Introduction

All acid-base disorders with high anion gap relate to disturbances in cellular respiratory processes such as glycolysis, citric acid (Krebs) cycle, and respiratory chain in the inner mitochondrial membrane. Conversely, acid-base disorders with normal to low anion gap are related to disturbances in ion concentration (cations and anions) and are generally caused by changes in membrane channel function, ion gradients, and passive or active transport mechanisms. Some of these disorders are congenital and some are iatrogenic in nature [¹].

Methodology

Original research article with systematic analysis and classification of data following a pattern based on biochemical processes that affect acid-base balance.

How to use the diagnostic algorithm (Table 1)

Step 1: Determine pH.

• <7.38 = acidosis

• >7.42 = alkalosis

Step 2: Determine anion gap (AG)/base excess (BE)

• High AG (Low BE) means disturbance in cellular respiration.

• Normal AG (neutral BE) means disturbance in ion transport across membranes

Step 3: Determine the byproduct or metabolite.

Past and recent medical history, clinical examination, and biochemical analysis play an important role. Metabolites analyzed with CO2 and HCO3- levels will explain the underlying process.

• Lactate

• Ketones - citric acid cycle with fatty acids instead of pyruvate - diabetic ketoacidosis, starvation, infections, alcohol abuse.

• Organic anions - citric acid cycle with amino acids instead of pyruvate - inborn errors of metabolism, severe catabolic state.

• Nitrogen derivates: Urea, ammonium - urea cycle disorders and generally related to citric acid cycle blockage in the alpha-ketoglutarate dehydrogenase enzyme.

• Salicylates - citric acid cycle blockage in succinic acid dehydrogenase and alpha-ketoglutarate dehydrogenase enzymes, coupled with ketoacid production [³].

• Hypercapnia (high CO₂) - buildup from lack of H₂O production in respiratory chain due to blockers or uncouplers (anesthetics, metformin, remdesivir, organophosphates, coenzyme deficiency, etc.) [⁴].

Once the disturbance is identified, proper treatment can be initiated [⁵].

Some anions, such as organic anions and respiratory chain blockers, are not routinely measured but can be inferred and then ordered to confirm and establish the correct diagnosis.

Discussion

Alterations in cellular respiratory (i.e. ATP) processes yield certain byproducts in weak acid form, which later dissociate, releasing hydronium ions and an anion [⁶]. Hydronium ions are responsible for changes in pH and cellular function (depolarization or hyperpolarization), leading to clinical manifestations. The dissociated anions elevate the anion gap, and their identification can help clinicians determine which step of the process is altered.

Most disturbances that present with high anion gap manifest as acidosis (pH <7.38). However, there are two exceptions: Urea cycle disorders and salicylate toxicity, which manifest as alkalosis with high anion gap. The most plausible explanation is that the byproducts of urea cycle and salicylates have a very high pH (9.8 and 13, respectively). Their buildup in plasma exerts an alkalinizing effect on serum pH (alkalemia) and masks the real acidosis occurring due to the disturbance of cellular respiration [⁷].

Table 1 Diagnostic Algorithm for Biochemical Approach of Acid-Base Disturbances 

Source: Author's elaboration with information provided in the text.

Under ideal conditions, the carbon:hydrogen:oxygen ratio and the amount of released CO₂ and H₂O remain constant [⁸]. This is known as the respiratory quotient (Q). The body maintains constant equilibrium between CO₂ and HCO₃- levels, as HCO₃- formation depends on that ratio. HCO₃- levels are a key component of base excess determination. Since changes in substrates or enzymatic activity of cellular respiration that alter the anion gap will also alter HCO₃- levels, it is logical to consider anion gap and base excess as mirror parameters of severity. The higher anion gap, the lower (more negative) the base excess. This is very useful in certain settings where the blood gas analyzer lacks the capacity to measure cations for the AG formula.

All disturbances in cellular respiration lower the respiratory quotient, resulting in increased oxygen demand, which is expressed clinically as tachypnea. It is also logical to consider tachypnea as a response mechanism to maintain adequate oxygen supply to ensure ATP production, rather than to eliminate CO₂ to "compensate" the "metabolic acidosis", as previous models state [⁹-¹¹].

Conclusion

The biochemical approach is the new model to understand, explain and diagnose acid-base balance and disturbances. All high anion gap disturbances occur in cellular respiration, while all normal anion gap disturbances occur in membrane channel function. The diagnosis algorithm simplifies and organizes information to describe medical conditions with data from a blood gas analysis. The biochemical approach is the first model to establish a linear correlation between lab results, biochemical cause, and clinical findings of acid-base disturbances.