Physiology, Metabolic Alkalosis

Article Author:
Joshua Brinkman
Article Editor:
Sandeep Sharma
Updated:
3/4/2019 10:57:09 AM
PubMed Link:
Physiology, Metabolic Alkalosis

Introduction

Normal human physiological pH is 7.35 to 7.45. A decrease in pH below this range is acidosis, an increase over this range is alkalosis. Metabolic alkalosis is defined as a disease state where the body’s pH is elevated to greater than 7.45 secondary to some metabolic process. Before going into details about pathology and this disease process, some background information about the physiological pH buffering process is important. The primary pH buffer system in the human body is the bicarbonate (HCO3)/carbon dioxide (CO2) chemical equilibrium system. Where:

  • H + HCO3 <--> H2CO3 <--> CO2 + H2O

HCO3 functions as an alkalotic substance. CO2 functions as an acidic substance. Therefore, increases in HCO3 or decreases in CO2 will make blood more alkalotic. The opposite is also true where decreases in HCO3 or an increase in CO2 will make blood more acidic. CO2 levels are physiologically regulated by the pulmonary system through respiration, whereas the HCO3 levels are regulated through the renal system with reabsorption rates. Therefore, metabolic alkalosis is an increase in serum HCO3.[1][2]

Related Testing

An arterial blood gas is a laboratory test used for the measurement of arterial pH, the arterial partial pressure of oxygen (PaO2), the arterial partial pressure of carbon dioxide (PaCO2), bicarbonate (HCO3), base excess, total CO2, and O2 saturation.

A venous blood gas is a laboratory test identical to an arterial blood gas measurement, except the blood is drawn from a venous site. This results in a slightly more acidic “normal” pH range.

Urine chloride is a direct measurement of chloride being excreted into urine. This test is useful to help determine the etiology of metabolic alkalosis.[3][4][5]

Pathophysiology

There is a multitude of disease states that induce metabolic alkalosis. In general, the causes can be narrowed down to an intracellular shift of hydrogen ions, gastrointestinal (GI) loss of hydrogen ions, excessive renal hydrogen ion loss, retention or addition of bicarbonate ions, or volume contraction around a constant amount of extracellular bicarbonate known as contraction alkalosis. All of which leads to the net result of increased levels of bicarbonate in the blood. As long as renal function is maintained, excess bicarbonate is excreted in the urine fairly rapidly. As a result, metabolic alkalosis will persevere if the ability to eliminate bicarbonate is impaired due to one of the following causes: hypovolemia, reduced effective arterial blood volume, chloride depletion, hypokalemia, reduced glomerular filtration rate, and/or hyperaldosteronism.

Intracellular Shift of Hydrogen

Anytime that hydrogen ions are shifted intracellularly, this imbalance in the buffer system has a relative increase in bicarbonate. Processes that drive hydrogen intracellularly include hypokalemia.

Gastrointestinal Loss of Hydrogen

Stomach fluids are highly acidic at a pH of approximately 1.5 to 3.5.  Hydrogen secretion is accomplished via parietal cells in the gastric mucosa. Therefore, the large volume loss of gastric secretions will correlate as a loss of hydrogen chloride, an acidic substance, leading to a relative increase in bicarbonate in the blood, thus driving alkalosis.  Losses can occur pathologically via vomitus or nasogastric suctioning.

Renal Loss of Hydrogen

Hydrogen is used within the kidneys are an antiporter energy gradient to retain a multitude of other elements. Of interest here, sodium is reabsorbed through an exchange for hydrogen in the renal collecting ducts under the influence of aldosterone. Therefore, pathologies that increase the levels of mineralocorticoids or increase the effect of aldosterone, such as Conn syndrome will lead to hypernatremia, hypokalemia, and hydrogen loss in the urine. In a similar vein of thought, loop and thiazide diuretics are capable of inducing secondary hyperaldosteronism by increasing sodium and fluid load to the distal nephron, which encourages the renin-angiotensin-aldosterone system.  Genetic defects that lead to decreased expression of ion transporters in the Loop of Henle are possible but less common. These syndromes are known as Bartter and Gitelman disease. The net effect of these genetic defects is akin to the action of loop diuretics.

Retention/Addition of Bicarbonate

Several etiologies lead to increases in bicarbonate within the blood. The simplest of which is an overdose of exogenous sodium bicarbonate in a medical setting. Milk-alkali syndrome is a pathology where the patient consumes excessive quantities of oral calcium antacids, which leads to hypercalcemia and varying degrees of renal failure. Additionally, since antacids are neutralizing agents, they add alkaline substances to the body while reducing acid levels thus increasing pH. A pathology that is in line with normal physiology is the body’s natural compensation mechanism for hypercarbia. When a patient hypoventilates, CO2 retention occurs in the lungs and subsequently reduces pH.  Over time, the renal system compensates by retaining bicarbonate to balance pH. This is a slower process.  Once the hypoventilation is corrected, such as with a ventilator-assisted respiratory failure patient CO2 levels will quickly decrease, but bicarbonate levels will lag in reducing. This causes post-hypercapnia metabolic alkalosis, which is self-correcting. It is possible to calculate the expected pCO2 in the setting of metabolic alkalosis to determine if it is a compensatory increase in bicarbonate, or if there is an underlying pathology driving alkalosis using the following equation:

  • Expected pCO2 = 0.7 (HCO3) + 20 mmHg +/- 5

If the expected pCO2 does not match the measured value, an underlying metabolic alkalosis is a likely present.

Contraction Alkalosis

This phenomenon occurs when a large volume of sodium-rich, bicarbonate low fluid is lost from the body. This occurs with diuretic use, cystic fibrosis, congenital chloride diarrhea, among others. The net concentration of bicarbonate increases as a result. This pathology is easily offset by the release of hydrogen from intracellular space to balance the pH in most incidences.

The exact etiology, if unknown or not obvious, can be elucidated in part by evaluation of urinary chloride. Metabolic alkalosis is split into 2 main categories: Chloride responsive with urine chloride less than 10 mEq/L and chloride resistant with urine chloride greater than 20 mEq/L.  Chloride responsive etiologies include loss of hydrogen via the gastrointestinal tract, congenital chloride diarrhea syndrome, contraction alkalosis, diuretic therapy, post-hypercapnia syndrome, cystic fibrosis, and exogenous alkalotic agent use. Chloride-resistant etiologies include retention of bicarbonate, the shift of hydrogen into intracellular spaces, hyperaldosteronism, Bartter syndrome, and Gitelman syndrome.[6][7][8][9][10][11]

Clinical Significance

Metabolic alkalosis is a relatively common diagnosis in medicine. The biological effects of metabolic alkalosis are directly resultant to associated problems such as hypovolemia and potassium and chloride depletion. These changes lead to decreased myocardial contractility, arrhythmias, decreased cerebral blood flow, confusion, increased neuromuscular excitability, and impaired peripheral oxygen unloading secondary to the shift of the oxygen dissociation curve to left.  Additionally, there is a compensatory increase in arterial pCO through hypoventilation. Overall there is a net effect on the body resulting in hypoxia.

Clinically it is important to understand the relationships between carbon dioxide and bicarbonate in the buffering system and to understand the interactions of how these components are regulated. Additionally, it is essential to understand the mechanism through which sodium, potassium, and hydrogen function to modulate pH when these ion channels are altered with medications. Therefore, the treatment of chloride resistant metabolic alkalosis is focused on treating the underlying condition that triggered the alkalotic event. Since many of these pathologies are resultant to the effect on the renin-angiotensin-aldosterone system, treatment includes inhibiting the effect of aldosterone on the nephron using potassium-sparing diuretics such as amiloride and triamterene. Additionally, an investigation for a malignant source should be considered, such as with primary hyperaldosteronism and Conn syndrome. In chloride responsive metabolic alkalosis, this includes repletion of electrolytes, specifically chloride and potassium along with the replenishment of fluid. In scenarios, such as congestive heart failure (CHF) or edematous states, diuresis is essential using potassium-sparing diuretics.[12][13]


References

[1] Gillion V,Jadoul M,Devuyst O,Pochet JM, The patient with metabolic alkalosis. Acta clinica Belgica. 2018 Oct 27;     [PubMed PMID: 30369299]
[2] Metabolic alkalosis., Palmer BF,Alpern RJ,, Journal of the American Society of Nephrology : JASN, 1997 Sep     [PubMed PMID: 9294840]
[3] Hopkins E,Sharma S, Physiology, Acid Base Balance 2018 Jan;     [PubMed PMID: 29939584]
[4] Stimson L,Reynolds T, Differential diagnosis for chronic hypokalaemia. BMJ case reports. 2018 Jun 5;     [PubMed PMID: 29871959]
[5] Metabolic alkalosis., Galla JH,, Journal of the American Society of Nephrology : JASN, 2000 Feb     [PubMed PMID: 10665945]
[6] Siegler JC,Marshall P, The effect of metabolic alkalosis on central and peripheral mechanisms associated with exercise-induced muscle fatigue in humans. Experimental physiology. 2015 Apr 20;     [PubMed PMID: 25727892]
[7] Metabolic alkalosis., Khanna A,Kurtzman NA,, Journal of nephrology, 2006 Mar-Apr     [PubMed PMID: 16736446]
[8] Symposium on acid-base homeostasis. The generation and maintenance of metabolic alkalosis., Seldin DW,Rector FC Jr,, Kidney international, 1972 May     [PubMed PMID: 4600132]
[9] The effect of metabolic alkalosis on the ventilatory response in healthy subjects., Oppersma E,Doorduin J,van der Hoeven JG,Veltink PH,van Hees HWH,Heunks LMA,, Respiratory physiology & neurobiology, 2018 Jan 4     [PubMed PMID: 29307724]
[10] Potassium intake modulates the thiazide-sensitive sodium-chloride cotransporter (NCC) activity via the Kir4.1 potassium channel., Wang MX,Cuevas CA,Su XT,Wu P,Gao ZX,Lin DH,McCormick JA,Yang CL,Wang WH,Ellison DH,, Kidney international, 2018 Jan 6     [PubMed PMID: 29310825]
[11] Adaptations to chloride-depletion alkalosis., Galla JH,Gifford JD,Luke RG,Rome L,, The American journal of physiology, 1991 Oct     [PubMed PMID: 1928424]
[12] Tetti M,Monticone S,Burrello J,Matarazzo P,Veglio F,Pasini B,Jeunemaitre X,Mulatero P, Liddle Syndrome: Review of the Literature and Description of a New Case. International journal of molecular sciences. 2018 Mar 11;     [PubMed PMID: 29534496]
[13] Bicarbonate transport in collecting duct segments during chloride-depletion alkalosis., Galla JH,Rome L,Luke RG,, Kidney international, 1995 Jul     [PubMed PMID: 7564091]