The prevalence of iron deficiency is very high in all age groups , and it has a great impact on the human body’s intelligence, physical development, immune function, digestion and absorption function, and labor capacity. Therefore, in-depth research and prevention of iron deficiency have Important clinical and social significance.
1. Causes of iron deficiency
The cause of iron deficiency includes both physiological and pathological aspects. Physiological iron deficiency is due to increased needs and insufficient intake. Need to increase the iron deficiency caused by 40% of preschool children, 30% of menstruating women, and 38% of pregnant women . Inadequate intake is common in developing and developed countries. In developing countries, it is mainly due to poverty, malnutrition, and famine; in developed countries, it is due to strict vegetarian and vegetarian diets.
Iron deficiency in pathological conditions includes malabsorption and chronic blood loss. Malabsorption is seen in partial or total gastric resection, duodenal bypass, bariatric surgery, Helicobacter pylori infection, steatorrhea, atrophic gastritis, inflammatory bowel disease, etc. In addition, some drugs can also affect the absorption of iron, such as glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs, and proton pump inhibitors. Hereditary iron deficiency anemia (IDA) is rare, iron refractory IDA (IRIDA) is caused by mutations in the transmembrane protease-serine 6 (TMPRSS6) gene, which leads to increased levels of hepcidin, which restricts iron absorption The site is absorbed and the storage site is released into the plasma. Chronic blood loss can be gastrointestinal, genitourinary, or systemic bleeding. Gastrointestinal bleeding includes esophagitis, erosive gastritis, peptic ulcer, diverticulitis, benign tumors, intestinal cancer, vascular dysplasia, hemorrhoids, and duodenal infections. Hemorrhage in the genitourinary system includes menstruation and intravascular hemolysis (paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, microangiopathic hemolysis). In patients with intravascular hemolysis, iron is lost through urine, and iron deficiency can be aggravated. Systemic bleeding includes hemorrhagic telangiectasia, chronic schistosomiasis, Monchosen syndrome, etc. The newly discovered causes of iron deficiency in recent years include severe obesity, long-term chronic inflammation, renal insufficiency, heart failure and old age, etc., all of which can reduce iron absorption by up-regulating hepcidin, thereby causing iron deficiency.
2. Regulation of iron steady state under iron deficiency
Iron participates in many physiological processes of the body, such as respiration, energy metabolism, DNA synthesis and cell proliferation. The daily iron requirement of a normal adult is 25 mg, while the human body’s daily iron absorption is only 1-2 mg. The other iron is provided by the recycling of iron in aging red blood cells.
Hepcidin is a hormone that regulates iron balance in the body. It is a cationic small molecule polypeptide specifically expressed by the liver. It regulates the absorption of iron in the intestine or the iron of macrophages in the liver, spleen and bone marrow by interacting with iron transporters. The release of . The expression of hepcidin increases when iron levels in the blood and tissues of patients with systemic inflammation and infection increase. Patients with anemia of chronic disease produce a large number of inflammatory factors, especially interleukin 6, which leads to an increase in the production of hepcidin, which leads to a decrease in erythrocyte production and iron sequestration. Iron deficiency, tissue hypoxia, hepcidin production is inhibited, bone marrow, liver, muscle tissue and fat cells produce signals to stimulate red blood cell production . The level of hepcidin in women of childbearing age is significantly lower than that of men and menopausal women, and the level of hepcidin in IDA patients is even lower, and some are even undetectable.
Iron deficiency is regulated by tissue hypoxia caused by hepcidin decline and anemia. In the early stage of iron deficiency, the translation of hypoxia-inducible factor (HIF-2α) is inhibited, and the synthesis of erythropoietin (EPO) is reduced to balance the iron deficiency. Ferritin is reduced, and the ligands of the two transferrin receptors (TFR1, TFR2) not only damage the intracellular iron uptake through erythroid TFR1, but also make the TFR2 on the surface of liver cells and red blood cells fluctuate. However, this disrupts the TFR2-EPO receptor interaction in red blood cells, leading to increased EPO sensitivity. Under the stimulation of EPO, the production of erythrocytes is increased, and the apoptosis of erythrocytes is reduced. The available iron is fully utilized for erythroid hematopoiesis, resulting in increased production of small-cell hypochromic erythrocytes. The senescent red blood cells are destroyed by macrophages, and the iron in the red blood cells participates in the circulation. The increase of erythropoietin inhibits the production of hepcidin . In mice, this effect is mediated by the secretion of erythroferrone from young red blood cells , and its function is to maintain adequate iron absorption and effective red blood cell production. HIF-2α also increases the expression of divalent metal ion transporter on the apical membrane surface of intestinal epithelial absorption cells , thereby increasing the transport of dietary iron from the intestinal lumen to intestinal epithelial absorption cells. The physiological signals that stimulate hepcidin are weakened (such as increased liver iron capacity and iron-binding transferrin levels), the activity of the inhibitor TMPRSS6 increases, the level of activated bone morphogenetic protein 6 decreases, and the inhibitory effect of erythropoietin on erythropoiesis As it increases, the level of hepcidin decreases.The level of hepcidin is reduced, the ferroportin is no longer broken down, and iron is transported to the blood circulation through the basement membrane of intestinal epithelial cells and mobilized macrophages. Once the stored iron is exhausted, the absorption of iron from the intestinal cavity increases, but the amount of circulating iron decreases. Decreased levels of iron in the liver cause increased synthesis of transferrin and decreased synthesis of iron-bound transferrin. Therefore, the transferrin receptor-mediated iron absorption of all cells and organs (eg, skeletal muscle and heart) is reduced. The stored ferritin is degraded by "ferritin phagocytosis", and ferritin is transported to the lysosome for degradation and reuse.
3. IDA with invalid iron supplementation
Most IDAs are acquired. With the in-depth study of systemic iron homeostasis, a rare autosomal recessive genetic disease-IRIDA has been newly identified. IDA after 4-6 weeks of oral iron treatment has no obvious hematological response (hemoglobin increase <10g/L), and it is defined as "refractory" . IRIDA is caused by the mutation of TMPRSS6, which encodes a type 2 transmembrane serine protease, and its role is to inhibit the signaling pathway that activates hepcidin. At present, mutations of TMPRSS6 loss of function have been found in more than 50 families, which lead to high expression of hepcidin and hinder intestinal absorption of iron [9, 10]. Children with gastrointestinal diseases that do not affect iron absorption and young IDA patients are not effective in oral iron treatment and should be suspected of this disease . Symptoms of this type of anemia vary in severity, and are more severe in children, and do not respond to oral iron therapy. Typical clinical manifestations include normal or low levels of ferritin, high levels of hepcidin, and extremely low transferrin saturation . Confirmation requires TMPRSS6 sequencing. IRIDA accounts for less than 1% of IDA. Clinicians should pay attention to this disease, because it clarifies the necessity of inhibiting hepcidin in the treatment of iron and suggests the susceptibility of iron deficiency. Studies have shown that TMPRSS6 variants are related to the regulation of personal serum hepcidin levels, changes in iron levels in population studies, and IDA in the elderly.
The genetic susceptibility to iron deficiency is of great significance to the selection of blood donors. Female blood donors who carry the TMPRSS6 mutant rs855791 allele associated with reduced hepcidin levels have a significantly lower probability of iron deficiency compared with blood donors who carry a mutant associated with high hepcidin levels . Male blood donors carrying the HIF-1α common polymorphism gene (P583S) have higher levels of hemoglobin and ferritin than blood donors who are homozygous for the wild-type allele, and iron deficiency is less likely to occur after blood donation . These studies provide theoretical basis for ensuring the health of blood donation, controlling iron deficiency and individualized blood donation.
Oral iron therapy is ineffective, and the cause of malabsorption needs to be considered. In most cases, iron malabsorption is due to gastrointestinal diseases. Partial or total gastrectomy or duodenal bypass surgery can cause oral iron to be ineffective. Bariatric surgery, such as laparoscopic Roux-en-Y gastric bypass surgery is the cause of iron deficiency and anemia, because this surgery effectively removes the active iron absorption site and changes the PH value in the stomach . The follow-up data of patients undergoing surgery shows that iron deficiency occurs in up to 45% of patients , especially in women, so lifelong nutritional monitoring and iron supplementation are recommended . Helicobacter pylori infection can reduce the absorption of iron, because microorganisms compete with the human host for available iron, reduce the bioavailability of vitamin C, and may cause erosion and cause bleeding . Since it is estimated that half of the world's population has been infected with Helicobacter pylori, the iron-ineffective IDA needs to rule out the possibility of Helicobacter pylori infection. Studies have shown that gluten allergy is associated with refractory IDA. However, only 2.5% of iron-deficient people are allergic to gluten . Autoimmune atrophic gastritis has immune damage to gastric parietal cells and can also lead to iron deficiency, but it is rare . In patients with inflammatory bowel disease, anemia may be caused by iron resistance, but this anemia is often caused by multiple factors, such as lack of iron, folic acid, vitamin B12, inflammation, and side effects of drug treatment.
Four, IDA diagnosis
IDA diagnosis includes two aspects: iron parameters and red blood cell characteristics.
1. Iron parameters: Serum ferritin level (<30 μg/L) is the most sensitive and specific indicator for identifying iron deficiency, which can accurately reflect the decline in iron storage. Iron deficiency gradually progresses. Due to low iron content, transferrin synthesis increases, transferrin saturation decreases (<16%), transferrin receptor ligand-trivalent iron transferrin decreases, and iron supplied to the bone marrow is not adequate. At this time, serum ferritin is usually <12 μg/L. At the same time, the soluble transferrin receptor that does not bind ligand is cleaved by the protein-converting enzyme subtilisin and released into the blood circulation .
IDA patients' transferrin saturation and serum ferritin levels decreased. In patients with chronic inflammatory anemia, the saturation of transferrin decreases, but the level of ferritin increases, which is mainly due to the disorder of iron release in macrophages. In addition, soluble transferrin receptor and transferrin do not increase in inflammatory anemia. Simply distinguishing anemia of chronic disease from IDA is simple. However, there is no clear cut-off value for inflammatory anemia combined with IDA, and the diagnosis cannot be made based on a single result. In IDA with inflammation, the saturation of transferrin decreases, and the ferritin level is defined as <100μg/L . In heart failure with IDA, the ferritin level is <300 μg/L. Chronic kidney disease with IDA, transferrin saturation <30% . Serum soluble transferrin receptor levels increase during iron deficiency, and normal or decrease during inflammation.
Bone marrow iron staining is a reliable method to assess the iron storage of macrophages and nucleated red blood cells. In chronic inflammatory anemia, macrophage iron is present, but there is iron deficiency in nucleated red blood cells. But because of the invasive inspection, the application is limited.
In IRIDA, transferrin saturation is very low, but serum ferritin levels are normal or on the line of normal low levels. Iron parameters can distinguish IRIDA from other small cell anemia, and normal C-reactive protein levels can be distinguished from inflammatory anemia. Determination of serum hepcidin level may be useful in IRIDA, but there is no reliable experimental method for detecting hepcidin level .
2. Red blood cell characteristics: The average red blood cell volume and average red blood cell hemoglobin content in IDA are significantly reduced. In the early stage of iron deficiency, when newly produced small cell hypochromic red blood cells coexist with normal red blood cells, the volume distribution width (RDW) increases. RDW also increased after iron treatment. In chronic inflammatory anemia, RDW and red blood cell index are not affected .
Iron deficiency affects the final step of heme production, leading to the accumulation of protoporphyrin IX and zinc protoporphyrin. The increase in erythrocyte zinc protoporphyrin can be used as an index for screening iron deficiency. But protoporphyrin is also increased in ring sideroblastic anemia.
3. Find out the cause of iron deficiency: In addition to iron deficiency caused by increased demand, patients should look for the cause of iron deficiency, usually gastrointestinal blood loss or iron malabsorption. Therefore, a diagnostic examination of the gastrointestinal tract should be performed. Capsule endoscopy can identify small intestinal bleeding that cannot be detected by ordinary endoscopy . Men and postmenopausal women with iron deficiency should pay more attention to finding the cause. Women with massive uterine bleeding should undergo obstetrics and gynecology examinations.
Non-invasive tests such as urea breath test or anti-Helicobacter pylori antibody and anti-glutaminase antibody test should be performed after oral iron treatment fails. C-reactive protein is associated with inflammatory/tumor diseases in the elderly. In addition to insufficient diet, many factors including clonal hematopoiesis should be excluded.
Patients suspected of IRIDA should undergo TMPRSS6 gene sequencing .
Five, IDA treatment
IDA patients should take iron supplements. Some studies have shown that measuring the level of hepcidin can determine the best timing of iron supplementation for children . New data indicate that unabsorbed iron is harmful to patients because it can imbalance the intestinal flora and accumulate intestinal pathogens . The current methods of iron supplementation include oral iron supplementation and intravenous iron supplementation.
1. Oral iron therapy: Oral iron supplementation is the first-line treatment for IDA. The recommended daily dose for iron deficiency is 100-200 mg elemental iron for adults and 3-6 mg/kg liquid iron for children; iron should be taken in divided doses on an empty stomach. Vitamin C can be added to promote iron absorption. Ferrous sulfate, iron gluconate, polysaccharide iron, and iron fumarate are all effective iron salts. Slow-release iron should be avoided because iron release occurs in the distal duodenum, which is not conducive to iron absorption. Oral iron is often not easily tolerated, and nausea, vomiting, abdominal pain, constipation, and diarrhea occur frequently, especially when taking iron on an empty stomach. A recent meta-analysis of randomized controlled trials showed that the gastrointestinal side effects of oral iron are more common than placebo and intravenous iron .
Oral iron is effective in correcting anemia. However, whether treatment of iron deficiency is beneficial before the development of anemia is uncertain. Some studies have shown that oral iron supplementation can improve the fatigue symptoms and quality of life in women with iron deficiency but not anemia. There are also some studies that show that oral iron is beneficial to the physical condition of women of childbearing age , but these studies have limited participants and significant heterogeneity. Iron supplementation in preschool children in low-income areas can correct anemia, but a meta-analysis of randomized trials has shown that iron supplementation does not improve cognitive performance or has a positive effect on growth and development . In malaria-endemic areas, iron supplementation may reverse the protective effect of iron deficiency and increase the susceptibility to co-infection. Therefore, in low-income areas, more detailed research is needed to determine the pros and cons of iron supplementation.
Oral iron is ineffective due to premature termination of treatment, poor patient compliance and refractory treatment. For refractory reactions, specific treatments include eradication of Helicobacter pylori infection or adopting a gluten-free diet in patients with celiac disease to restore iron absorption. There are currently no indications to predict whether a patient will respond to oral iron therapy. Preliminary studies have shown that the determination of serum hepcidin levels can help determine whether patients are effective in oral iron .
2. Intravenous iron supplementation: The indications for intravenous iron supplementation include oral iron intolerance, intestinal malabsorption, hereditary IRIDA, rapid increase in hemoglobin, severe anemia in late pregnancy or chronic blood loss due to birth defects. Patients with chronic kidney disease anemia, chronic heart failure anemia, and cancer patients who fail to use red blood cell stimulants during chemotherapy can also receive intravenous iron supplementation. Both the normal level of hemoglobin and the intravenous iron dose to replenish stored iron can be calculated. Studies have shown that intravenous iron supplementation has a better hematological response than oral iron supplementation . The results of meta-analysis showed that intravenous iron supplementation and hemoglobin concentration increased (average difference 6.5 g/L, 95% CI: 5.1 ~7.9 g/L ) And decreased blood transfusion risk (relative risk 0.74, 95% CI: 0.62~0.88).
In patients with chronic kidney disease, intravenous iron supplementation combined with erythropoietin is more effective than oral iron. In patients undergoing dialysis, intravenous iron supplementation may delay or even avoid the use of erythropoietin .
Clinical trials in patients with iron deficiency and chronic heart failure have shown that intravenous iron supplementation can improve the general condition of patients  and reduce the number of hospitalizations .
Contraindications for intravenous iron supplementation include infection, early pregnancy, and allergy to iron and other drugs .
The short-term side effects of intravenous iron supplementation include nausea, vomiting, skin itching, flushing, headache, myalgia, arthralgia, and chest and back pain, which are relieved within a constant hour ; hypersensitivity reactions are rare and severe cases can be life-threatening . Preventive measures include slow infusion and close monitoring of patients.
In summary, a breakthrough has been made in the study of iron homeostasis regulation mechanism centered on hepcidin. IRIDA clarified the necessity of hepcidin for iron supplementation. Comprehensive utilization of serum ferritin, hepcidin and other indicators can improve the accuracy of IDA diagnosis. In terms of treatment, oral iron is still the first choice for iron supplementation in most patients, and intravenous iron supplementation is increasingly being valued.