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 control the body’s iron levels and help maintain its balance (homeostasis). Iron is an essential micronutrient necessary for the proper functioning of the body. However, when its levels are too high, it becomes toxic [1].
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 breaking it down [2, 3].
Hepcidin is produced in the liver. The following factors control hepcidin levels:
- Blood and liver iron levels. Low iron levels decrease hepcidin, while high levels increase it [1, 4].
- The production of red blood cells, which cannot happen without iron. In anemia, hepcidin is lowered to increase the supply of iron for red blood cell production [4, 5].
- Inflammation (IL-6) and infection increase hepcidin to limit iron availability to invading microbes, which need this electrolyte to survive [1, 4, 6].
- Low oxygen levels (hypoxia). This happens in conditions when there is a lower supply of oxygen to the tissues, such as in anemia [7].
Source: [2]
Hepcidin Levels
Lab results are commonly shown as a set of values known as a “reference range”, which is sometimes referred to as a “normal range”. A reference range includes the upper and lower limits of a lab test based on a group of otherwise healthy people.
Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.
Some lab-to-lab variability occurs due to differences in equipment, techniques, and chemicals used. Don’t panic if your result is slightly out of range in the app – as long as it’s in the normal range based on the laboratory that did the testing, your value is normal.
However, it’s important to remember that a normal test doesn’t mean a particular medical condition is absent. Your doctor will interpret your results in conjunction with your medical history and other test results.
Have in mind that a single test isn’t enough to make a diagnosis. Your doctor will interpret this test, taking into account your medical history and other tests. A result that is slightly low/high may not be of medical significance, as this test often varies from day to day and from person to person.
There are many ways to measure hepcidin levels, so normal reference ranges vary a lot. The four main types of measurements are [8]:
- 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 [4].
In a study (ELISA) of 120 healthy people, the average hepcidin level was 9.2 ng/mL (the range was 1.23-36.46 ng/mL) [9].
Hemochromatosis patients have lower levels, while Hodgkin’s lymphoma and kidney disease patients have higher levels (average of 114 ng/mL) [8].
Patients with sepsis, inflammatory bowel disease, myeloma, and burns have significantly elevated hepcidin levels [4].
Health Benefits of High Hepcidin Levels
1) May Be Antimicrobial
Scientists initially identified hepcidin as an antimicrobial peptide. That is actually how it got its name: hepatic (liver) bactericidal (microbe-killing) protein – or hepcidin for short [4].
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 [10].
In mice, hepcidin was associated with bacterial removal and reduced inflammation [11].
Hepcidin protects the kidneys from bacterial infections. Hepcidin-deficient mice had much higher bacterial levels in their kidneys in one study. In addition, hepcidin administration to healthy mice significantly lowered Escherichia coli (E. coli) bacterial activity in their kidneys [12].
Hepcidin from zebrafish prevented the bacterial growth of E. coli, Vibrio anguillarum, Staphylococcus aureus, and Bacillus subtilis in test tubes [13].
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 [14].
2) 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 [15].
The hepcidin peptide prevented expression (production) of transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin 1 (Fpn1), and reduced iron uptake and iron release [15].
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 of them [16].
Although the use of hepcidin in normal doses is safe, excessive doses damaged the intestines in rats [16].
Diseases Linked to High Hepcidin Levels
The following conditions are commonly associated with high hepcidin levels, but this symptom alone is insufficient for a diagnosis. Work with your doctor to determine what underlying condition is causing your unusually high hepcidin levels and to develop a plan to properly treat it.
1) Obesity
Obese adults have a higher risk of low iron levels. Obesity triggers the production of several inflammatory markers, one of them being IL-6. This cytokine increases hepcidin levels, which in turn decreases iron levels [17].
Multiple human studies have shown an association between obesity and high hepcidin levels in both overweight adults and children [18, 19, 20].
2) Non-Iron Deficiency Anemia
Although hepcidin levels are significantly decreased in regular iron deficiency anemia (low red blood cell levels), they can actually be high in other types of anemia [4].
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 [4, 21].
In a study of 90 children, pure chronic disease anemia patients had increased hepcidin levels. This was likely because chronic inflammation increased hepcidin and caused anemia [22].
High hepcidin levels are also markers 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 [21].
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 [21].
3) Cancer
The following cancers have been associated with higher hepcidin levels [23]:
- Stomach
- Breast
- Brain
- Small lung
- Prostate
- Liver
- Ovarian
- Kidney
- Leukemia
In a study of 85 breast cancer patients, hepcidin levels were associated with those of inflammation markers (IL-6 and Hb). High hepcidin was a risk factor for breast cancer and its spread (metastasis) to the bone [24].
4) Artery Hardening (Atherosclerosis)
In a clinical study examining the iron levels for 1,819 patients, an increased hepcidin/ferritin ratio was associated with a higher incidence of plaque buildup in arteries [25].
5) Sleep Disorders
Obstructive sleep apnea patients suffer from chronic inflammation. In a study of 294 obstructive sleep apnea syndrome patients, their hepcidin levels were higher than those of healthy controls. Hepcidin levels were also significantly higher in severe sleep apnea patients compared with mild patients [26].
6) Heart Disease
Iron plays a key role in heart disease. In rats with oxygen deficiency and heart inflammation hepcidin levels were higher in the heart and liver. Oxygen deficiency resulted in an increased hepcidin production in the heart [27].
A human study examined the relationship between hepcidin and the risk of dying from cardiovascular events in 405 hemodialysis patients. High hepcidin levels were associated with an increased incidence of both fatal and non-fatal heart events through inflammation [28].
7) Psoriasis
In a study, 46 people with psoriasis (a condition in which skin cells build up and form itchy, dry patches) had higher levels of hepcidin when compared to 32 healthy volunteers [29].
While they also had lower iron levels, there was no significant difference in their ferritin levels. Chronic inflammation during psoriasis increased IL-6, which in turn increased hepcidin production [29].
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 [30, 4].
Thus, no health benefits have been reported [31].
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) [4].
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 [30].
Iron overload and low hepcidin stop the maturation of human red blood cells, which may become abnormal [32].
Diseases Linked to Low Hepcidin Levels
The following conditions are commonly associated with abnormally low hepcidin levels, but this symptom alone is insufficient for a diagnosis. Work with your doctor to determine what underlying condition is causing your unusually low hepcidin levels and to develop a plan to properly treat it.
1) 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 [4].
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 [4].
2) 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, and joints, among other tissues [1].
Hereditary hemochromatosis is a group of genetic disorders in which hepcidin levels are low due to gene mutations in the genes encoding either hepcidin or its regulators. The severity of iron overload (excess iron) depends on the deficiency [30, 33].
Hereditary hemochromatosis is most frequently due to a certain point mutation (C282Y) in the HFE gene, but can also derive from mutations in TfR2 [21].
3) 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 [34].
In 2 clinical trials of 239 non-diabetic people and 101 type 2 diabetics, the diabetic patients had significantly lower hepcidin levels [35].
In diabetic rats, there was a significant decrease in liver hepcidin level and an increase in intestinal iron absorption and liver iron content [34].
Diseases Linked to Both High and Low Hepcidin Levels
The following conditions are associated with both abnormally low and high hepcidin levels, but this symptom alone is insufficient for a diagnosis. Work with your doctor to determine what underlying condition is altering your hepcidin levels and to develop a plan to properly treat it.
Inflammatory Bowel Disease
Anemia is one of the most common non-gut-related symptoms of inflammatory bowel disease (IBD). This type of anemia combines features of iron deficiency anemia and anemia of chronic diseases, which may explain why hepcidin levels are low in some and high in other cases [36].
In an observational study, hepcidin levels were lower in 61 IBD patients than in 25 healthy volunteers, whether they had anemia or not [37].
In a study of 15 children with IBD, hepcidin levels were significantly higher when compared to healthy children [37].
Additionally, high hepcidin levels are associated with high ferritin levels and erythrocyte sedimentation rate, an inflammation indicator [36].
Factors that May Increase Hepcidin Levels
The most important thing is to work with your doctor to determine what underlying condition is causing your low hepcidin levels and establish a treatment plan. The additional strategies below are other measures that you may try as an add-on to your treatment regime if you and your doctor determine that they could be appropriate.
Lifestyle
1) Exercise (Short-Term)
Short-term (acute) exercise may increase hepcidin levels.
In a small clinical trial on 12 healthy people, 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 [38].
Another week-long study of 12 athletes also showed increased hepcidin levels after running exercises [39].
Supplements
2) Iron
Oral iron supplements may cause increases hepcidin levels to maintain iron balance [40].
80 mg/day of iron supplementation increased hepcidin levels in a 4-week clinical trial on 145 people [41].
Factors that May Decrease Hepcidin Levels
Again, the most important thing is to work with your doctor to determine what underlying condition is causing your high hepcidin levels and properly treat it. The following complementary strategies may also work as an add-on to your treatment regime if your doctor determines that they could be helpful in your case.
Lifestyle
1) Weight Loss
Weight loss can help reduce IL-6 and hepcidin levels [17].
15 obese children that partook in a 6-month weight loss program had a significant decrease in their BMI and hepcidin levels [42].
In 20 previously-obese people who underwent weight loss surgery, their hepcidin levels were significantly decreased 6 months after the procedure [43].
2) Exercise (Long-Term)
In a 120-day study (crossover) of 16 athletes, long-term exercise caused a steady decrease in hepcidin levels [44].
Supplements
3) Vitamin D
In a pilot trial on 7 healthy volunteers, 100,000 IU vitamin D decreased hepcidin levels [45].
4) Curcumin
Curcumin significantly reduced hepcidin production in mouse liver cells by blocking the STAT3 transmission pathway [46].
Drugs
The following drugs may also help lower hepcidin levels based on the existing evidence. While they may help if you are already taking them for their approved uses, you shouldn’t take them to lower your hepcidin levels without discussing it with your doctor beforehand.
5) Aspirin
In rat cells, aspirin decreased hepcidin production by decreasing inflammation (and the inflammatory cytokine IL-6) [47].
6) Testosterone
In a clinical trial on 109 men, 20 weeks of testosterone administration suppressed hepcidin levels. However, inflammatory markers and iron levels did not change [48].
7) Estrogen
In a clinical trial on 31 women, estrogen treatment decreased hepcidin levels [49].
Estrogen may inhibit hepcidin so the body can have higher iron levels to compensate for iron loss during menstruation [50].
8) Alcohol and Smoking
Although we highly advise against these habits due to their multiple negative health effects, both drinking alcohol and smoking cigarettes seem to lower hepcidin levels based on the existing evidence.
Patients with alcoholic kidney disease had suppressed hepcidin production, suggesting that alcohol consumption may cause a decrease in hepcidin [51].
In mice, chronic alcohol consumption decreased hepcidin levels [52, 53].
In a study of 40 non-smokers and 41 smokers, smokers had significantly lower blood hepcidin and iron levels [54].
Hepcidin-Associated Genes
HAMP
Hepcidin is a protein encoded by the HAMP gene in humans [55].
The G variant of a SNP in this gene, rs10421768, is associated with lower hepcidin levels and increased susceptibility to extrapulmonary tuberculosis [56].
BMP6
Bone morphogenetic proteins (BMPs) are a group of growth factors that induce bone growth and use iron sensing mechanisms to adjust hepcidin production. BMP6 is the primary regulator of hepcidin [4].
HFE
A polymorphism at HFE (rs1800562, C282Y variant) can cause lower hepcidin levels and increased iron buildup in the liver [57].
MT2
The TMPRSS6 gene encodes MT2. It normally reduces hepcidin production. Mutations in this gene can cause increased hepcidin production and iron-refractory iron deficiency anemia [21].
TFR2
Transferrin receptor 2 (TFR2) regulates hepcidin, but the mechanism is still unknown. In mice, disruption of TFR2 may cause decreased hepcidin are: production [21].
HFE2
Hemojuvelin is the protein responsible for juvenile hemochromatosis in humans, which is a severe form of hemochromatosis (excessive iron in the body). The HFE2 gene encodes the hemojuvelin protein [58].
Hemojuvelin (from liver cells, bone, and heart muscle) acts as a coreceptor for BMP6 to cause hepcidin production [21].
