Haptoglobin: Definition, Types, Production, Function, Levels and Associated Diseases

It is a protein produced mainly in the liver.

It is also produced in other tissues, including the lungs, fat tissue, skin, spleen, brain , intestine, arterial vessels, and kidneys, and is released into the bloodstream.

It is abbreviated as follows: Hp, medical abbreviation: hpt.

Hemoglobin is normally found within red blood cells, but is released when they break down; This process is called hemolysis . Hemolysis occurs in some diseases, including infections, malaria, and some types of anemia.

In addition to being normally found in the body, Hp can also be given in surgery or in some diseases where hemolysis is increased.

How can you find out what type of haptoglobin you have?

A DNA test is the only way to find out what type of haptoglobin you have.

Three common types, numbered 1-1, 2-1, and 2-2, and three rare types of haptoglobin are known and are believed to be the result of combinations between three alleles (forms of genes).

The serum haptoglobin level rises during inflammations and certain other conditions; It is reduced in hemolytic disease and some types of liver disease.


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

Thus, H p is an acute phase reagent that increases with infection, inflammation, and injury.

Haptoglobin function

Eliminates 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 conditions, including hardening of the arteries and kidney malfunction.

Hp binds to free hemoglobin in the bloodstream. White blood cells form and eliminate a stable complex of haptoglobin and hemoglobin. This prevents hemoglobin-induced inflammation and oxidative tissue damage.

PH prevents kidney damage by recycling iron bound to hemoglobin and preventing it from accumulating in the kidneys.

Patients undergoing cardiac surgery who received Hp showed lower rates of postoperative acute kidney damage.

In adults, low (undetectable) levels of Hp after severe burn injury (due to hemolysis) were associated with significant adverse effects and injury to the kidneys.

Brain trauma, aneurysms, and brain tumors can cause bleeding and expose the brain to free hemoglobin. That is why in situations involving traumatic brain injury, Hp can function as a neuroprotective protein.

In mice and rats, Hp deficiency worsened brain injury, while Hp overproduction alleviated it.

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

Decrease inflammation

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

Mice without Hp developed more severe inflammation in a multiple sclerosis model.

Hp appears to have a protective role in reducing the severity of Th1 / Th17-mediated inflammation [4].

Polarizes the immune response

Hp plays an important role in the balance between the Th1 and Th2 response by promoting a dominant Th1 and inhibiting the Th2 cellular response.

Las cytocinas Th2 disminuidas por haptoglobina including IL-4, IL-5, IL-10 and IL-13.

Promotes the growth of new blood vessels

HP is an essential growth factor for forming new blood vessels.

Increasing Hp levels in inflammatory or ischemic conditions (low oxygen) is important to improve blood supply and promote the growth of collateral vessels, which play an important role in tissue repair.

Preaptoglobin-2, a precursor to haptoglobin, can promote the growth of new blood vessels through the VEGF signaling pathway.

Prehaptoglobin-2 can increase the production of VEGF and VEGF receptors (VEGFR2) and increase the germination and branching of new blood vessels.

Haptoglobin blood test

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

You can request that your doctor test your haptoglobin. Conventional doctors will test for high or low haptoglobin levels and will not mention anything.

Sometimes a lab result may be in the reference range, but it is not actually in the optimal range. Reference ranges are not the same as optimal ranges.

This is why haptoglobin, even in the “normal” range, can be unhealthy and indicate that certain processes in the body are not optimal.

Normal range

Hp levels can decrease during pregnancy with normal laboratory tests. Hp levels usually return to normal after delivery.

The cause of low Hp values ​​in pregnancy is probably due to increased fluid retention (also known as hemodilution).

High levels

Elevated levels of Hp are found in patients with:

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

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

Elevated Hp can also be the result of hypersplenism (overactive spleen), megaloblastic anemia (a condition characterized by fewer and larger numbers of blood cells), or the use of medications such as androgens and corticosteroids.

Low levels

Decreased Hp in patients could be indicative of a number of conditions.

It is a reliable marker for the instant diagnosis of accelerated destruction of red blood cells (hemolytic anemia) because Hp levels are depleted in the presence of large amounts of free hemoglobin.

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

Lack of Hp in newborns is common. By three months of age, haptoglobin is present in most infants.

False positives for anemia based on low Hp levels can occur due to improper sample preparation, cirrhosis, elevated estrogen levels, and hemodilution.

Hp tests are also less reliable for detecting anemia during periods of inflammation when Hp is high, such as after surgery.

Haptoglobin in disease

Low diseases associated with haptoglobin:

hemolytic anemia

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

During the destruction of red blood cells, substantial amounts of hemoglobin are released into the circulation and absorbed by Hp.

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

Diseases associated with high haptoglobin


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

Hp is produced by fat cells. Higher levels in fat tissue and blood are associated with obesity.

Neurodegenerative diseases

Neurodegenerative diseases like Alzheimer’s and Huntington’s disease involve inflammation and oxidative stress. Haptoglobin levels in both diseases were higher than in healthy individuals.

Transplant rejection

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

Approximately 80% of the Hp-deficient mice exhibited more than 100 days survival after heart transplantation, while the Hp mice rejected their transplants on day 21 after the operation.

Similarly, HP of donor tissue accelerated skin graft rejection in mice. In contrast, when donor animals were Hp deficient, rejection was delayed.

Haptoglobin and cancer

Both low and high haptoglobin are implicated in cancer.

Haptoglobin was elevated in liver cancer patients compared to those with non-malignant liver disease.

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

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

Tumor-prone mice exhibited an increase in the number of tumors, when lacking Hp, suggesting that Hp suppresses tumor formation. This may be because Hp promotes Th1 (anti-tumor) immune responses.

Factors that increase and decrease Hp

Factors that increase haptoglobin

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

Factors that decrease haptoglobin

  • Injected testosterone was shown to decrease Hp levels in humans.
  • Estrogen therapy lowers Hp levels in humans.

Haptoglobin Genetics

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

  • Hp1-1 (from the Hp1 variants).
  • Hp1-2 (a Hp1 and a Hp2 variant).
  • Hp2-2 (from the Hp2 variants).

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

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

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

Hp1 is the original variant. Hp2 is believed to have originated in India about 2 million years ago and has since spread throughout the world.

Hp1 more effectively inhibits the damage associated with free hemoglobin compared to the Hp2 variant, which produces a larger and more voluminous protein.

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

In addition to the Hp1 and Hp2 variants, other mutations in this gene can cause a lack or excess of haptoglobin in humans.


People with Hp1-1 have a stronger Th1 response.

Hp1-1 can protect against:

Hp1-1 can increase the risk of:

  • Stroke
  • Worse cognitive function in diabetes and after brain injury.
  • Parasitic worms.

Hp1-2 can increase the risk of:

  • Parkinson.
  • Insulin resistance
  • Impaired fertility.
  • Celiac Disease.

H2-2 can protect against:

  • Malaria.

Hp2-2 can increase the risk of:

  • Heart disease.
  • Hardening of the arteries.
  • Diabetes.
  • Complications related to diabetes (heart and kidney disease).
  • Immune / inflammatory diseases (lupus, rheumatoid arthritis, type 1 diabetes, IBD).
  • High blood pressure.
  • Low HDL cholesterol.
  • Vitamin C deficiency.
  • Viral infections
  • Leaky intestine.

Hp2-2 and heart disease

People with diabetes who have Hp2-2 had a 500% higher risk of heart disease compared to people with Hp1-1 diabetes.

The hemoglobin that glucose binds to is known as glycated hemoglobin. Glycated hemoglobin that is not removed by white blood cells can cause oxidative damage to tissue, resulting in hardening of the arteries.

A slower rate of hemoglobin clearance in those with the Hp2 variant increases the hardening of the arteries and therefore poses an increased risk of cardiovascular disease.

Hp2-2 has been shown to be a significant risk factor for heart attack, cardiovascular disorders, stroke, and heart failure.

The Hp2-2 genotype has also been associated with other complications such as aneurysms, carotid plaque ruptures, and decreased survival after coronary artery bypass.

In addition, people with the Hp 2-2 variants also have lower levels of Hp in their blood, which can further contribute to the development of heart disease.

Hp2-2 people benefit from vitamin E supplementation

Diabetic patients with Hp2-2 benefit from supplementation with antioxidants such as vitamin E, iron chelators, or a combination of both to reduce the severity of heart disease.

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

Vitamin E supplementation in individuals with Hp2-2 has the potential to reduce cardiovascular events by up to 35-50%.

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

Supplementation with vitamin E slowed the progression of kidney disease in Hp2-2 mice but did not affect the progression in Hp1-1 mice.

Hp2, Zonulin y Leaky Gut

Prehaptoglobin-2, a precursor to Hp2 (the protein that Hp2 is made of), is also called zonulin. Zonulin causes the opening of tight junctions in the intestine, which increases intestinal permeability.

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

People with Hp2-2 (2 Hp2 variants) may be at increased risk for immune and inflammatory disorders due to increased intestinal permeability.


This variant results in a non-functional gene (no protein product). People with two copies of this variant have no detectable levels of haptoglobin in their blood. Hp0 is mainly found in East Asia (1-4%).

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