Physiology, Bohr Effect


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Aakash Patel
Andrew Benner


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Updated:
7/29/2019 6:45:20 PM

Introduction

Oxygen (O2) competitively and reversibly binds to hemoglobin, with certain changes within the environment altering the affinity in which this relationship occurs. The sigmoidal shape of the oxygen dissociation curve illustrates hemoglobin’s propensity for positive cooperativity, as hemoglobin undergoes conformational changes to increase its affinity for oxygen as molecules progressively bind to each of its four available binding sites. The Bohr effect describes hemoglobin’s lower affinity for oxygen secondary to increases in the partial pressure of carbon dioxide and decreases in blood pH. This lower affinity, in turn, enhances the unloading of oxygen into tissues to meet the oxygen demand of the tissue.[1]

Issues of Concern

Increases in PCO2 and Decreases in pH 

Through the biochemical reactions necessary for cellular respiration, increases in metabolic activity within tissues result in the production of carbon dioxide (CO2) as a metabolic waste product. This increase in tissue PCO2 leads to an increase in hydrogen ion (H+) concentration, represented as a decrease in pH as the environment undergoes the process of acidosis. These effects decrease hemoglobin’s affinity for oxygen, weakening it’s binding capacity and increasing the likelihood of dissociation; this is represented as a rightward shift of the hemoglobin dissociation curve, as hemoglobin unloads oxygen from its binding sites at higher partial pressures of oxygen. Specifically, it is the association of protons (H+ ions) with the amino acids in hemoglobin that cause a conformational change in protein folding, ultimately reducing the affinity of the binding sites for oxygen molecules. This configuration shift of hemoglobin under the influence of protons is classified as the taut (T) form.

Hemoglobin exists in 2 forms, the taut form (T) and the relaxed form (R). This structural change to the taut form leads to low-affinity hemoglobin whereas the relaxed form leads to a high-affinity form of hemoglobin, with respect to oxygen binding. In the lungs, the highly saturated oxygen environment can overcome the lower affinity T-form of hemoglobin, effectively binding despite disadvantageous binding capacity. During this process, initial O2 binding induces an alteration in hemoglobin from the taut to relaxed form, dissociating H+ protons and progressively increasing hemoglobin’s affinity for oxygen at each of the remaining binding sites through positive cooperativity. Under the influence of acidic environments, hemoglobin has a propensity for undergoing the reverse of this conformational change, releasing oxygen in favor of the attachment of H+ protons as hemoglobin shifts from the higher oxygen affinity relaxed form to the lower oxygen affinity taut form.

Overall, this relationship can be quantified by an increase in the P50, as 50% hemoglobin oxygen saturation is achieved at higher-than-normal values of pO2, in comparison to the accepted normal P50 of 27 mmHg. This results in a greater unloading of oxygen in the presence of the acidic environments surrounding body tissues as a result of cellular respiration. [2]

Cellular

Through the enzyme carbonic anhydrase, the carbon dioxide and water released as byproducts from cellular respiration are converted to carbonic acid (H2CO3). In the pursuit of achieving biochemical equilibrium, carbonic acid partially and reversibly dissociates into hydrogen ions and its conjugate base, bicarbonate (HCO3). This release of hydrogen ions increases the available concentration of H+ ions within the blood, effectively decreasing the pH of the environment. Due to the reversibility of this reaction, the resulting bicarbonate conjugate base form of carbonic acid indirectly represents the majority of the blood carbon dioxide (CO2) content (70%).[3]

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

This process usually takes place in peripheral tissues, as the desired effect is to unload oxygen into these tissues and load oxygen in the lungs. To limit the decrease in pH of the environment surrounding peripheral tissues, hemoglobin serves as a buffering agent by releasing its oxygen molecules in favor of binding H+ ions. Additionally, the increased bicarbonate molecules move down their concentration gradient, diffusing out of the red blood cell, exchanging chlorine ions into the red blood cell to maintain the electrical neutrality. This buffering process is known as the Haldane effect. In the setting of lung alveoli, the less acidic and highly oxygenated environment favors the dissociation of the scavenged H+ protons from hemoglobin in exchange for oxygen binding. The effect of this relatively increased pH environment and its effect on hemoglobin oxygen affinity is graphically represented as a left shift in the oxy-hemoglobin dissociation curve as the P50 effectively decreases, resulting in greater attachment of oxygen to hemoglobin.[4]

Related Testing

The measurement of the oxygen and carbon dioxide content in the blood, in addition to acid-base status in the form of pH level, can be quantified through an arterial blood gas (ABG) analysis. As a result, the global interpretation of all available data within an ABG provides an approximation of the body’s ventilation and metabolism efforts. Based on the PaCO2 on the blood gas, clinicians can get a sense of the amount of CO2 retention and the effect it may have on the Bohr effect, and ultimately oxygen delivery to body tissues. The accepted “normal” PaCO2 concentration is commonly described as 40 mm Hg, with hypercapnia and hypocapnia defined as a PaCO2 greater than 45 and less than 35 mmHg, respectively. In the clinical circumstance of PaCO2 greater than 45 mmHg combined with a PaO2 less than 60 mm Hg, the patient may be experiencing hypercapnic respiratory failure with an ensuing right shift in the oxygen dissociation curve in order to increase oxygen delivery.

Pathophysiology

Through the Bohr effect, more oxygen is released to those tissues with higher carbon dioxide concentrations. The sensitivity to these effects can be suppressed in chronic diseases, leading to decreased oxygenation of peripheral tissues. Chronic conditions such as asthma, cystic fibrosis, or even diabetes mellitus, can lead to a chronic state of hyperventilation in order to maintain adequate tissue oxygenation. These states can have ventilation of up to 15 L per minute compared to the average normal minute ventilation of 6 L per minute. This hyperventilation minimizes the potential of the Bohr effect through excess exhalation of carbon dioxide resulting in hypocapnia, causing a left shift the oxygen dissociation and unnecessarily increased oxygen-hemoglobin binding affinity with impaired oxygen release to peripheral tissues, including our most vital organs (brain, heart, liver, kidney). Thus, the Bohr effect is essential in maximizing oxygen transport capabilities of hemoglobin and functionally dynamic oxygen-binding/release secondary to carbon dioxide equilibrium. [5]

Carbon Monoxide Effect

While the presence of carbon dioxide leads to the greater unloading of oxygen, carbon monoxide has the opposite effect. Carbon monoxide (CO) has a 200-times greater affinity for hemoglobin than oxygen, out-competing oxygen for available binding sites in a nearly irreversible fashion (reversible, but very minimally). Carbon monoxide further decreases oxygen delivery through the stabilization of hemoglobin in the R-form. Counter-intuitively, although this facilitates oxygen loading to the remaining binding sites, hemoglobin becomes resistant to environmental influences that would normally encourage conformational changes into taut-form, limiting the potential for unloading of oxygen. Under the influence of carbon monoxide, the oxy-hemoglobin dissociation curve significantly shifts left in addition to the reduction of the sigmoidal curve shape as a result of blunted positive cooperativity response of hemoglobin. In the presence of significant carbon monoxide inhalation, tissue hypoxia occurs despite normal pO2 levels, as carbon monoxide competitively binds hemoglobin while inhibiting the release of oxygen from the remaining binding sites. Carbon monoxide poisoning is treated with hyperbaric oxygen therapy, delivering 100% O2 at increased atmospheric pressures to facilitate hemoglobin oxygen binding in the presence of highly competitive carbon monoxide.[6]

Clinical Significance

The Bohr effect describes the ability of red blood cells to adapt to changes in the biochemical environment, maximizing hemoglobin-oxygen binding capacity in the lungs while simultaneously optimizing oxygen delivery to tissues with the greatest demand. The Bohr effect maintains significant clinical relevance within the field of Anesthesiology, as it directly influences patient outcomes throughout the perioperative process. Whether through hypo or hyperventilation, the alterations in carbon dioxide content and acid-base status results in shifts in the oxy-hemoglobin dissociation curve, either amplifying or dampening the magnitude of the Bohr Effect regarding hemoglobin re-oxygenation at the alveoli and delivery/release at peripheral tissues.

In addition to hypercarbia and acidemia described by the Bohr effect, other factors that cause a right shift in the oxy-hemoglobin dissociation curve include increases in temperature, 2,3-Bisphosphoglyceric acid (2-3-BPG). The summation of these factors determines the level of the influence on the hemoglobin oxygen binding capacity. For example, in the setting of exercising skeletal muscle, high metabolic demands require maximal oxygen delivery for cellular respiration. Increased metabolic rates at skeletal muscle results in both carbon dioxide and lactic acid from aerobic and anaerobic cellular respiration, respectively, drastically lowering the surrounding blood pH in addition to temperature increases as a result of exothermic reactions. The environmental alterations from the summation of these factors and resulting hemoglobin conformational optimize hemoglobin oxygen delivery to peripheral tissues. Similarly, under the stress of chronic hypoxic conditions ranging from high altitude to chronic lung disease or congestive heart failure, the body relies on glycolysis to meet metabolic demands. Through increased levels of glycolysis under hypoxic conditions, the resulting 2,3-BPG byproduct further shifts the oxy-hemoglobin dissociation curve to the right, in favor of oxygen unloading.[7]


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Physiology, Bohr Effect - Questions

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The Bohr effect describes the relationship between oxygen and which of the following?

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Which factors cause the Bohr effect?



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Which of the following will not decrease hemoglobin affinity for oxygen?



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A 57-year-old caucasian male relocated from a low altitude to a high altitude location less than 48 hours ago. His past medical history is significant for COPD, hyperlipidemia, and hypertension. His immunizations are up to date and he has no significant surgical history. During his first few days in his new place of residence, the man noticed that he is breathing at a significantly increased respiratory rate, even at rest. Concerned that his COPD may be worsening, he sets up an appointment with a clinician in the area. Under the new circumstances, how has the Bohr effect been influenced?



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Physiology, Bohr Effect - References

References

Malte H,Lykkeboe G, The Bohr/Haldane effect: A model based uncovering of the full extent of its impact on O{sub}2{/sub} delivery to and CO{sub}2{/sub} removal from tissues. Journal of applied physiology (Bethesda, Md. : 1985). 2018 May 10     [PubMed]
Kaufman DP,Dhamoon AS, Physiology, Oxyhemoglobin Dissociation Curve null. 2018 Jan     [PubMed]
Mesquida J,Saludes P,Espinal C,Gruartmoner G, In response: Blood CO{sub}2{/sub} exchange monitoring, Haldane effect and other calculations in sepsis and critical illness. Journal of clinical monitoring and computing. 2018 Jun 12     [PubMed]
Du Y,Wang J,Li H,Mao S,Wang D,Xiang Z,Guo R,Chen J, The dual function of the algal treatment: Antibiotic elimination combined with CO{sub}2{/sub} fixation. Chemosphere. 2018 Jul 30     [PubMed]
Kuo SC,Hsu CK,Tsai CT,Chieh MJ, [Hyperbaric Oxygen Therapy and Acute Carbon Monoxide Poisoning]. Hu li za zhi The journal of nursing. 2018 Aug     [PubMed]
Tsuji B,Filingeri D,Honda Y,Eguchi T,Fujii N,Kondo N,Nishiyasu T, Reply to Parkes: Effect of hypocapnia on the sensitivity of hyperthermic hyperventilation and the cerebrovascular response in resting heated humans. Journal of applied physiology (Bethesda, Md. : 1985). 2018 May 1     [PubMed]
Jendroszek A,Malte H,Overgaard CB,Beedholm K,Natarajan C,Weber RE,Storz JF,Fago A, Allosteric mechanisms underlying the adaptive increase in hemoglobin-oxygen affinity of the bar-headed goose. The Journal of experimental biology. 2018 Jul 19     [PubMed]

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