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• Acid-Base Regulation and Disorders
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Metabolic processes continually produce acid and, to a lesser degree, base. Hydrogen ion (H⁺) is especially reactive; it can attach to negatively charged proteins and, in high concentrations, alter their overall charge, configuration, and function. To maintain cellular function, the body has elaborate mechanisms that maintain blood H⁺ concentration within a narrow range—typically 37 to 43 nmol/L (pH 7.43 to 7.37, where pH = −log [H⁺]) and ideally 40 nmol/L (pH = 7.40). Disturbances of these mechanisms can have serious clinical consequences.

Acid-base equilibrium is closely tied to fluid and electrolyte balance, and disturbances in one of these systems often affect another. Fluid metabolism is discussed in discussed in Fluid Metabolism, and electrolytes are discussed in see Electrolyte Disorders.

Acid-Base Physiology

Most acid comes from carbohydrate and fat metabolism, which generates 15,000 to 20,000 mmol of CO₂ daily. CO₂ is not an acid itself but combines with water (H₂O) in the blood to create carbonic acid (H₂CO₃), which in the presence of the enzyme carbonic anhydrase dissociates into H⁺ and HCO₃⁻. The H⁺ binds with Hb in RBCs and is released with oxygenation in the alveoli, at which time the reaction is reversed, creating H₂O and CO₂, which is exhaled in each breath.

Lesser amounts of organic acid derive from the following:

• Incomplete metabolism of glucose and fatty acids into lactic acid and ketoacids
• Metabolism of sulfur-containing amino acids (cysteine, methionine) into sulfuric acid
• Metabolism of cationic amino acids (arginine, lysine)
• Hydrolysis of dietary phosphate

This “fixed” or “metabolic” acid load cannot be exhaled and therefore must be neutralized or excreted.

Most base comes from metabolism of anionic amino acids (glutamate and aspartate) and from oxidation and consumption of organic anions such as lactate and citrate, which produce HCO₃⁻.

Acid-Base Balance

Acid-base balance is maintained by chemical buffering and by pulmonary and renal elimination.

Chemical buffering: Chemical buffers are solutions that resist changes in pH. Intracellular and extracellular buffers provide an immediate response to acid-base disturbances. Bone also plays an important buffering role. A buffer is made up of a weak acid and its conjugate base. The conjugate base can accept H⁺ and the weak acid can relinquish it thereby minimizing changes in free H⁺ concentration.

The most important extracellular buffer is the HCO₃⁻/CO₂ system, described by the equation:

H⁺ + HCO₃⁻ ⇔ H₂CO₃ ⇔ CO₂ + H₂O

An increase in H⁺ drives the equation to the right and generates CO₂. This important buffer system is highly regulated; CO₂ concentrations can be finely controlled by alveolar ventilation, and H⁺ and HCO₃⁻ concentrations can be finely regulated by renal excretion.

The relationship between HCO₃⁻ and CO₂ in the system can be described by the Kassirer-Bleich equation, derived from the Henderson-Hasselbalch equation:

H⁺ = 24 × Pco₂/HCO₃⁻

This equation illustrates that acid-base balance depends on the ratio of Pco₂ and HCO₃⁻, not on the absolute value of either one alone. With this formula, any 2 values (usually H⁺ and Pco₂) can be used to calculate the other (usually HCO₃⁻).

Other important physiologic buffers include intracellular organic and inorganic phosphates and proteins, including Hb in RBCs. Less important are extracellular phosphate and plasma proteins. Bone becomes an important buffer after consumption of extracellular HCO₃⁻. Bone initially releases sodium carbonate (NaHCO₃) and potassium carbonate (KHCO₃) in exchange for H⁺. With prolonged acid loads, bone releases calcium carbonate (CaCO₃) and calcium phosphate (CaPO₄). Long-standing acidemia therefore contributes to bone demineralization and osteoporosis.

Pulmonary regulation: CO₂ concentration is finely regulated by changes in tidal volume and respiratory rate (minute ventilation). A decrease in pH is sensed by arterial chemoreceptors and leads to increases in tidal volume or respiratory rate; CO₂ is exhaled and blood pH increases. In contrast to chemical buffering, which is immediate, pulmonary regulation occurs over minutes to hours. It is about 50 to 75% effective; it does not completely normalize pH.

Renal regulation: The kidneys control pH by adjusting the amount of HCO₃⁻ that is reabsorbed and the amount of H⁺ that is excreted; increase in HCO₃⁻ is equivalent to removing free H⁺. Changes in renal acid-base handling occur hours to days after changes in acid-base status.

HCO₃⁻ reabsorption occurs mostly in the proximal tubule and, to a lesser degree, in the collecting tubule. H₂O within the tubular cell dissociates into H⁺ and hydroxide (OH⁻); in the presence of carbonic anhydrase, the OH⁻ combines with CO₂ to form HCO₃⁻, which is transported back into the peritubular capillary, while the H⁺ is secreted into the tubular lumen and joins with freely filtered HCO₃⁻ to form CO₂ and H₂O, which are also reabsorbed. Thus, reabsorbed HCO₃⁻ ions are newly generated and not the same as those that were filtered. Decreases in effective circulating volume (such as occur with diuretic therapy) increase HCO₃⁻ reabsorption, while increases in parathyroid hormone in response to an acid load decrease HCO₃⁻ reabsorption. Also, increased Pco₂ leads to increased HCO₃⁻ reabsorption, while Cl⁻ depletion (typically from volume depletion) leads to increased Na⁺ reabsorption and HCO₃⁻ generation by the proximal tubule.

Acid is actively excreted into the proximal and distal tubules where it combines with urinary buffers—primarily freely filtered HPO₄⁻², creatinine, uric acid, and ammonia—to be transported outside the body. The ammonia buffering system is especially important because other buffers are filtered in fixed concentrations and can be depleted by high acid loads; by contrast, tubular cells actively regulate ammonia production in response to changes in acid load. Arterial pH is the main determinant of acid secretion, but excretion is also influenced by K⁺, Cl⁻, and aldosterone levels. Intracellular K⁺ concentration and H⁺ secretion are reciprocally related; K⁺ depletion causes increased H⁺ secretion and hence metabolic alkalosis.

Last full review/revision July 2008 by James L. Lewis, III, MD

Content last modified July 2008