Overview of Metabolic Acidosis

With metabolic acidosis, “acidosis” refers to a process that lowers blood pH below 7.35, and “metabolic” refers to the fact that it’s a problem caused by a decrease in the bicarbonate HCO3− concentration in the blood.

Normally, blood pH depends on the balance or ratio between the concentration of bases, mainly bicarbonate HCO3−, which increases the pH, and acids, mainly carbon dioxide CO2, which decrease the pH. The blood pH needs to be constantly between 7.35 and 7.45, and in addition the blood needs to remain electrically neutral, which means that the total cations, or positively charged particles, equals the total anions, or negatively charged particles.

Now, not all of the ions are easy or convenient to measure, so typically the dominant cation, sodium Na+, which is typically around 137 mEq/L and the two dominant anions, chloride Cl−, which is about 104 mEq/L, and bicarbonate HCO3−, which is around 24 mEq/L, are measured. The rest are unmeasured. So just counting up these three ions, there’s usually a difference, or “gap” between the sodium Na+ concentration and the sum of bicarbonate HCO3− and chloride Cl− concentrations in the plasma, which is 137 minus 128 (104 plus 24) or 9 mEq/L. This is known as the anion gap, and normally it ranges between 3 and 11 mEq/L. The anion gap largely represents unmeasured anions like organic acids and negatively charged plasma proteins, like albumin.

So, basically, metabolic acidosis arises either from the buildup of acid in our blood, which could be because it’s produced or ingested in increased amounts, or because the body can’t get rid of it, or from excessive bicarbonate HCO3− loss from the kidneys or gastrointestinal tract. The main problem with all of this is that they lead to a primary decrease in the concentration of bicarbonate HCO3− in the blood.

They can be broken down to two categories, based on whether the anion gap is high or normal. So, the first category of metabolic acidosis is a high anion gap metabolic acidosis. In this case, the bicarbonate HCO3− ion concentration decreases by binding of bicarbonate HCO3− ions and protons H+, which results in the formation of H2CO3 carbonic acid, which subsequently breaks down into carbon dioxide CO2 and water H2O. These protons can come from organic acids which have accumulated in the blood, but they can also come from increased production in our body. One such example is lactic acidosis, which is where decreased oxygen delivery to the tissues leads to increased anaerobic metabolism and the buildup of lactic acid. Another example is diabetic ketoacidosis, which can occurs in uncontrolled diabetes mellitus, where the lack of insulin forces cells to use fats as primary energy fuel instead of glucose. Fats are then converted to ketoacids, such as acetoacetic acid and β-hydroxybutyric acid. Another way acids can build up in our blood is due to an inability of the kidneys to throw them away, although they are produced in normal amounts. This can happen in cases of chronic renal failure, in which organic acids such as uric acid or sulfur- containing amino acids can accumulate because they aren’t excreted normally.

In other cases, organic acids don’t come from inside our bodies at all, but, instead, they are accidentally ingested. These include oxalic acid which can build up after an accidental ingestion of ethylene glycol, which is a common antifreeze, formic acid, which is a metabolite of methanol, a highly toxic alcohol, or hippuric acid, which comes from toluene, which is found in paint and glue. All of these organic acids have protons, and at a physiologic pH, these organic acids dissociate into protons H+ and corresponding organic acid anions. The protons H+ attach to bicarbonate HCO3− ions floating around, decreasing its plasma concentration and shifting the pH towards the acidic range. The key is that the plasma maintains its electroneutrality, because for each new negatively charged organic acid anions, there’s one less bicarbonate HCO3− ion, and because the organic acid anions are not part of the anion gap equation, the anion gap will be high.

In contrast, in other cases of metabolic acidosis, the decrease in bicarbonate HCO3− ions is offset by the buildup of Cl- ions which are part of the anion gap equation, so the anion gap remains normal. The most common cause is severe diarrhea, where bicarbonate- rich intestinal and pancreatic secretions rush through the gastrointestinal tract before they can be reabsorbed.

Another cause is type 2 renal tubular acidosis, which is the most common type of renal tubular acidosis, and develops because the proximal convoluted tubule, a part of the nephron, is unable to reabsorb bicarbonate HCO3−. Other types of renal tubular acidosis also result in normal anion gap metabolic acidosis, but the underlying mechanism is an inability to excrete protons H+ in the urine. The excessive loss of bicarbonate HCO3− results in a low plasma bicarbonate HCO3− concentration, which lowers the pH. In response, the kidneys start reabsorbing more chloride Cl- anions, so for each bicarbonate HCO3− ion that’s lost, there’s a new chloride Cl- anion. This is why normal anion gap metabolic acidosis is sometimes called a hyperchloremic metabolic acidosis.

Now, if there’s a decrease in the HCO3− concentration in the blood, threatening to decrease blood pH, the body has a number of important mechanisms to help keep the pH in balance. One of them is moving hydrogen ions out of the blood and into cells. To accomplish this, cells usually need to exchange the hydrogen ion for a potassium ion, using a special ion transporter located across the cell membrane. So, in order to help compensate for an acidosis, hydrogen ions enter cells and potassium ions leave the cells and enter the blood. This might help with the acidosis, but it results in hyperkalemia. In cases, though, when there’s a metabolic acidosis from excess organic acids, like lactic acid and ketoacids, protons can enter cells with the organic anion rather than having to be exchanged for potassium ions.

Another important regulatory mechanism involves the respiratory system, and begins with chemoreceptors that are located in the walls of the carotid arteries and in the wall of the aortic arch. These chemoreceptors start to fire when the pH falls, and that notifies the respiratory centers in the brainstem that they need to increase the respiratory rate and depth of breathing. As the respiratory rate and depth of each breath increase, the minute ventilation increases - that’s the volume of air that moves in and out of the lungs in a minute. The increased ventilation, helps move more carbon dioxide CO2 out of the body, reducing the PCO2 in the body, which increases the pH.

An additional mechanism, is that if metabolic acidosis is not caused by some renal problem, then several days later, the kidneys usually correct the imbalance. The kidneys excrete more hydrogen ions, while also, reabsorbing bicarbonate HCO3− so that it’s not lost in the urine.

All right, as a quick recap, metabolic acidosis caused by a decreased bicarbonate HCO3− concentration in the blood. It can be classified into high anion gap cases, which are caused by the accumulation of organic acids, either due to their increased production in the body, decreased excretion or exogenous ingestion, and normal anion gap cases, which are caused directly by a loss of bicarbonate HCO3−, as in diarrhea or type 2 renal tubular acidosis.