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Factors that Increase/Decrease Hemoglobin + Hemoglobin Genes

Written by Biljana Novkovic, PhD | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:
Medically reviewed by
Ognjen Milicevic, MD, PhD (Bioinformatics), Puya Yazdi, MD | Written by Biljana Novkovic, PhD | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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Hemoglobin

As an essential part of red blood cells, hemoglobin delivers oxygen to all parts of the body. In this post, we cover factors that modify (increase or decrease) hemoglobin naturally. In addition, we also cover genes and SNPs that affect hemoglobin levels.

Factors that Increase Hemoglobin

Low hemoglobin can be an indicator of an underlying disease or disorder that requires medical attention. Before attempting to increase hemoglobin on your own, talk to your doctor about appropriate strategies, which may include some of the things discussed in this section. Never use any of the strategies in this section in place of something your doctor prescribes.

1) Iron-Rich Food

Iron deficiency is the most common cause of low hemoglobin (Hb).

Consuming iron-rich food (like red meat, eggs, vegetables, and grains) is usually the best way to increase iron in the blood [1].

Around 10% of the iron you consume is absorbed into the bloodstream [1].

A study of 40 young adults showed that three weeks’ supplementation of leafy green vegetables taken with oil resulted in a significant increase of Hb by 9%. According to the authors of the study, consuming oil alongside vegetables may increase the bioavailability of certain nutrients [2].

2) Iron Supplementation

Iron supplementation significantly increases Hb levels in those who are iron deficient [3].

In iron-deficient girls, five months of iron supplementation was associated with a 0.52 g/dl greater increase in Hb compared to girls who didn’t take supplements (279 schoolgirls) [4].

Taking too much iron can upset the stomach and cause tissue damage in extreme cases. However, iron supplementation does not appear to elevate Hb above normal values. [3].

3) Vitamins

If you are deficient in vitamins that are essential in red blood cell production, correcting those deficiencies should restore normal Hb values.

First, it is important to have adequate amounts of folate and B12. Deficiencies of these vitamins will cause anemia (low Hb) [5].

Vitamins A, D, and E may also be beneficial in those who are deficient [6, 7, 8].

Vitamin A treatment increased the production of erythropoietin (EPO), a stimulant of red blood cell production [9].

Vitamin A supplements increased hemoglobin in children (2,397 and 81 subjects) [10, 9].

These supplements also increased Hb in pregnant women (152 and 190 subjects) [11, 12].

Supplementing beta-carotene significantly increased Hb levels (11%) in young healthy adults (40 subjects)[2]. It is converted to vitamin A in the body.

Vitamin D deficiency was also associated with lower Hb (meta-analysis, 7 studies, 5183 subjects) [13].

Also, a study showed that high-dose vitamin D supplementation increased Hb levels in mechanically ventilated critically ill adults (pilot study, 30 subjects) [14].

Finally, it was shown that vitamin E supplementation also improved Hb levels in mildly anemic healthy adults (86 and 60 subjects) [15].

Talk to your doctor to determine if you are deficient in any of these vitamins and whether supplements are appropriate for you.

4) Minerals

Zinc, copper, and selenium are trace elements that are all important to maintain adequate Hb levels.

Zinc plays an important role in iron energy production [16].

A study showed that patients with low zinc levels have a higher risk of developing anemia (503 subjects) [17].

Adding zinc to iron treatment further increases Hb, improves iron indexes, and has positive effects on diarrhea in anemic children [18].

Zinc and vitamin C supplementation increased Hb levels in patients with malaria (vitamin C increases iron absorption) [19].

Selenium and copper have also been associated with anemia, and supplementation is beneficial if you are deficient [5].

Talk to your doctor to determine if you are deficient in any of these minerals and whether supplements are appropriate for you.

5) Altitude

Oxygen is more scarce at higher altitudes; to compensate, the body produces more red blood cells and more hemoglobin. Conditions simulating high altitudes significantly increased hemoglobin levels in end-stage kidney disease patients with anemia [20].

Some athletes deliberately train at high altitudes to increase their Hb levels and improve performance. Three weeks of traditional altitude training at 2,050 meters increases red blood cell production even in world-class endurance athletes [21].

In a study, 10 Swiss national team orienteers who lived at 2,500 meters (18 hours per day) and trained at 1,800 and 1,000 meters above sea level for 24 days, improved both their Hb levels and their 5,000 m running times, compared to athletes who trained at sea level (7 subjects) [22].

6) Erythropoietin

In 8 healthy subjects, EPO (erythropoietin) administered for 15 weeks increased red blood cell volume but decreased plasma (liquid part of the blood) volume. Both of these result in an increase in Hb levels [23].

Erythropoietin is banned in competitive sports because it artificially increases the oxygen capacity of an athlete’s blood. A test for EPO was introduced at the 2000 Summer Olympic Games in Sydney (Australia) [24].

While EPO is beneficial in those with low Hb levels, using it to increase Hb above normal levels has adverse consequences. EPO, by thickening the blood, increases the risk of heart disease, stroke, and brain or pulmonary embolism. The misuse of EPO may also promote autoimmune disease [24].

7) Transfusion

Blood transfusions are typically performed when hemoglobin levels are very low (less than 6 – 8 g/dl) [25].

In sports, this method is also abused for performance enhancement. Especially the so-called autologous blood doping, which is the transfusion of one’s own blood, which has been stored (refrigerated or frozen) until needed [24].

Factors that Decrease Hemoglobin

Although rare, high hemoglobin can be an indicator of an underlying disease or disorder that requires medical attention. Before attempting to decrease hemoglobin on your own, talk to your doctor about appropriate strategies, which may include some of the things discussed in this section. Never use any of the strategies in this section in place of something your doctor prescribes.

1) Hydration

Hb tends to become elevated when the body is dehydrated. This is because of a reduction in blood volume (plasma – the liquid part of blood is decreased) [3].

Acute dehydration can raise the Hb concentration by 10 to 15% [3].

Adequate hydration is important to maintain normal Hb levels, especially during exercise.

2) Quit Smoking

Smokers tend to have higher hemoglobin than non-smokers. This elevation makes it more difficult to detect anemia and other conditions associated with low Hb in people who smoke [26, 27].

3) Bloodletting

Phlebotomy, known also as bloodletting, is a major therapeutic procedure that we often associate with antiquated and historical practices. However, therapeutic phlebotomy is still used for the treatment of diseases with high Hb, such as polycythemia vera [28].

It is also occasionally used in conditions such as chronic lung diseases and cyanotic heart disease (both can cause elevated Hb) [28].

One of the major goals of this treatment is to reduce blood clots and the risk of associated adverse events [28].

Do not, under any circumstances, attempt therapeutic bloodletting on your own.

Laboratory Testing for Hemoglobin Variants

Hemoglobin Electrophoresis

A technique called hemoglobin electrophoresis can be used to identify the types of Hb a person has. In many countries, routine testing of all newborns is performed to identify common Hb variants such as thalassemias and sickle-cell anemia [29].

Hemoglobin Genes

Hemoglobin levels are influenced by your genes. There are more than 1,000 human Hb gene variants (SNPs) [29].

These variants are common, affecting an estimated 7% of the world’s population [29].

The most common and important Hb variants include HbS (found in sickle-cell anemia) and HbE (found in thalassemia) [29].

These are all maintained with relatively high frequency in humans because they confer survival advantages when it comes to malaria [29].

Those who have one copy of the sickle-cell gene or for alpha-thalassemia are protected against malaria [30].

However, in individuals who carry both copies of these mutations, the protective effect is completely lost and they are equally prone to malaria as individuals who have normal Hb copies [30].

Most of the people with only one copy remain without symptoms and many go undiagnosed [31].

Some Hb variants are clinically benign but produce obvious changes in skin color, a ruddy complexion, or a blue-tinged skin. These variants are not clinically damaging beyond their cosmetic effects [29].

Note that some of the Hb variants may artificially elevate HbA1c levels and interfere with the diagnosis and treatment of diabetes [29].

HBA1 and HBA2

HBA1 (hemoglobin subunit alpha 1) and HBA2 (hemoglobin subunit alpha 2) both produce the alpha chain of Hb. Normally, people have two copies each (four copies in total).

Two alpha chains (either HBA1 or HBA2) plus two beta chains constitute HbA, which is the normal adult hemoglobin. It normally accounts for about 97% of the total hemoglobin [32].

Alpha-thalassemias can result from losing more than two copies of the alpha chain (either HBA1 or HBA2) [33].

Losing one or two copies is clinically silent, and doesn’t produce any drastic symptoms [33].

Losing three copies causes hemoglobin H disease, with moderate anemia [33].

Losing all four copies results in the death of the fetus [33].

Copies are most often deleted, and these deletions are not usually assayed by genomics companies (you have to undergo special hemoglobin typing tests).

However, some cases of alpha-thalassemia are also caused by single nucleotide variants (mutations).

T to C mutation in this position causes alpha-thalassemia [34].

HbH disease occurs due to having two copies of this variant [35].

HBB

HBB (hemoglobin subunit beta) produces the beta chain of hemoglobin. Normally, people have two copies of this gene.

Two alpha chains plus two beta chains constitute HbA, which is the normal adult hemoglobin. HbA accounts for about 97% of the total hemoglobin [32].

Mutations in the HBB gene cause sickle-cell disease or beta-thalassemia.

However, these mutations are at the same time beneficial, conferring resistance to malaria.

The term “thalassemia intermedia” refers to milder mutations where the hemoglobin level is maintained above 6.5 g/dL [33].

The term “beta-thalassemia major” refers to having a serious disease in which there is an inability to maintain hemoglobin to levels above 6.5 g/dL [33].

  • RS334

rs334(T), is also known as i3003137 (A) or HbS, is the most prevalent mutation in the hemoglobin beta subunit [33].

Having two copies of this variant (rs334 T/T) causes a serious disease known as sickle cell anemia.

On the other hand, people having a single copy (rs334 A/T) are resistant to malaria and develop only slight anemia [36].

This variant is also known as HbC.

The mutation is particularly prevalent in West African populations [37].

HbC provides near full protection against malaria in people with two copies (CC) and intermediate protection in people with a single copy (AC) [37].

Having two HbC copies causes mild hemolytic anemia (anemia due to red blood cell breakdown). Usually, no treatment is needed.

This variant is known as HbE.

Having a single HbE copy causes no adverse symptoms.

Two HbE copies cause mild anemia.

However, HbE is inherited together with beta-thalassemia (E/beta-thalassemia). Cases like this represent approximately 50% of those affected with severe beta-thalassemia [38].

The highest frequencies are observed in India, Bangladesh, and throughout Southeast Asia, particularly in Thailand, Laos, and Cambodia, where it is common for individuals to inherit copies for both hemoglobin E (HbE) and beta-thalassemia [38].

This condition affects a million people worldwide and is increasing in North America [39].

HBD

HBD (hemoglobin subunit delta) produces the delta chain of hemoglobin.

Two alpha chains plus two delta chains constitute HbA2, which accounts for about 2.5% of total adult hemoglobin [32].

Mutations in the delta chain gene are associated with delta-thalassemia. Because of the low frequency of HbA2 in the blood, people with mutations in HBD are without symptoms.

HBG1 and HBG2

HBG1 (hemoglobin subunit gamma 1) and HBG2 (hemoglobin subunit gamma 2) are genes that normally function in the fetus.

Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is usually replaced by adult hemoglobin (HbA) in the year following birth [29].

Thus, fetal hemoglobin accounts for 80% of hemoglobin in newborns, but only about 0.5% in adults [32].

In some cases, the F hemoglobin persists in adult red blood cells. This is a state without symptoms known as hereditary persistence of fetal hemoglobin (HPFH) [40].

In cases of beta-thalassemia and related conditions, gamma chain production may persist, possibly as a mechanism to compensate for the mutated beta-chain.

HBE1 and HBZ

HBE1 (hemoglobin subunit epsilon) and HBZ (hemoglobin subunit zeta) are genes for hemoglobin subunits that are normally found in the early embryo.

Embryonic hemoglobin is composed of any of the following combinations: two epsilon and two zeta chains, two epsilon and two alpha chains, two zeta and two gamma chains, or two zeta and two beta chains.

Haptoglobin

Haptoglobin is an important protein that sequesters free Hb from the blood. Free Hb causes oxidative stress and inflammation, and this is mostly prevented by haptoglobin [41].

In humans, the haptoglobin gene has two variants, Hp1 and Hp2 [42].

Hp2 forms a larger, bulkier protein. However, due to its size, it may be less efficient.

Hp1 more efficiently inhibits free Hb-associated damage compared to the Hp2 variant [42].

Having two copies of the Hp2 variant is a risk factor for heart disease in both type I and type II diabetic patients [42].

Having two Hp2 copies has also been linked to a greater risk of brain damage in people with subarachnoid hemorrhage (bleeding into the compartment surrounding the brain) [42].

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About the Author

Biljana Novkovic

PhD
Biljana received her PhD from Hokkaido University.
Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science & health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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