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.
Haptoglobin is a very important marker to monitor, especially if you haven’t been leading the best lifestyle or you have chronic health issues.
What Is Haptoglobin?
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 [1, 2].
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.
Therefore, Hp is an acute phase reactant that increases with infection, inflammation, and injury .
1) 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 .
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 [7, 1].
Hp prevents kidney injury by recycling hemoglobin-bound iron and preventing it from accumulating in the kidneys .
Patients undergoing cardiac surgery who were administered Hp showed lower rates of postoperative acute kidney injury .
In adults, low (undetectable) Hp levels after serious burn injury (due to hemolysis) were linked with major adverse effects and injury in the kidneys .
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 [11, 12].
In mice and rats, Hp deficiency worsened brain injury, whereas Hp overproduction alleviated it .
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 .
2) Decreases Inflammation
3) Polarizes the Immune Response
Hp-deficient mice exhibited stunted development of the spleen, resulting in fewer 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 .
4) 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 [21, 17].
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 .
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 look at high or low haptoglobin levels and not mention anything. Sometimes, a lab result may be in the reference range, but not actually be 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 aren’t optimal.
Hp levels can decrease during pregnancy with otherwise normal laboratory tests. Usually, Hp levels return to normal after delivery .
The cause of low Hp values in pregnancy is likely due to the increased retention of fluids (otherwise known as hemodilution) .
- Tissue injury
- Traumatic brain injury
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 .
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 [24, 25].
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 .
Haptoglobin In Diseases
Low Haptoglobin-Associated Diseases
During red blood cell destruction, substantial amounts of hemoglobin are released into circulation and taken up by Hp .
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 .
High Haptoglobin-Associated Diseases
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 .
Elevated in Neurodegenerative Diseases
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 .
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 .
Haptoglobin and Cancer
Both low and high haptoglobin are implicated in cancer.
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 .
Mice prone to tumors exhibited an increase in tumor number, when they lack Hp, suggesting that Hp suppresses tumor formation . 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, the use of synthetic anabolic-androgen steroids has been shown to increase Hp levels [40, 41].
- 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 [42, 43].
- Smoking: Hp levels were higher in smokers than in non-smokers .
Factors That Decrease Haptoglobin
- Injected testosterone was shown to decrease Hp levels in humans .
- Estrogen therapy decreases Hp levels in humans .
- 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 .
In Southeast Asia, about 90% of all people have Hp2-2 .
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 .
Hp1 inhibits more efficiently free hemoglobin-associated damage compared to the Hp2 variant, which produces a larger, bulkier 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 least active .
Apart from the Hp1 and Hp2 variants, other mutations in this gene can cause a lack or an excess of haptoglobin in humans .
People with Hp1-1 have a stronger Th1 response .
Hp1-1 may protect against:
- Heart disease 
- High cholesterol (total and LDL) 
- Inflammatory and immune disorders (systemic sclerosis, IBD) 
- Infections 
- Preeclampsia 
Hp1-1 may increase the risk of:
- Stroke [56, 57]
- Worse cognitive function in diabetes and after brain injury [58, 59, 60]
- Parasite worms 
Hp1-2 may increase the risk of:
H2-2 may protect against:
Hp2-2 may increase the risk of:
- Heart disease 
- Hardening of the arteries 
- Diabetes 
- Diabetes-related complications (heart and kidney disease) [72, 17, 73]
- Immune/Inflammatory diseases (lupus, rheumatoid arthritis, type 1 diabetes, IBD) [4, 74]
- Elevated blood pressure 
- Low HDL cholesterol [49, 75]
- Vitamin C deficiency [76, 77]
- Viral infections 
- Leaky gut 
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 .
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.
A 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 .
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 aneurysms, carotid plaque ruptures, and decreased survival after a coronary artery bypass .
Furthermore, people with the Hp 2-2 variants also have lower blood Hp levels, which may additionally contribute to heart disease development .
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 .
A meta-analysis of 8 studies with 3,939 patients showed that Hp2-2 carriers with diabetes benefit from vitamin E supplementation .
Vitamin E treatments in individuals with Hp2-2 improved blood vessel function after eight weeks of treatment .
Supplementation of vitamin E slowed kidney disease progression in Hp2-2 mice, but did not affect progression in Hp1-1 mice .
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 [4, 17].
People with Hp2-2 (2 Hp2 variants) may have an increased risk of immune and inflammatory disorders due to higher intestinal permeability .
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%) [82, 83].
Hp0 increases the risk of anaphylactic reaction after blood transfusion (due to anti-haptoglobin antibodies) .
Haptoglobin (HP gene) SNPs
The A variant of rs5472 is associated with higher Hp levels .
The G variant is associated with higher Hp levels (GG and GA compared to AA carriers) .
The T variant of rs8062041 may be protective against sleeping sickness in Africans .
Irregular Haptoglobin Levels?
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