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Hemoglobin is an extremely important protein. As an essential part of red blood cells, it delivers oxygen to all parts of the body. In this post (Part 1), we go over health benefits, roles, and harms of hemoglobin. In addition, we discuss hemoglobin lab tests, normal values, and reference ranges.

Hemoglobin Series

This is part one of a three-part series:

Introduction

Hemoglobin Structure

Human hemoglobin (Hb) consists of four proteins (subunits). These proteins are called chains. Most of the normal adult hemoglobin is built of two alpha- and two beta chains [R].

Each of the four chains contains a ‘heme’ part. ‘Heme’ is the chemical structure where the iron is. It binds oxygen, carbon monoxide, or other small molecules such as nitric oxide [R, R].

The iron found in Hb is responsible for the red color of the blood.

Hemoglobin Function

The main function of hemoglobin is to transport oxygen from the lungs to tissues, and carbon dioxide (CO2) from the tissues to the lungs [R, R].

However, it also interacts with two other gases, carbon monoxide (CO) and nitric oxide (NO) [R].

The human body contains about 750 g of Hb, mostly contained within red blood cells (RBCs) [R].

A mature red blood cell contains ∼270 million Hb molecules [R].

Finally, each Hb molecule is capable of binding up to four oxygen molecules, enabling each red blood cell to carry over onebillion oxygen molecules [R].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824146/

The oxygen-carrying function of hemoglobin is affected by [R]:

  • pH – Lower pH (more acidic) in tissues increases the release of oxygen and stimulates the binding of carbon dioxide. Higher pH (more alkaline) in the lungs causes carbon dioxide to be released and stimulates the binding of oxygen
  • Levels of other molecules (hydrogen ions, CO2, 2,3-bisphosphoglyceric acid, IHP, chloride, and phosphate) – In people acclimated to high altitudes, the concentration of 2,3-BPG in the blood increases, which allows a larger amount of oxygen to be delivered to the tissues
  • Temperature – Increases in temperature decrease oxygen saturation of hemoglobin

Note that inside the body, the pH and temperature are generally within very narrow range, from 7.35 – 7.45 and 97.0 – 99.8 degrees Fahrenheit, respectively [R].

Apart from the blood, Hb seems to play some unexpected roles in other tissues.

Hb chains are also present in white blood cells (macrophages), blood vessel walls (endothelial cells), lungs (alveolar cells), eye lens, kidneys (mesangial cells), and dopamine-releasing neurons (A9) [R, R].

In the blood vessel walls, Hb helps control the level of nitric oxide, and thereby participates in the constricting or expanding of blood vessels. This means that Hb influences blood pressure, blood flow, and oxygen delivery to tissues.

On the other hand, Hb in dopamine-releasing neurons seems to be involved in mitochondrial function and may play a role in normal brain physiology [R].

Hemoglobin Types

In red blood cells of healthy adults [R]:

  • 97% of total hemoglobin is the HbA type (with two alpha and two beta chains)
  • 2.5% is HbA2 (with two alpha and two delta chains
  • 0.5% is HbF or fetal hemoglobin (with two alpha and two gamma chains)

As the name would suggest, fetal hemoglobin accounts for 80% of hemoglobin in newborns [R].

Fetal hemoglobin (HbF) has a slightly higher oxygen affinity than the adult hemoglobins [R].

After birth, production gradually switches to adult hemoglobin over the course of several months [R].

Normally, by the end of the first year of life, the “adult” hemoglobins (A and A2), are predominant [R].

In some cases, the HbF persists in adult red blood cells. This is a condition largely without symptoms, known as the hereditary persistence of fetal hemoglobin [R].

Hemoglobin Metabolism

When red blood cells get old and/or damaged, Hb escapes into the blood. There are several molecules within our blood that recognize and bind free Hb, including haptoglobin (Hp) and hemopexin (Hpx) [R].

Haptoglobin (Hp) is the primary Hb scavenger in the blood [R].

It irreversibly binds Hb that circulates in the blood and transports it to special white blood cells called monocytes or macrophages [R].

These cells transform the heme group into biliverdin (a bile pigment), carbon monoxide, and iron [R].

Iron is usually recycled to be incorporated into new red blood cells [R].

In cases of massive red blood cell destruction, which happens in some diseases, Hb is also cleared by kidneys. However, kidney excretion is accompanied by the release of free iron, which causes organ damage from oxidative stress [R].

Hemoglobin Testing

You can easily check your Hb values by doing a complete blood count (CBC) test.

A CBC is a routine test, and the results are usually ready in a couple of hours.

This test gives you several important values, including the red blood cell count (RBC) and the amount of Hb in your blood.

The Hb level is given in grams (g) per deciliter (dL) of whole blood (a deciliter is 100 milliliters or 1/10 of a liter).

Normal Hemoglobin Levels

Normal Hb values are different depending on age and gender. They also may vary slightly between laboratories:

  • Newborns: 14 to 24 g/dL
  • Children: 9.5 to 13 g/dL
  • Men: 13.5 to 17.5 g/dL
  • Women: 12 to 15.5 g/dL
  • Older men: 12.4 to 14.9 g/dL
  • Older women: 11.7 to 13.8 g/dL

Normal Hb levels are decreased in pregnancy [R, R].

African Americans may have lower Hb values than Caucasians [R].

Hemoglobin: Benefits of Higher Levels

1) Hemoglobin Supplies Tissues with Oxygen

We cannot live without hemoglobin. It supplies tissues with oxygen and supports all body functions.

That said, Hb also has some other lesser-known beneficial functions listed below.

2) Hemoglobin Expands Blood Vessels

Hb is capable of producing and releasing nitric oxide (NO) molecules [R].

It seems Hb increasingly produces NO as red blood cells enter regions of low oxygen (hypoxia). There, NO increases blood flow by expanding blood vessels and thereby increases the oxygen supply [R].

3) Hemoglobin Is Important for Cognitive Function

Several large studies have shown that anemia or low Hb can predict dementia or cognitive decline [R].

Anemia increases the risk of dementia because of the chronic lower oxygen supply to the brain [R].

A study showed that children with anemia performed worse on two tests of cognitive function (322 subjects) [R].

In elderly, those with lower Hb levels (below 13 g/dL in men and 12 g/dL women), had a higher risk of developing dementia three years later (1435 subjects) [R].

Similarly, people with anemia had a 60% increased risk of developing Alzheimer’s (881 older subjects) [R].

Furthermore, in another study, lower Hb resulted in both cognitive and physical decline in older women (558 subjects) [R].

4) Hemoglobin Is Important for Immunity

A low Hb level is a risk factor for acute lower respiratory tract infections in children (110 cases and 110 controls). Patients with anemia are 4.6 times more susceptible to this type of infection [R].

5) Healthy Hemoglobin Levels Reduce Risks of Postpartum Depression

Women suffering from early post-delivery anemia have an increased risk of developing postpartum depression (37 subjects) [R].

6) Hemoglobin Improves Odds in Diseases

Adequate Hb levels are important for our bodies to function properly. This is especially true in people with various disorders and diseases.

Anemia is associated with worse clinical outcomes including longer length of hospital stay, diminished quality of life, and increased risk of morbidity and mortality [R].

7) Hemoglobin-Derived Peptides Act As Opiates

Some Hb-derived peptides have opiate-like activity [R]. This means they potentially relieve pain.

Hemoglobin: Negatives of Higher Levels

Hemoglobin has a number of adverse effects. This happens either when the Hb levels are high, or when larger amounts of free Hb are released into the blood flow because of increased red blood cell destruction.

1) Hemoglobin Increases Oxidative Stress

Hb produces a substantial amount of reactive oxygen species (ROS) [R].

To cope with this challenge, red blood cells are equipped with highly effective antioxidant defenses. They contain enzymes such as Cu/Zn superoxide dismutase (SOD1), catalase (Cat), glutathione peroxidase (Gpx-1), and peroxiredoxins (Prdx1 and Prdx2). Glutathione (GSH) also contributes to this protection [R].

As long as Hb is contained within red blood cells, these reactive oxygen species are taken care of. However, when red blood cells burst and allow the hemoglobin to run free in the blood without these antioxidant molecules, Hb wreaks oxidative havoc in the blood vessels and exposed tissues [R].

This happens when scavengers (such as haptoglobin) cannot remove free hemoglobin from the blood efficiently [R].

When clearance and detoxifying systems are overwhelmed, Hb and its component hemin trigger blood vessel and organ dysfunction [R].

Conditions that result in red blood cell destruction, releasing a massive amount of free Hb into the blood stream, include:

  • Infection by bacteria, parasites (malaria), and influenza virus [R]
  • Inherited and acquired blood disorders, such as sickle-cell anemia, glucose-6-phosphate dehydrogenase deficiency, and paroxysmal nocturnal hemoglobinuria [R]
  • Treatment with anti-infective anti-inflammatory drugs, such as cotrimoxazole, ciprofloxacin, fludarabine, lorazepam, and diclofenac [R]

2) Hemoglobin Increases Inflammation

Free heme (the iron-containing part of Hb) can induce inflammation [R].

Both Hb-derived free heme and Hb degradation products act in a pro-inflammatory fashion. They increase inflammatory cytokines (such as IL-8) and recruit pro-inflammatory cells [R].

3) Hemoglobin Increases the Risk of Blood Clots

Once Hb concentrations reach ≥ 18 g/dL, the blood thickness (viscosity) reaches a level that impairs microcirculation. Microcirculation is the circulation of the blood in the smallest of blood vessels, present within organ tissues [R].

As a result, less oxygen is transported to tissues. The effects are similar to the situation found in severe anemia (very low Hb) [R].

This is often manifested as cyanosis (bluish discoloration) and impaired mental function resulting from compromised brain circulation [R].

Additionally, because of the poor blood flow, the risk of having blood vessels obstructed by blood clots (thromboembolism) increases substantially [R].

High Hb concentration indicates an increased risk of stroke (143 patients) [R].

Elevated Hb (>15.2g/dL) was associated with an increased incidence of brain infarction in Tibetans (284 subjects) [R].

On the other hand, in pathological conditions with increased red blood cell destruction, cell-free hemoglobin binds nitric oxide, which normally plays an important beneficial role by expanding blood vessels [R].

Without the nitric oxide, involuntary muscle contractions (smooth muscle dystonia), blood clots (thrombosis), and blood vessel dysfunction may ensue [R].

4) Free Hemoglobin May Contribute to the Hardening of the Arteries

Hb may contribute to the hardening of the arteries (atherosclerosis).

The pro-inflammatory and oxidative effects of free Hb (outside of RBCs) initiates and promotes plaque formation in the arteries [R].

Furthermore, free Hb effectively binds up nitric oxide (NO). Reduced availability of nitric oxide contracts arterial blood vessels [R].

A slightly lower Hb level was beneficially associated with arterial stiffness in community-dwelling women but not men (343 subjects) [R].

However, in some cases, Hb is also beneficial.

Free Hb serves as an alarm molecule that signals bleeding and tissue damage. It drives macrophage (a type of white blood cell) production towards a protective, antioxidative macrophage type, that halts lesion progression at later stages of the disease [R].

5) High Hemoglobin Elevates Blood Pressure

High Hb may contribute to the development of high blood pressure.

Higher Hb levels are associated with higher blood pressure in healthy individuals (101,377 subjects) [R].

6) High Hemoglobin May Contribute to Metabolic Syndrome

Higher Hb was associated with metabolic syndrome in a large population-based study (57,510 subjects) [R].

7) High Hemoglobin Impairs Cognitive Function

Higher Hb levels were associated with a greater rate of global cognitive decline in the elderly [R].

Participants with high Hb had an increased risk of developing Alzheimer’s disease (881 older subjects) [R].

Older people with high Hb performed worse on semantic memory and perceptual speed tests (793 older subjects) [R].

Note that low Hb also impairs cognitive function, and it is, therefore, important to keep Hb levels in check.

8) Free Hemoglobin Exacerbates Diseases

Free Hb adversely affects the outcome of many conditions, including hemolytic anemias, sepsis, and malaria [R].

Acute free Hb exposure exaggerates inflammatory and oxidative tissue damage in nontolerant malaria-infected individuals [R].

The appearance of free Hb in the blood has been linked to the development of brain malaria, which remains the most severe and difficult to treat complication of the disease [R].

In mice, the deleterious effects of free Hb is neutralized by administration of hemopexin (a scavenger of free hemoglobin) [R].

9) Free Hemoglobin Adversely Affects Blood Transfusion

Older stored blood has more free Hb as a result of red blood cell destruction. Transfusion of such blood increases immune suppression, infection, heart complications, kidney injury, and mortality [R].

Guinea pigs subjected to massive transfusion of older blood had increased hemoglobinuria (abnormally high Hb in the urine), acute kidney failure, high blood pressure, and blood vessel injury [R].

Administering scavengers (like haptoglobin) with older storage blood reduced adverse kidney and blood vessel effects in these animals [R].

Hemoglobin Series

This is part one of a three-part series:

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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