Properties of Hepcidin's and its Role in Iron-Related Disorders
Hepcidin is a peptide hormone that manages the body’s blood iron levels. Although it is antimicrobial and can help protect against Parkinson’s and Alzheimer’s, excess hepcidin can cause many disorders. Read more to learn about its function and role in iron-related disorders.
What is Hepcidin?
Hepcidin is a peptide hormone. Its main function is to controls the body’s iron levels and helps maintain its balance (homeostasis). Iron is necessary for our bodies to function properly. However, when the levels of iron are high it becomes toxic [R].
Hepcidin blocks iron that comes from the gut, immune cells (macrophages), and liver cells. It inhibits iron entry into the blood by binding to ferroportin (an iron transporter) and degrading it [R, R].
The liver produces hepcidin. The following factors control hepcidin levels:
- Blood and liver iron levels. Low iron levels decrease hepcidin, while high levels increase it [R, R].
- The production of red blood cells, which cannot happen without iron. In anemia, hepcidin is decreased to increase the supply of iron for red blood cell production [R, R].
- Inflammation (IL-6) and infection increase hepcidin to limit iron availability to invading microbes (which need iron to survive) [R, R, R].
- Hypoxia (low oxygen levels). This happens in conditions where there is a lower supply of oxygen to the tissues, such as anemia [R].
There are many ways to measure hepcidin levels, so normal reference ranges vary a lot. The four main types of measurements are [R]:
- RIA (radioimmunoassays) uses radioactive labels to measure hepcidin. Although it is highly specific, it may not be safe.
- ELISA uses antibodies and enzymes to measure hepcidin levels. It is the most common measurement technique. Normal levels range from 2 to 56 ng/ml (with an average of 11 ng/mL).
- Ligand binding assay
- MS (mass spectrometry)
Hepcidin levels are lower in the morning and increase in the afternoon [R].
In a study of 120 health subjects, using ELISA, the average hepcidin level was 9.2 ng/mL (the range was 1.23 – 36.46 ng/mL) [R].
Hemochromatosis patients have lower levels, and Hodgkin’s lymphoma and kidney disease patients have higher levels (average of 114 ng/mL) [R].
Patients with sepsis, inflammatory bowel disease, myeloma, and burns have significantly elevated hepcidin levels [R].
Health Benefits of High Hepcidin Levels
1) Hepcidin Is Antimicrobial
Scientists initially identified hepcidin as an antimicrobial peptide. That is actually how it got its name: hepatic (liver) bactericidal protein – or hepcidin for short [R].
During infection, hepcidin causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens [R].
In mice, hepcidin was associated with bacterial removal and reduced inflammation [R].
Hepcidin protects the kidneys from bacterial infections. Hepcidin-deficient mice have much higher bacterial levels in their kidneys compared to normal mice. In addition, hepcidin administration to normal mice significantly lowered Escherichia coli (E. coli) bacterial activity in their kidneys [R].
Hepcidin from zebrafish prevented bacterial growth of E. coli, Vibrio anguillarum, Staphylococcus aureus, and Bacillus subtilis [R].
However, in another study, hepcidin was unable to disrupt E. coli bacterial growth at higher pH levels. The ability of hepcidin to disrupt bacterial growth might, therefore, be pH-dependent [R].
2) Hepcidin May Protect Against Parkinson’s and Alzheimer’s Disease
Excess iron levels can contribute to Parkinson’s and Alzheimer’s disease. In rats with excess iron levels in their brain, hepcidin (when artificially increased) significantly reduced brain iron levels and prevented iron transport into the brain [R].
Negative Effects of High Hepcidin Levels
In rats, hepcidin added to rat feed caused an increase in blood sugar in all female rats, and intestinal inflammation in some female rats [R].
Although the use of hepcidin in normal doses is safe, excessive doses may damage the intestines [R].
Diseases Linked to High Hepcidin Levels
1) Hepcidin Increase Inflammation During Obesity
Obese adults have a higher risk of low iron levels. There are a lot of inflammatory markers in the body during obesity, including IL-6. IL-6 increases hepcidin levels, which then decreases iron levels [R].
2) High Hepcidin Is Associated With Iron-Refractory Iron Deficiency Anemia And Anemia of Chronic Disease
Iron-refractory iron deficiency anemia is a genetic disorder in which the red blood cells are smaller and lighter than normal. It is characterized by increased hepcidin production due to a gene (MT2) mutation [R, R].
In a study of 90 children, pure chronic disease anemia patients had increased hepcidin levels. This is because chronic inflammation increased hepcidin and caused anemia [R].
High hepcidin levels are also indications of anemia from chronic diseases. Anemia of chronic disease (ACD) is associated with long-term immune activation disorders such as diabetes, chronic infections, chronic kidney disease, Crohn’s, and cancer [R].
During chronic diseases, inflammation (caused by IL-6) increases hepcidin levels. This reduces FPN1 activity and decreases the available iron for red blood cell formation [R].
3) Hepcidin and Cancer
The following cancers are associated with higher hepcidin levels [R]:
- Small lung
In a study of 85 breast cancer patients, hepcidin levels were positively correlated with inflammation marker levels (IL-6 and Hb). High hepcidin was a risk factor for breast cancer and its bone metastasis (cancer spread to the bone) [R].
4) High Hepcidin May Increase the Risk of Atherosclerosis (Hardening of the Arteries)
A clinical study examined iron levels for 1,819 patients to determine its relation to atherosclerosis (plaque buildup in arteries) [R].
5) High Hepcidin Levels Indicate Sleep Disorder
Obstructive sleep apnea patients suffer from chronic inflammation which is linked as a sign of high hepcidin [R].
In a clinical study of 294 obstructive sleep apnea syndrome patients, the patients had a significantly higher hepcidin level compared with healthy controls. Hepcidin levels were also significantly higher in severe sleep apnea patients compared with mild patients [R].
6) High Hepcidin May Indicate Heart Disease
Iron plays a key role in heart diseases. In rats with oxygen deficiency and inflammation in their hearts, they had an increase in heart and liver hepcidin levels. Oxygen deficiency resulted in an increase of hepcidin (production) in their heart [R].
A human study examined the relationship between hepcidin and: risk of dying in cardiovascular events in 405 hemodialysis patients, a person who undergoes a process in which the blood in purified of toxins where hepcidin levels are increased [R].
Hepcidin levels were associated with fatal and non-fatal heart events through inflammation [R].
7) Hepcidin Is Higher in Psoriasis Patients
In a clinical study, 46 patients with psoriasis (a condition in which skin cells build up and form itchy, dry patches) had higher levels of hepcidin compared to 32 healthy volunteers [R].
While they also had lower iron levels, there was no significant difference in their ferritin levels. Chronic inflammation during psoriasis increased IL-6, which increased hepcidin production [R].
Health Benefits of Low Hepcidin Levels
Low hepcidin levels cause high levels of iron in the body, which leads to cell toxicity. High iron in the cells causes reactive oxygen species formation and oxidative stress. This can lead to dysfunction of the heart, liver, and hormone glands [R, R].
Thus, no health benefits have been recorded [R].
Negative Effects of Low Hepcidin Levels
Mutations in the proteins involved in iron sensing and transmission can cause inadequate hepcidin levels, leading to excess iron in the body (iron overload) [R].
Low hepcidin allows unchecked ferroportin activity, giving rise to excess dietary iron absorption and rapid iron release. Iron is taken up by the liver, causing excess iron levels and cell death [R].
Iron overload and low hepcidin stop the maturation of red blood cells in humans and the cells may become abnormal [R].
Diseases Linked to Low Hepcidin Levels
1) Low Hepcidin Can Indicate Iron Deficiency Anemia
This is the most common type of anemia.
In pure iron deficiency anemia, hepcidin levels are significantly decreased and can even be undetectable [R].
Even in the absence of anemia, hepcidin appears to be a sensitive indicator of iron deficiency. Compared to hematocrit or hemoglobin, a decrease in hepcidin is an early marker of iron deficiency together with transferrin saturation and decreased ferritin [R].
2) Low Hepcidin Levels Cause Hepcidin Hemochromatosis
Hepcidin hemochromatosis is a disorder where there is excessive iron in the body. This can lead to cell toxicity by causing iron buildup in the liver, heart, tissue, and joints [R].
Hereditary hemochromatosis is a group of genetic disorders in which hepcidin levels are low, due to gene mutations in either hepcidin or its regulators. The severity of iron overload (excess iron) depends on the deficiency [R, R].
Hereditary hemochromatosis is most frequently due to a C282Y mutation point in the HFE gene, but can also derive from mutations in the TfR2 protein [R].
3) Low Hepcidin Causes Excess Iron Levels in Diabetes
Type 2 diabetes patients usually have excess iron levels (iron overload). Hepcidin can be directly decreased by insulin, and the suppressed liver hepcidin production may be a cause of excess iron in type 2 diabetes [R].
Two studies (one cross-sectional and one 4 month DB-RCT) of 239 non-diabetic subjects and 101 type II diabetics, the diabetic patients had significantly lower hepcidin levels [R].
In rats with streptozotocin-induced diabetes, there was a significant decrease in liver hepcidin level and an increase in intestinal iron absorption and liver iron content[R].
Diseases Associated with Both High and Low Hepcidin Levels
Hepcidin and Inflammatory Bowel Disease
That may explain why hepcidin levels are low in some and high in other cases.
In one pilot study, the level of hepcidin was lower in 61 IBD patients than in 25 healthy volunteers, both in patients with and without anemia [R].
In a study of 15 children with IBD, hepcidin levels were significantly higher than in healthy patients [R].
Factors that Increase Hepcidin Levels
1) Iron Supplements
Oral iron supplements may cause increases hepcidin levels to maintain iron balance [R].
80 mg/day of iron supplementation increased hepcidin levels in a 4-week study (RCT) of 145 subjects [R].
2) Exercise – Short-Term
Short-term (acute) exercise may increase hepcidin levels.
In a study of 12 subjects, both 60 min and 120 min runs increased hepcidin levels 3 hours after exercise. This may be due to the increase in IL-6 levels immediately after exercise [R].
Another week-long study of 12 athletes also showed increased hepcidin levels after running exercises [R].
Factors That Decrease Hepcidin Levels
1) Vitamin D
In a pilot study of 7 healthy subjects, 100,000 IU Vitamin D decreased hepcidin levels [R].
In rat cells, aspirin decreased hepcidin production by decreasing inflammation (and the inflammatory cytokine IL-6) [R].
4) Weight Loss
Weight loss can help reduce IL-6 and hepcidin levels [R].
15 obese children that partook in a 6-month weight loss program had a significant decrease in their BMI and hepcidin levels [R].
In 20 previously-obese subjects who underwent weight loss surgery, their hepcidin levels were significantly decreased 6 months after their surgery [R].
5) Exercise – Long-Term
In a 120-day study (crossover) of 16 athletes, long-term exercise caused a steady decrease in hepcidin levels [R].
Patients with alcoholic kidney disease have suppressed hepcidin production, and alcohol consumption may cause a decrease in hepcidin [R].
In a study of 40 non-smokers and 41 smokers, the smoking subjects had significantly lower hepcidin blood levels. Smoking may reduce iron and hepcidin levels [R].
In a study (DB-RCT) of 109 men, 20 weeks of testosterone administration suppressed hepcidin levels. However, inflammatory markers and iron levels did not change [R].
In a study of 31 females, estrogen treatment decreased hepcidin levels [R].
Estrogen may inhibit hepcidin so the body can have higher iron levels to compensate for iron loss during menstruation [R].
Hepcidin is a protein that is encoded by the HAMP gene in humans [R].
The G variant of an SNP in this gene, rs10421768, is associated with lower hepcidin levels and increased susceptibility to extrapulmonary tuberculosis [R].
Bone morphogenetic proteins (BMPs) are a group of growth factors that induce bone growth. The growth factors use iron sensing mechanisms to adjust hepcidin production. BMP6 is the primary regulator of hepcidin [R].
C282Y HFE (rs1800562) mutation can cause lower hepcidin levels. Patients with this mutation have increased iron buildup (deposition) in their liver cells [R].
Transferrin receptor 2 (TFR2) regulate hepcidin, but the mechanism is still unknown. In mice, disruption of TFR2 may cause decreased hepcidin are: production [R].
Hemojuvelin is the protein that is responsible for juvenile hemochromatosis in humans, which is a severe form of hemochromatosis (excessive iron in the body). In humans, the HFE2 gene encodes the hemojuvelin protein [R].
Hemojuvelin (from liver cells, bone, and heart muscle) acts as a coreceptor for BMP6 to cause hepcidin production [R].
Irregular Hepcidin Levels?
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