution (compared to the weak base) the lower the resulting pH of the solution. Similarly, if the weak base predominates the higher the resulting pH.{{cn|date=November 2024}}

This principle is exploited to ''regulate'' the pH of the extracellular fluids (rather than just ''buffering'' the pH). For the [[Bicarbonate buffer system|carbonic acid-bicarbonate buffer]], a molar ratio of weak acid to weak base of 1:20 produces a pH of 7.4; and vice versa—when the pH of the extracellular fluids is 7.4 then the ratio of carbonic acid to bicarbonate ions in that fluid is 1:20.<ref name="Bray1999">{{Cite book |title=Lecture notes on human physiology |vauthors=Bray JJ |publisher=Blackwell Science |year=1999 |isbn=978-0-86542-775-4 |location=Malden, Mass. |page=556}}</ref>

=== Henderson–Hasselbalch equation ===
{{Main|Henderson–Hasselbalch equation}}
The [[Henderson–Hasselbalch equation]], when applied to the [[Bicarbonate buffering system|carbonic acid-bicarbonate buffer system]] in the extracellular fluids, states that:<ref name="Bray1999" />

:<math> \mathrm{pH} = \mathrm{p}K_{\mathrm{a}~\mathrm{H}_2\mathrm{CO}_3} + \log_{10}  \left ( \frac{[\mathrm{HCO}_3^-]}{[\mathrm{H}_2\mathrm{CO}_3]} \right ),</math>

where:
* {{math|pH}} is the negative logarithm (or [[cologarithm]]) of molar concentration of hydrogen ions in the extracellular fluid.
* {{math|p''K''<sub>a H<sub>2</sub>CO<sub>3</sub></sub>}} is the cologarithm of the [[acid dissociation constant]] of [[carbonic acid]]. It is equal to 6.1.
* {{math|[HCO{{su|b=3|p=−}}]}} is the molar concentration of [[bicarbonate]] in the blood plasma.
* {{math|[H<sub>2</sub>CO<sub>3</sub>]}} is the molar concentration of [[carbonic acid]] in the extracellular fluid.

However, since the carbonic acid concentration is directly proportional to the [[partial pressure]] of carbon dioxide (<math>P_{{\mathrm{CO}}_2}</math>) in the extracellular fluid, the equation can be [[Henderson–Hasselbalch equation#Estimating blood pH|rewritten as follows]]:<ref name="silverthorn" /><ref name="Bray1999" />

:<math> \mathrm{pH} = 6.1 + \log_{10}  \left ( \frac{[\mathrm{HCO}_3^-]}{0.0307 \times P_{\mathrm{CO}_2}} \right ),</math>

where:
* {{math|pH}} is the negative logarithm of molar concentration of hydrogen ions in the extracellular fluid.
* {{math|[HCO{{su|b=3|p=−}}]}} is the molar concentration of bicarbonate in the plasma.
* {{math|''P''<sub>CO<sub>2</sub></sub>}} is the [[partial pressure]] of [[carbon dioxide]] in the blood plasma.

The pH of the extracellular fluids can thus be controlled by the regulation of <math>P_{{\mathrm{CO}}_2}</math> and the other metabolic acids.

=== Homeostatic mechanisms ===

[[Homeostasis#Blood partial pressure of and carbon dioxide|Homeostatic control]] can change the [[PCO2|{{math|''P''<sub>CO<sub>2</sub></sub>}}]] and hence the pH of the arterial plasma within a few seconds.<ref name="silverthorn" /> The partial pressure of carbon dioxide in the arterial blood is monitored by the [[central chemoreceptors]] of the [[medulla oblongata]].<ref name="silverthorn" /><ref name="J. 2010 907">{{Cite book |title=Principles of anatomy and physiology |vauthors=Tortora GJ, Derrickson BH |date=2010 |publisher=John Wiley & Sons |others=Derrickson, Bryan. |isbn=9780470233474 |edition=12th |location=Hoboken, NJ |pages=907 |oclc=192027371}}</ref> These chemoreceptors are sensitive to the levels of carbon dioxide and pH in the [[cerebrospinal fluid]].<ref name="Bray1999" /><ref name="tortora1">{{Cite book |url=https://archive.org/details/principlesofanat05tort |title=Principles of anatomy and physiology |vauthors=Tortora GJ, Derrickson BH |date=1987 |publisher=Harper & Row, Publishers |isbn=0-06-350729-3 |edition=Fifth |location=New York |pages=[https://archive.org/details/principlesofanat05tort/page/494 494], 556–582 |url-access=registration}}</ref><ref name="J. 2010 907" />

The central chemoreceptors send their information to the [[respiratory center]]s in the medulla oblongata and [[pons]] of the [[brainstem]].<ref name="tortora1" /> The respiratory centres then determine the average rate of ventilation of the [[Pulmonary alveolus|alveoli]] of the [[lungs]], to keep the {{math|''P''<sub>CO<sub>2</sub></sub>}} in the arterial blood constant. The respiratory center does so via [[motor neuron]]s which activate the [[muscles of respiration]] (in particular, the [[Thoracic diaphragm|diaphragm]]).<ref name="silverthorn" /><ref name="Levitzky2013_9">{{Cite book |title=Pulmonary physiology |vauthors=Levitzky MG |date=2013 |publisher=McGraw-Hill Medical |isbn=978-0-07-179313-1 |edition=Eighth |location=New York |page=Chapter 9. Control of Breathing}}</ref> A rise in the {{math|''P''<sub>CO<sub>2</sub></sub>}} in the arterial blood plasma above {{Convert|5.3|kPa|mmHg|abbr=on}} reflexly causes an increase in the rate and depth of [[breathing#Mechanics|breathing]]. Normal breathing is resumed when the partial pressure of carbon dioxide has returned to 5.3&nbsp;kPa.<ref name="medline">{{MedlinePlusEncyclopedia|000335|Metabolic acidosis}}</ref> The converse happens if the partial pressure of carbon dioxide falls below the normal range. Breathing may be temporally halted, or slowed down to allow carbon dioxide to accumulate once more in the lungs and arterial blood.{{cn|date=November 2024}}

The sensor for the plasma HCO{{su|b=3|p=−}} concentration is not known for certain. It is very probable that the [[Kidney|renal]] tubular cells of the [[distal convoluted tubule]]s are themselves sensitive to the pH of the plasma. The metabolism of these cells produces CO<sub>2</sub>, which is rapidly converted to H<sup>+</sup> and HCO{{su|b=3|p=−}} through the action of [[carbonic anhydrase]].<ref name="silverthorn" /><ref name="tortora2">{{Cite book |url=https://archive.org/details/principlesofanat05tort |title=Principles of anatomy and physiology |vauthors=Tortora GJ, Derrickson BH |date=1987 |publisher=Harper & Row, Publishers |isbn=0-06-350729-3 |edition=Fifth |location=New York |pages=[https://archive.org/details/principlesofanat05tort/page/581 581]–582, 675–676 |url-access=registration}}</ref><ref name="stryer">{{Cite book |title=Biochemistry. |vauthors=Stryer L |date=1995 |publisher=W.H. Freeman and Company |isbn=0-7167-2009-4 |edition=Fourth |location=New York |pages=39, 164, 630–631, 716–717}}</ref> When the extracellular fluids tend towards acidity, the renal tubular cells secrete the H<sup>+</sup> ions into the tubular fluid from where they exit the body via the urine. The HCO{{su|b=3|p=−}} ions are simultaneously secreted into the blood plasma, thus raising the bicarbonate ion concentration in the plasma, lowering the carbonic acid/bicarbonate ion ratio, and consequently raising the pH of the plasma.<ref name="silverthorn" /><ref name="tortora1" /> The converse happens when the plasma pH rises above normal: bicarbonate ions are excreted into the urine, and hydrogen ions into the plasma. These combine with the bicarbonate ions in the plasma to form carbonic acid (H<sup>+</sup> + HCO{{su|b=3|p=−}} <math>\rightleftharpoons</math> H<sub>2</sub>CO<sub>3</sub>), thus raising the carbonic acid:bicarbonate ratio in the extracellular fluids, and returning its pH to normal.<ref name="silverthorn" />

In general, metabolism produces more waste acids than bases.<ref name="silverthorn" /> Urine produced is generally acidic and is partially neutralized by the ammonia (NH<sub>3</sub>) that is excreted into the urine when [[glutamate]] and [[glutamine]] (carriers of excess, no longer needed, amino groups) are [[deamination|deaminated]] by the [[Distal convoluted tubule|distal renal tubular epithelial]] cells.<ref name="silverthorn" /><ref name="stryer" /> Thus some of the "acid content" of the urine resides in the resulting ammonium ion (NH<sub>4</sub><sup>+</sup>) content of the urine, though this has no effect on pH homeostasis of the extracellular fluids.<ref name="silverthorn" /><ref>{{Cite book |url=https://archive.org/details/renalpathophysio0000rose |title=Renal Pathophysiology |vauthors=Rose B, Rennke H |publisher=Williams & Wilkins |year=1994 |isbn=0-683-07354-0 |location=Baltimore |url-access=registration}}</ref>

==Imbalance==
[[File:Grogono Acid-Base-Diagram.png|thumb|right|An acid-base diagram for human plasma, showing the effects on the plasma pH when {{math|''P''<sub>CO<sub>2</sub></sub>}} in mmHg or Standard Base Excess (SBE) occur in excess or are deficient in the plasma<ref>{{Cite journal |vauthors=Grogono AW |date=April 2019 |title=Acid-Base Reports Need a Text Explanation |journal=Anesthesiology |volume=130 |issue=4 |pages=668–669 |doi=10.1097/ALN.0000000000002628 |pmid=30870214 |ref=Anesthesiology April 2019, Vol. 130, 668–669. |doi-access=free}}</ref>]]
[[Acid–base imbalance]] occurs when a significant insult causes the blood pH to shift out of the normal range (7.32 to 7.42<ref name="ciba" />). An abnormally low pH in the extracellular fluid is called an ''acidemia'' and an abnormally high pH is called an ''alkalemia''.{{cn|date=November 2024}}

''Acidemia'' and ''alkalemia'' unambiguously refer to the actual change in the pH of the extracellular fluid (ECF).<ref name="dorland" /> Two other similar sounding terms are ''acidosis'' and ''alkalosis''. They refer to the customary effect of a component, respiratory or metabolic. ''Acidosis'' would cause an ''acidemia'' on its own (i.e. if left "uncompensated" by an alkalosis).<ref name="dorland">{{Cite book |title=Dorland's illustrated medical dictionary |vauthors=Andertson DM |publisher=Saunders |year=2003 |isbn=0-7216-0146-4 |edition=30th |location=Philadelphia |pages=17, 49}}</ref> Similarly, an ''alkalosis'' would cause an ''alkalemia'' on its own.<ref name="dorland" /> In medical terminology, the terms ''acidosis'' and ''alkalosis'' should always be qualified by an adjective to indicate the [[etiology]] of the disturbance: ''respiratory'' (indicating a change in the partial pressure of carbon dioxide),<ref>{{Cite web |title=Acid-base physiology |url=http://www.anaesthesiamcq.com/AcidBaseBook/ab4_1.php |quote=Respiratory acidosis: definition. |vauthors=Brandis K}}</ref> or ''metabolic'' (indicating a change in the Base Excess of the ECF).<ref name="Base Excess" /> There are therefore four different acid-base problems: [[metabolic acidosis]], [[respiratory acidosis]], [[metabolic alkalosis]], and [[respiratory alkalosis]].<ref name="silverthorn" /> One or a combination of these conditions may occur simultaneously. For instance, a ''metabolic acidosis'' (as in uncontrolled [[diabetes mellitus]]) is almost always partially compensated by a ''respiratory alkalosis'' (hyperventilation). Similarly, a ''respiratory acidosis'' can be completely or partially corrected by a ''metabolic alkalosis''.{{cn|date=November 2024}}

== References ==
{{Reflist}}

== External links ==
* [http://www.acidbase.org Stewart's original text at acidbase.org]
* [http://www.anaesthesiamcq.com/AcidBaseBook/ABindex.php On-line text at AnaesthesiaMCQ.com]
* [https://web.archive.org/web/20061217055347/http://www2.kumc.edu/ki/physiology/course/nine/9_1.htm Overview at kumc.edu]
* [http://www.acid-base.com/physiology.php Acid-Base Tutorial]
* [http://www.anaesthesiamcq.com/AcidBaseBook/ABindex.php Online acid–base physiology text]
* [http://www.lakesidepress.com/pulmonary/ABG/MixedAB.htm Diagnoses at lakesidepress.com]
* [https://web.archive.org/web/20040618202049/http://www.nda.ox.ac.uk/wfsa/html/u16/u1602_01.htm Interpretation at nda.ox.ac.uk]
* Acids and Bases [https://web.archive.org/web/20111204070653/http://www.sky-web.pwp.blueyonder.co.uk/Science/acids.htm – definitions]

{{Acid-base disorders}}
{{Renal physiology}}
{{Human homeostasis}}
{{Authority control}}

{{DEFAULTSORT:Acid-base homeostasis}}
[[Category:Human homeostasis]]
[[Category:Acid–base physiology]]
[[Category:Acid–base disturbances]]
[[Category:Equilibrium chemistry]]
[[Category:Respiratory therapy]]