Understanding Acid-base Balance and Imbalance

Introduction

Acid–base balance (of body fluids) refers to the balance between input (intake and production) and output (elimination) of hydrogen ions. The focus is not on acids per se but on hydrogen ions because H+can affect the cell function by altering the charge of functional proteins including enzymes. Acids release hydrogen ions and bases bind to it; they are thus referred to as “hydrogen donors” and “hydrogen acceptors”,

The H+ concentration in body fluids is very low (0.00004 mmol/l) and is thus expressed as its negative log i.e. pH (historically, the “power of hydrogen”).

pH = – log 10{ H+}

Acids are produced in excess of bases (50 mmol/day more) , but the homeostatic mechanisms are so efficient that the body fluids pH is alkaline, at 7.35 + 0.05, the pH being lower in the tissues. It is important to maintain the alkaline pH because most enzymes function best at alkaline pH except for a few e.g. pepsin which acts best at very low pH ,(1 to 2) helped by gastric HCl.

Fig.1- Curve showing relationship between pH and enzyme activity. Note that the optimum pH is around 7.4.

Addition of small amounts of acid or base are quickly compensated by dilution in the blood. Additions that can affect pH are counteracted by the homeostatic mechanisms vizthe blood buffers (in plasma and haemoglobin), respiratory adjustments, renal adjustments and tissue buffers (particularly the bone buffers).

Source of acids

Endogenous

• CO₂is the main source of hydrogen ions, but it is quickly eliminated by the lungs and kidneys; it is a volatile acid, transported from tissues to lungs in the dissolved form as carbonic acid. About 12,500 mEq of carbon dioxide are produced daily, and the average person exhales about 500 litres of carbon dioxide per day.
• Nonvolatile or fixed acids (mainly from protein metabolism, e.g. sulfur-containing amino acids which become sulphuric acid (H₂SO₄) ; and phsphorylated aminoacids which are converted into phosphoric acid ( H₃PO₄)
• Lactic acid production by hypoxic muscle cells
• Ketoacid production by liver (increased in diabetes)
• Retention of
  • CO₂ and carbonic acid in hypoventilation
  • H⁺ ions in renal failure

Exogenous

• food rich in acids (meat),
• ingestion of acids (salicylic acid, NH₄Cl)( many indigenous drugs in Myanmar contain NH₄Cl)

Sources of bases

Bases are produced by dissociation of acids (H2CO3 dissociates into H+ and HCO3-) and there is no production of base except in the kidneys, where ammonia formed from glutamine diffuses into the urine where it binds a hydrogen ion (NH3+H+→NH4+). The antacids magnesium hydroxide or sodium hydrogen carbonate are exogenous sources.

Regulation of pH of body fluids

1. The Buffer systems

A buffer is a chemical substance that resists changes in pH. They act within seconds of alteration in pH, working in pairs in biological systems, as acid (H+ donor) and base (H+ acceptor) e.g. NaHCO3/HHCO3, NaHPO4/HHPO4. A buffer is like a sponge. When hydrogen ions are in excess, the sponge mops up the extra ions. When in short supply, the sponge can be squeezed out to release more hydrogen ions.

Blood has intracellular (haemoglobin) and extracellular (plasma proteins and HCO3/HHCO3 system). Haemoglobin dissociates into H+ and Hb. Plasma proteins are zwitter ions i.e. they can be positively or negatively charged, but have negative charges at pH of body fluids, HProt dissociating into H+ and Prot-.

Tissue and bone buffers act only when the buffer system, respiratory adjustments and renal adjustment cannot restore the pH to its normal range. These are the potassium and phosphate buffers. KHHPO4 dissociates into H+ and KHPO4-; HHPO4 dissociates into H+ and HPO4-.

When a strong acid e.g. HCl is added to the blood, it dissociates into H+ and its anion. The H+ binds to the anions in the buffer system, and the reaction is driven to the left. The blood levels of the three “buffer anions” Hb– (hemoglobin), Prot– (protein), and HCO3– consequently drop. The anions of the added acid arefiltered into the renal tubules. They are accompanied (“covered”) by cations, particularly Na+, to maintain electrical neutrality. The tubules replace the Na+ with H+ and in so doing reabsorb equimolar amounts of Na+ and HCO3– , thus conserving the cations, eliminating the acid, and restoring the supply of buffer anions to normal. When CO2 is added to the blood, similar reactions occur, except that since it is H2CO3 that is formed, the plasma HCO3– rises rather than falls.¹

Fig.2– Shifts in equilibrium with addition or removal of hydrogen ion.

When a strong base. e. g. NaOH is added into the body fluids, it dissociates into OH- and its cation. OH- binds with H+ in the buffer system. The reaction shifts to the right as the weak acid in the system (HA) dissociates to replenish the H+.

The three major buffer systems are:

1.1. Bicarbonate buffer – most important ( in ECF and ICF)

1.2. Phosphate buffer (in ICF; plasma concentration is too low to be an effective ECF buffer)

1.3. Blood buffers- Protein buffer – Largest buffer store; Albumins and globulins (ECF) and haemoglobin in RBC NB –there are protein anions in tissue cells (ICF)

1.1. The bicarbonate buffer

The HCO3/HHCO3 system is of utmost importance because of its association with respiratory adjustments.

This scheme of events occurs when the addition or removal of hydrogen ions occurs as a result of non-respiratory / metabolic causes. If the cause is respiratory, respiratory adjustments obviously cannot take place.

NB in non-respiratory/ metabolic acidosis /alkalosis, the pH and bicarbonate change in the same direction.

Fig.3- Respiratory adjustments to pH change²

3.Renal adjustments

If the pH change persists despite the buffer and respiratory adjustments, or pH had been restored at the expense of altered HCO3/HHCO3 ratio, renal adjustments take place. Carbon dioxide is hydrated to HHCO3 in the renal tubules in the presence of carbonic anhydrase, thence dissociating into H+ and HCO3-. The tubules excrete H+ in exchange for Na+ reabsorption; and reabsorb HCO₃-.i.e. it adds to the numerator and reduces the denominator in the HCO3/HHCO3 equation, raising the pH.

If the secreted hydrogen ions are left unbound, the luminal pH would fall rapidly, and limit its secretion at around pH 4.5 (the “limiting pH”). However, this pH is not reached because H+ is bound by three mechanisms: (1) binding with filtered HCO₃ to become HHCO₃ which further dissociates into water and CO₂ (2) binding with NaNaHPO₄ to become Na HHPO₄ (“titratable acidity”). (3) binding with NH₃ produced from amino acids in the tubules by the action of glutaminase enzyme, resulting in NH₄+ to be excreted as ammonium salts.

Fig.4– Renal adjustments to pH change.2

Fig.5- Binding of secreted hydrogen ions (Source: S.I.Fox (1996) Human Physiology)

In alkalosis, less hydrogen ions are excreted and less bicarbonate reabsorbed, bringing down the pH towards normal.

Fig.6– The restoration of pH to normal by the buffers, lungs and kidneys (redrawn from WF Ganong .Review of Medical Physiology)

However, restoration of pH associated with abnormal HCO3, pCO2 are termed “compensated metabolic/ respiratory acidosis/alkalosis”.

Fig.7– Compensated metabolic acidosis and alkalosis. (Source: WF Ganong, Review of Medical Physiology)

Fig.8– Compensated respiratory acidosis and alkalosis. (Source: WF Ganong, Review of Medical Physiology)

Acid-base imbalance

The pH changes outside the normal range of 7.4 +0.05. is termed “alkalosis” and “acidosis”. Acidosis results when excess acid is added to body fluids either by an increase in production or from exogenous sources, or due to retention of hydrogen in the body. Alkalosis results from any deficit of acid except carbonic acid (loss of H+) or addition of base. These causes may be respiratory or non-respiratory (“metabolic”).

Metabolic acidosis and alkalosis

Table 1- Principal causes of metabolic acidosis

( Source: WF Ganong. Review of Medical Physiology)

Table 2-Principal causes of metabolic alkalosis (Source: WF Ganong.Review of Medical Physiology)

Most causes of metabolic acidosis are accompanied by an increase in anioanion gap because acid is added .Acidosis caused by loss of alkali does not exhibit an increased anion gap.

Respiratory acidosis and alkalosis

Retention of carbon dioxide due to ventilation /perfusion/diffusion failure results in respiratory acidosis whilst carbon dioxide washout as in hyperventilation results in respiratory alkalosis. Free calcium ions bind to protein, and can cause alkalotictetany.

Table 3– Principal causes of respiratory acidosis.

(Source: WF Ganong.Review of Medical Physiology)

When the lungs cannot excrete carbon dioxide, it is retained in the body, and the blood pCO2 rises. It is hydrated to HHCO3 which dissociates into H+ and HCO3- in the blood. Thus, the pH falls and HCO3rises. This happens in the renal tubules as well, and the kidneys excrete H+ whilst reabsorbing HCO3, raising the level further, but pushing the pH towards normal (“compensated respiratory acidosis”/“chronic respiratory acidosis”). When bicarbonate level exceeds the renal threshold, it spills over in the urine (alkaline urine in acidosis).

Table 4– Principal causes of respiratory alkalosis

(Source: WF Ganong. Review of Medical Physiology)

In respiratory alkalosis, pCO2 level falls, HHCO3 dissociates into water and CO2 to replenish the carbon dioxide. As HHCO3 level falls, H+ and HCO3 bind to replenish HHCO3. So pH rises and HCO3 level falls. Because pCO2 is low, less HHCO3 is formed in the renal tubule; less H+ is excreted and less HCO3 reabsorbed, pushing the pH towards normal but lowering the HCO3 further. (“compensated respiratory alkalosis”/”chronic respiratory alkalosis”).

Fig.9– The four types of acid-base imbalance and compensated respiratory acidosis/ alkalosis.

(Source – WF Ganong. Review of Medical Physiology)

Assessing acid-base status

Acid-base disorders are commonly encountered in clinical practice and a structured approach to assessment includes taking a history, performing a physical examination and careful interpretation of routine biochemical tests and arterial blood gas analysis. Additional investigations such as lactate, glucose, ketones or toxicology testing may be needed to more fully characterise a metabolic acidosis. Answering four questions will help determine the problems present in the clinical scenario: What is the pH? What is the bicarbonate? What is the PaCO2? What is the anion gap? Using this approach will help guide further investigations and management of the patient

Fig.10- Analysis of acid-base status. (Source: Body Fluids and kidneys. Guyton & Hall Textbook of Medical Physiology)

Question 1: What is the pH?– Is it acidosis, alkalosis or normal? Because the body compensates for acid-base disorders, it is possible that a disorder might be present even if the pH is normal. It should also be borne in mind that the body never over-compensates.

Question 2: What is the bicarbonate? A reduced bicarbonate concentration is a hallmark of metabolic acidosis and an elevated bicarbonate concentration is a feature of metabolic alkalosis. A high bicarbonate is seen in respiratory acidosis and low bicarbonate in respiratory alkalosis.

NB- pH and bicarbonate go in the same direction in metabolic acidosis/alkalosis; and in opposite directions in respiratory acidosis/alkalosis.

Fig.11- Assessing acid-base status. (Source: S.I.Fox. 1996Human Physiology)

Question 3: What is the PaCO2? A decreased PaCO2 is a feature of respiratory alkalosis. An elevated PaCO2 is a feature of respiratory acidosis.

Question 4: What is the anion gap?

The “anion gap” is an indirect measurement of unmeasured anions (sulphates, phosphates, organic acids) calculated as [Anions other than sodium]- [cations other than chloride and bicarbonate] and is about 12 mEq/l. In the assessment of acid–base disorders, commonly measured electrolytes are serum Na+, K+, H+ (as pH), Cl−, and HCO3−. Other anions (e.g., sulfates, phosphates, proteins) and cations (e.g., calcium, magnesium, proteins) are not measured routinely but can be estimated indirectly, since (to maintain electrical neutrality) the sum of the cations must equal that of the anions. Serum Na+ and K+ content accounts for 95% of cations, and Cl− and HCO3− for about 85% of anions. 3

Unmeasured anions = [Na+] + [K+] − [Cl−] − [HCO3−]

Disorders that cause a high anion gap are metabolic acidosis, dehydration, therapy with sodium salts of strong acids, therapy with certain antibiotics (e.g., carbenicillin), and alkalosis. If HAGMA is identified, the three common aetiologies (lactic acidosis, ketoacidosis or kidney failure) should be identified5. If these can be excluded, then the HAGMA may be linked to ingestion of a toxin e.g. methanol or ethylene glycol, or be due to the build-up of another acid such as 5-oxyproline (also known as pyroglutamic acid) which may accumulate with chronic paracetamol use in susceptible individuals 6.

Metabolic acidosis with a normal anion gap (NAGMA) are conditions caused by los of bicarbonate, retention of chloride (Hyperchloraemic acidosis in renal tubular acidosis) saline infusion (adds chloride to the system so bicarbonate level drops because CL- + HCO3– is kept constant) present with a normal anion gap.

A decrease in the normal anion gap occurs in various plasma dilution states, hypercalcemia, hypermagnesemia, hypernatremia, hypoalbuminemia, disorders associated with hyperviscosity,

Fig.12– Normal anion gap and high anion gap metabolic acidosis (HAGMA)
(Source: “Understanding Acid-Base Disorders”Hamiltonet al)

Fig.13– Hyperchloraemic acidosis presents with a normal anion gap. The primary abnormality is an increase in Cl-. This is matched by a fall in HCO3- (and vice versa so that the sum of Cl- and HCO3- remains the same ).The fall in bicarbonate results in metabolic acidosis.

Management of acid-base imbalance⁷

Acid-base derangements are encountered frequently in clinical practice and many have life-threatening implications. Treatment is dependent on correctly identifying the acid-base disorder and, whenever possible, repairing the underlying causal process. Bicarbonate is the agent of choice for the treatment of acute metabolic acidosis.Controversy surrounds the use of alkali therapy in lactic acidosis and diabetic ketoacidosis, but bicarbonate should clearly be administered for severe acidosis.

In most patients with mild to moderate chloride-responsive metabolic alkalosis, providing an adequate amount of a chloride salt will restore acid-base balance to normal over a matter of days. In contrast, therapy of the chloride-resistant metabolic alkalosis is best directed at the underlying disease. When alkalemia is severe, administering hydrochloric acid or a hydrochloric acid precursor may be necessary.

Treatment of respiratory acidosis should be targeted at restoring ventilation; alkali should be administered only for superimposed metabolic acidosis. The therapy of respiratory alkalosis is centred on reversal of the root cause; short of this goal, there is no effective treatment of primary hypocapnia. The coexistence of more than one acid-base disorder (i.e. a mixed disorder) is not uncommon. When plasma bicarbonate concentration and arterial carbon dioxide tension (paCO2) are altered in opposite directions, extreme shifts in pH may occur. In such cases, it is imperative that the nature of the disturbance is identified early and therapy directed at both disorders.

References

1. WFGanong .Review of Medical Physiology Chapter 40. Acidification of the Urine &Bicarbonate Excretion
2. https://open.oregonstate.education/aandp/chapter/26-4-acid-base-balance/
3. Bhagavan NV, Chung-Eun Ha.2015.“Water, Electrolytes, and Acid–Base Balance”.
   Essentials of Medical Biochemistry (Second Edition)

4. HamiltonPK, Morgan NA, ConnollyGM  and. MaxwellAP. 2017. “Understanding Acid-Base Disorders”.Ulster Med J.  86(3): 161–166.

5. Kraut JA, Madias NE. 2016, “Lactic acidosis: current treatments and future directions”. Am J Kidney Dis..68((3)):473–82. [PubMed]
6. Fenves AZ, Kirkpatrick HM, 3rd, Patel VV, Sweetman L, Emmett M.2006. “Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen”. Clin J Am SocNephrol.;1((3)):441–7. [PubMed]

Author information

MB,BS (Rgn);M.Sc(Mdy);PhD(Lond); FRCP(Edin)(Hon);Cert.in Leadership for Physician Educators ( Harvard Business School).
Honorary Professor, University of Medicine 1, Yangon