Carboxyhemoglobin: Definition, Physiology, Environmental Sources and Consequences of the Different Levels of this Protein

Hemoglobin is the oxygen-carrying protein contained in red blood cells (erythrocytes).

Although usually present in trace amounts, three hemoglobin species cannot carry oxygen.

The three species, collectively called dyshemoglobins because of their functional redundancy, are methemoglobin, sulfhemoglobin, and carboxyhemoglobin.

Carboxyhemoglobin, which usually comprises less than 1 to 2% of total hemoglobin, is the product of the reaction between carbon monoxide and hemoglobin.

Carbon monoxide is produced endogenously, but it is also a common environmental pollutant; both sources contribute to the amount of carboxyhemoglobin in the blood.

Carbon monoxide is present in today’s industrial society and is odorless, tasteless, and highly toxic.

Carbon monoxide in concentrations of 500 ppm inspired will produce lethal carboxyhemoglobin levels if the exposure lasts long enough.


Carbon monoxide binds to hemoglobin 250 times more strongly than oxygen and competes with it for sites in hemoglobin to form carboxyhemoglobin.

This means that since there is 21% O 2 in the air, only 0.1% CO is needed to ‘compete’ on equal terms for O 2 transport sites in hemoglobin and resulting in arterial blood having a 50 % HBO 2 and 50% HbCO, which is useless for tissues.

This is equivalent to being 50% anemic; for this low concentration of CO to come into equilibrium with the blood takes more than an hour, but once there, it takes just as long for the CO to be eliminated from the blood.

Normal physiology

The normal function of cells depends primarily on a continuous supply of oxygen. A primary part of the blood is oxygen supply in the inspired air from the lungs to each tissue cell.

This essential gas transport function depends on the hemoglobin protein in red blood cells ( erythrocytes ).

Each of the erythrocytes in each ml of blood contains 280 million hemoglobin molecules.

The hemoglobin molecule has four polypeptide subunits attached to a heme group.

An iron atom in a ferrous state is at the center of the four heme groups. Oxygen reversibly binds to these four iron atoms, the product of which is oxyhemoglobin.

The oxygen transport function of hemoglobin, which is its ability to pick up oxygen in the lungs, transport it throughout the body as oxyhemoglobin and then release it to the cells of the tissues, is made possible by a change in the quaternary structure of the hemoglobin molecule, which alters the affinity of hemoglobin for oxygen.

Oxygen has to compete with other hemoglobin-binding ligands that may be present in the blood to occupy hemoglobin-binding sites.

Among these ligands is carbon monoxide, a colorless, odorless gas produced during normal metabolism.

More than 50 years ago, it was shown for the first time that carbon monoxide is produced during the normal metabolism of the individual.

About 0.4 ml of CO is produced every hour almost exclusively from the catabolism of heme-containing proteins.

Hemoglobin is the most abundant heme-containing protein and, therefore, the most endogenous source of CO.

At the end of their 120-day life, erythrocytes are sequestered from the circulation by the reticuloendothelial system.

Hemoglobin released from senescent erythrocytes is degraded into its constituent parts: heme and protein polypeptide. The protein is recycled, but the heme is further metabolized.

Heme is converted to equimolar amounts of biliverdin, iron, and CO in a reaction catalyzed by the rate-limiting enzyme heme oxygenase.

Biliverdin is subsequently converted to the yellow pigment bilirubin, which is excreted by the liver in the bile, and iron is recycled.

Catabolism of heme derived from other heme-containing proteins, e.g., myoglobin and cytochromes, contributes to endogenous CO production by the same heme-oxygenase-mediated pathway.

There is evidence that CO is also derived from non-heme sources, for example, lipid peroxidation, but compared to that derived from heme catabolism, this is of very little importance; in fact, this can only occur in pathological situations.

The biological effect of endogenous CO is mainly due to the high affinity that heme has for CO and the resulting binding of CO for heme-containing proteins.

By a curious peculiarity of nature, heme is both the source of CO and the mediator of its biological effect.

The function modulation of some heme-containing proteins that result from CO binding has significant physiological effects.

Therefore, endogenously produced carbon monoxide is not, as was supposed, simply a potentially toxic waste product of metabolism but is involved in many physiological functions.

These include regulation of respiration, neuronal signaling, blood pressure, and uterine contraction during pregnancy.

Of all the heme-containing proteins, hemoglobin is the most abundant, but it also has the highest affinity for carbon monoxide, which is why most of the CO in the blood is bound to hemoglobin.

Reversible binding occurs at the same iron atom at the heme site where oxygen binds; The product of this union is carboxyhemoglobin.

This provides how endogenous carbon monoxide can be transported before elimination from the body through the lungs in expired air.

A minimum of 0.5 to 1.0% carboxyhemoglobin is inevitably present in the blood due to endogenously produced CO.

Environmental sources of carbon monoxide

In addition to the CO produced endogenously, the air we breathe contains CO, partly the result of natural processes but mainly the incomplete combustion of hydrocarbons.

The most crucial unnatural source of environmental CO is motor vehicle exhaust.

Although usually present in concentrations of less than ten parts per million, carbon monoxide in inspired air has a significant additive effect on carboxyhemoglobin in the blood due to the high affinity of hemoglobin for CO.

The combined effect of endogenous and environmental CO results in a carboxyhemoglobin of less than 3% for most urban dwellers who do not smoke and maybe as low as 1 to 2% for those who live in rural areas where the air is less polluted with CO.

Cigarette smoke contains a high concentration of CO, and smokers are exposed to an estimated 400 to 500 ppm of CO while smoking and consequently have a much higher carboxyhemoglobin.

Causes of elevated carboxyhemoglobin

The amount of carboxyhemoglobin in the blood is mainly determined by the amount of CO in the blood.

The source of CO in the blood is both endogenous (heme catabolism) and environmental (CO content in inspired air), so the causes of elevated COHb can be addressed by increasing both factors.

Increase in endogenous CO production

Increased endogenous CO production is a feature of any condition associated with increased heme catabolism.

Hemolytic anemias are a group of conditions of variable etiology whose common pathological characteristic is an increased rate of destruction of red blood cells (hemolysis).

Increased destruction of red blood cells causes increased heme catabolism and therefore increased CO production.

The severity of hemolysis is closely correlated with CO production and measured carboxyhemoglobin.

The slight increase in carboxyhemoglobin is often a characteristic of severe inflammatory diseases, such as sepsis and pneumonia; therefore, it is a relatively common finding in critically ill patients.

This increase is believed to be the increased expression of heme oxygenase (the enzyme responsible for CO production) induced by inflammatory cytokines.

Increase in exogenous CO production

Subjects who inhale toxic amounts of methylene chloride vapor, usually due to working in poorly ventilated conditions, have increased carboxyhemoglobin caused by increased CO production.

Carboxyhemoglobin levels can be severe enough to be life threatening, with high CO contaminated breathing air and carbon monoxide poisoning.

Most clinical requests for carboxyhemoglobin measurement are made in the setting of known or suspected acute or chronic carbon monoxide poisoning.

Consequences of elevated carboxyhemoglobin

The toxicity of CO is partly due to the effect that the binding of hemoglobin to CO has on the oxygen-carrying capacity of the blood.

Reduced oxygen-carrying capacity and reduced oxygen delivery leave tissues starved of oxygen (hypoxic).

Organs such as the brain and heart, whose average oxygen consumption is relatively high compared to other organs, are particularly sensitive to relative anoxia induced by increased carboxyhemoglobin.

Fetal hemoglobin shows an even higher affinity for CO than adult hemoglobin, so because CO diffuses readily across the placental membrane, the fetus is particularly vulnerable to tissue anoxia in cases of maternal exposure. To the CO.

A high suspicion index is required to diagnose carbon monoxide poisoning unless CO exposure is accurate, as all mild to moderate poisoning symptoms are nonspecific.

The classic “cherry red” skin color of carbon monoxide poisoning is not usually apparent.

The most common symptoms are headache, dizziness, nausea, vomiting, and confusion, which reflect the marked sensitivity of the brain to relative anoxia.

Affected patients may be short of breath, especially during exertion, and have clinical signs (tachycardia, tachypnea) that indicate compensation for the oxygen deficit.

There are frank signs and symptoms of cardiac involvement in the most severe cases, including palpitations, hypotension, ischemic chest pain (angina), and even myocardial infarction, and seizures and coma occur in cases of severe toxicity.

A carboxyhemoglobin level is the most useful diagnostic test obtained in a suspected case of carbon monoxide poisoning.

A systemic arterial blood gas measurement to identify carbon monoxide poisoning is not helpful except in determining the presence of metabolic acidosis.

Pulse oximetry is also inadequate for detecting carbon monoxide poisoning because carboxyhemoglobin can be misinterpreted as oxyhemoglobin.

Therefore, decisions to administer hyperbaric oxygen therapy should be made only based on carboxyhemoglobin levels.