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Haptoglobin binds to hemoglobin and reduces inflammation and oxidative stress. It plays a role in heart and kidney health, leaky gut, obesity, and cancer. A common genetic variant of haptoglobin increases the risk of heart disease, diabetes, and other inflammatory and immune disorders. Read on to learn more about this protein and the ways in which it keeps you healthy.

What Is Haptoglobin?

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Haptoglobin (Hp, medical abbreviation: hpt) is a protein primarily produced in the liver, but also in other tissues including the lungs, fat tissue, skin, spleen, brain, intestine, arterial vessels, and kidneys, and released into the bloodstream [R, R].

A major function of Hp is to bind free hemoglobin in the bloodstream.

Hemoglobin is normally found within red blood cells, but gets released when they rupture – this process is called hemolysis. Hemolysis occurs in some diseases, including infections, malaria, and some types of anemia.

Apart from normally being found in the body, Hp can also be administered in surgery or some diseases where hemolysis is increased.

Haptoglobin Production

Hp is mainly produced by liver cells (hepatocytes). Its production is stimulated by inflammatory cytokines such as IL-1,IL-6, and TNF [R, R].

Therefore, Hp is an acute phase reactant that increases with infection, inflammation, and injury [R].

Haptoglobin Function

1) Haptoglobin Removes Free Hemoglobin and Protects Tissues from Oxidative Stress

Free hemoglobin in the blood causes oxidative damage to cells and tissues, contributing to a number of pathological situations, including hardening of the arteries and kidney malfunction [R].

Hp binds free hemoglobin in the bloodstream. A stable haptoglobin-hemoglobin complex is formed and cleared by white blood cells. This prevents hemoglobin-induced inflammation and oxidative tissue damage [R, R].

Hp prevents kidney injury by recycling hemoglobin-bound iron and preventing it from accumulating in the kidneys [R].

Patients undergoing cardiac surgery who were administered Hp showed lower rates of postoperative acute kidney injury [R].

In adults, low (undetectable) Hp levels after serious burn injury (due to hemolysis) were linked with major adverse effects and injury in the kidneys [R].

Brain trauma, aneurysms, and brain tumors can all lead to hemorrhage, exposing the brain to free hemoglobin. That is why in situations involving traumatic brain injury, Hp may function as a neuroprotective protein [R, R].

In mice and rats, Hp deficiency worsened brain injury, whereas Hp overproduction alleviated it [R].

Finally, in 387 critically ill patients with sepsis (with high free hemoglobin levels), elevated Hp levels were associated with a decreased risk of in-hospital mortality [R].

2) Haptoglobin Decreases Inflammation

Hp has anti-inflammatory properties due to its ability to suppress the production of inflammatory cytokines:TNF-alpha, IL-10, and IL-12 [R].

Mice without Hp developed more severe inflammation in a model of multiple sclerosis [R].

Hp seems to have a protective role in reducing the severity of Th1/Th17-mediated inflammation [R].

3) Haptoglobin Polarizes the Immune Response

Hp plays an important role in the balance between Th1 and Th2 response by promoting a dominant Th1 and inhibiting the Th2 cell response [R, R].

Th2 cytokines decreased by haptoglobin include IL-4, IL-5, IL-10, and IL-13 [R].

Hp-deficient mice exhibited stunted development of the spleen, resulting in less lymphocytes (white blood cells), which are necessary to fight disease and infections. These mice were incapable of defending against Salmonella infection or generating anti-tumor immune responses [R].

4) Haptoglobin Promotes the Growth of New Blood Vessels

Hp is a growth factor essential to forming new blood vessels. Increased levels of Hp in inflammatory or ischemic (low oxygen) conditions are important for improving blood supply and promoting the growth of collateral vessels, which play an important role in tissue repair [R, R].

Preaptoglobin-2, a precursor of haptoglobin, can promote the growth of new blood vessels via the VEGF signaling pathway. Prehaptoglobin-2 can increase the production of VEGF and VEGF receptors (VEGFR2), and increase sprouting and branching of new blood vessels [R].

Haptoglobin Blood Test

You can check your Hp levels with a simple blood test.

Haptoglobin Normal Range

While levels vary by individual, the normal range of in blood (serum) is 33 to 213 mg/100 mL [R].

Hp levels can decrease during pregnancy with otherwise normal laboratory tests. Usually, Hp levels return to normal after delivery [R].

The cause of low Hp values in pregnancy is likely due to the increased retention of fluids (otherwise known as hemodilution) [R].

High Haptoglobin

Increased levels of Hp are found in patients with [R, R, R]:

  • Inflammation
  • Tissue injury
  • Trauma
  • Burns
  • Traumatic brain injury
  • Cancer

Levels are high in the days following the inflammatory or traumatic injury and return to normal within several weeks.

Elevated Hp may also be a result of hypersplenism (overactive spleen), megaloblastic anemia (a condition characterized by fewer and larger blood cells), or the use of drugs such as androgens and corticosteroids [R].

Low Haptoglobin

Decreased Hp in patients could be indicative of a number of conditions. It is a reliable marker for the instant diagnosis of accelerated red blood cell destruction (hemolytic anemia) because Hp levels become depleted in the presence of large amounts of free hemoglobin [R, R].

Decreased Hp levels can also occur due to liver disease, malnutrition, allergic reactions, and seizure disorders [R, R].

A lack of Hp in newborns is common. By three months of age, haptoglobin becomes present in the majority of infants [R, R].

False positives for anemia based on low Hp levels can occur due to improper specimen preparation, cirrhosis, elevated estrogen levels, and hemodilution. Hp testing is also less reliable for the detection of anemia during periods of inflammation when Hp is high, such as post-surgery [R].

Haptoglobin In Diseases

Low Haptoglobin-Associated Diseases

Haptoglobin Is Low in Hemolytic Anemia

Hemolytic anemia is a condition that occurs when red blood cells are prematurely destroyed [R].

During red blood cell destruction, substantial amounts of hemoglobin are released into circulation and taken up by Hp [R].

This clearance of excess hemoglobin from the blood leads to a depletion of Hp. Eighty percent of patients with hemolytic anemia show low levels of Hp [R].

High Haptoglobin-Associated Diseases

Haptoglobin Is Increased in Obesity

Obesity is a low-grade, chronic systemic inflammatory condition. In 312 obese subjects, increased Hp showed a strong correlation with body mass index (BMI), leptin, C-reactive protein (CRP), and age [R].

Hp is produced by fat cells. Higher levels in fat tissue and in the blood are associated with obesity [R, R].

Haptoglobin Is Elevated in Neurodegenerative Diseases

Neurodegenerative diseases such as Alzheimer’s and Huntington’s involve inflammation as well as oxidative stress. Haptoglobin levels in both diseases were higher than in healthy individuals [R, R].

High Haptoglobin May Cause Transplant Rejection

After organ transplants, graft inflammation may occur within hours in both mice and humans. Haptoglobin activates the immune system and can cause transplant rejection.

Roughly 80% of Hp deficient mice exhibited more than 100 days of survival after heart transplantation, while mice with Hp rejected their transplants by day 21 post operation [R].

Similarly, Hp from the donor tissue accelerated skin graft rejection in mice. In contrast, when the donor animals were Hp deficient the rejection was delayed [R].

Haptoglobin and Cancer

Both low and high haptoglobin are implicated in cancer.

Haptoglobin was elevated in patients with liver cancer compared to those with nonmalignant liver diseases [R, R].

Furthermore, patients with higher serum levels of Hp had poor survival rates in cancers such as colon, ovarian, and lung cancer [R].

On the other hand, lower Hp was highly correlated with poor 5-year overall survival rate in liver cancer patients [R].

Mice prone to tumors exhibited an increase in tumor number, when they lack Hp, suggesting that Hp suppresses tumor formation [R]. This may be because Hp promotes Th1 (anti-tumor) immune responses.

Factors That Increase Haptoglobin

  • 17α-alkylated anabolic steroids: Hp increased in patients with infective hepatitis through steroid therapy. Also, use of synthetic anabolic-androgen steroids has been shown to increase Hp levels [R, R].
  • High-fat diet/obesity: Rats born to mothers who were fed a high-fat diet during the last two weeks of pregnancy had higher levels of blood Hp. However, Hp in the brain actually decreased [R, R].
  • Smoking: Hp levels were higher in smokers than in non-smokers [R].

Factors That Decrease Haptoglobin

  • Injected testosterone was shown to decrease Hp levels in humans [R].
  • Estrogen therapy decreases Hp levels in humans [R].

Haptoglobin Genetics

In humans, there are two common variants of haptoglobin, Hp1 and Hp2. Most people carry two copies of either variant or a copy of each [R, R]:

  • Hp1-1 (two Hp1 variants)
  • Hp1-2 (one Hp1 and one Hp2 variant)
  • Hp2-2 (two Hp2 variants)

In whites, Hp1-1 is found in 15%, Hp2-1 in 50%, and Hp2-2 in 35% of people [R].

The Hp1 frequency is low in Southeast Asia and India (7%) and high in parts of West Africa and South America (70%) [R, R].

In Southeast Asia, about 90% of all people have Hp2-2 [R].

Hp1 is the original variant. Hp2 is thought to have originated in India about 2 million years ago, and has since spread over the world [R].

Hp1 inhibits more efficiently free hemoglobin-associated damage compared to the Hp2 variant, which produces a larger, bulkier protein [R].

Hp1-1 is the most effective in binding free hemoglobin and suppressing inflammatory responses, while Hp1-2 is moderately active, and Hp2-2 is least active [R].

Apart from the Hp1 and Hp2 variants, other mutations in this gene can cause a lack or an excess of haptoglobin in humans [R].

Hp1-1

People with Hp1-1 have a stronger Th1 response [R].

Hp1-1 may protect against:

  • Heart disease [R]
  • High cholesterol (total and LDL) [R]
  • Inflammatory and immune disorders (systemic sclerosis, IBD) [R]
  • Infections [R]
  • Preeclampsia [R]

Hp1-1 may increase the risk of:

  • Stroke [R, R]
  • Worse cognitive function in diabetes and after brain injury [R, R, R]
  • Parasite worms [R]

Hp1-2

Hp1-2 may increase the risk of:

Hp2-2

H2-2 may protect against:

  • Malaria [R, R]

Hp2-2 may increase the risk of:

  • Heart disease [R]
  • Hardening of the arteries [R]
  • Diabetes [R]
  • Diabetes-related complications (heart and kidney disease) [R, R, R]
  • Immune/Inflammatory diseases (lupus, rheumatoid arthritis, type 1 diabetes, IBD) [R, R]
  • Elevated blood pressure [R]
  • Low HDL cholesterol [R, R]
  • Vitamin C deficiency [R, R]
  • Viral infections [R]
  • Leaky gut [R]

Hp2-2 and Heart Disease

Diabetic individuals who are Hp2-2 were at 500% greater risk of heart disease compared to diabetic Hp1-1 individuals [R].

Hemoglobin to which glucose is bound is known as glycosylated hemoglobin. Glycosylated hemoglobin that is not cleared by white blood cells can cause oxidative tissue damage, which results in hardening of the arteries.

Slower rate of hemoglobin clearance in those with the Hp2 variant increases hardening of the arteries, and therefore poses a greater risk of cardiovascular disease [R].

Hp2-2 was shown to be a significant risk factor for heart infarction, cardiovascular disorders, stroke, and heart failure. The Hp2-2 genotype has also been associated with other complications such as aneurysm, carotid plaque rupture, and decreased survival after coronary artery bypass [R].

Furthermore, people with the Hp 2-2 variants also have lower blood Hp levels, which may additionally contribute to heart disease development [R].

Hp2-2 People Benefit from Vitamin E Supplementation

Hp2-2 diabetic patients benefit from antioxidant supplementation such as vitamin E, iron chelators, or a combination of both to reduce the severity of heart disease [R].

A meta-analysis of 8 studies with 3,939 patients showed that Hp2-2 carriers with diabetes benefit from vitamin E supplementation [R].

Supplementation with vitamin E in Hp2-2 individuals has the potential to reduce cardiovascular events by up to 35-50% [R, R].

Vitamin E treatments in individuals with Hp2-2 improved blood vessel function after eight weeks of treatment [R].

Supplementation of vitamin E slowed kidney disease progression in Hp2-2 mice, but did not affect progression in Hp1-1 mice [R].

Hp2, Zonulin, and Leaky Gut

Prehaptoglobin-2, a precursor of Hp2 (the protein that Hp2 is made from), is also called zonulin. Zonulin causes tight junctions in the gut to open, thereby increasing intestinal permeability [R, R].

Zonulin is increased in immune and inflammatory diseases related to increased gut permeability, such as celiac disease and type 1 and type 2 diabetes [R, R].

People with Hp2-2 (2 Hp2 variants) may have an increased risk of immune and inflammatory disorders due to higher intestinal permeability [R].

Hp0

This variant results in a nonfunctional gene (no protein product). People with two copies of this variant don’t have detectable haptoglobin levels in the blood. Hp0 is found mainly in East Asia (1-4%) [R, R].

Hp0 increases the risk of anaphylactic reaction after blood transfusion (due to anti-haptoglobin antibodies) [R].

Haptoglobin (HP gene) SNPs

rs5472

The A variant of rs5472 is associated with higher Hp levels [R].

rs2000999

The G variant is associated with higher Hp levels (GG and GA compared to AA carriers) [R].

The A variant is associated with higher total and LDL cholesterol [R, R].

rs8062041

The T variant of rs8062041 may be protective against sleeping sickness in Africans [R].

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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