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(Hematology department， Qinghai University Affiliated Hospital，Xining, Qinghai 810001)
Contents:
1.Abstract
2.Key words
3.Introduction
4.Causes of IDA
5.Conclusion
ABSTRACT:
Iron deficiency anemia (IDA) is the major cause of microcytic hypochromic anemia in the world. World population is suffering from IDA due to many factors. Lack of Proper nutritional diet, malabsorption due to GI disorders, occult blood loss or chronic blood loss are the few causes of IDA. Recently new causes of IDA has been found such as, Chronic Kidney Disease(CKD) impairing the production of Erythropoises, chronic use of Proton Pump Inhibitor(PPI) increasing the gastric PH by inhibiting H+/K+ ATPase pump, chronic use of Green Tea where it contains antioxidant interfering iron absorption, Hepcidin elevation in Obese and Kawasaki Disease(KD) patient, Pseudopolyps , Celiac Diseases and Autoimmune Gastristis associated IDA caused by malabsorption, parietal cell and villi destruction impairing iron metabolism causing IDA.
Key words: Iron Deficiency Anemia, Proton Pump Inhibitor, Obesity, Kawasaki Disease, Chronic Kidney Disease.
1.INTRODUCTION:
Iron deficiency affects more than 2 billion people worldwide, and iron-deficiency anemia remains the top cause of anemia, as confirmed by the analysis of a large number of reports on the burden of disease in 187 countries between 1990 and 2010 [1]. ?Absorption impairment of iron has many causes for example gestroenterolgy diseases, liver diseases, kidneys diseases and lack of proper nutritional diet.
1.1.IRON METABOLISM
The circulating pool of iron is comparatively small (2–4 mg) and must be turned over every few hours to meet the daily requirement of iron to support erythropoiesis and other body needs (20–25 mg) [2]. Hemoglobin (Hb) contains 0.34% of iron by weight. Each day Macrophages recycle 1 out of 120 iron of Hb and deliver it to bone marrow erythroblasts. Macrophages stores iron as ferritin or as hemosiderin. Ferritin is water soluble protein iron complex while hemosiderin is insoluble protein iron complex. Iron is in ferric form in ferrtin and hemosiderin. Ferritin is availabe in all cells of the body and in tissue ?uids, while Hemosiderin is available in macrophages. Iron in muscles is presented as myoglobin. Transportation of Iron and storage is mediated by transferrin receptor 1 (TfR1), transferrin, and ferritin.
1.2. IRON ABSORPTION
Absorption of iron is through gastrointestinal tract, mostly through the enterocytes of duodenum. Approximately 2 mg of iron is absorbed daily in the duodenum and proximal jejunum. To enter the systemic circulation iron must cross the basolateral membrane of intestinal enterocytes. This is achieved by the only known iron exporter, ferroportin [3].Iron homeostasis is regulated according to our body need. Organic dietary iron is absorbed in form of haem and broken down to organic iron in guts, absorbed through duodenum. Dietary iron is absorbed in several forms: inorganic,heme, and ferritin. Inorganic dietary iron is mainly present in the oxidized form Fe3+ and must be reduced to the Fe2+ form prior to intestinal uptake [2].
?? -aminolaevulinic acid synthase (ALA-S), divalent metal transporter 1 (DMT-1), TfR1, and Ferritin, regulates the iron homeostasis. In case of iron overload the tissue ferritin level is high while TfR1 and DMT-1 level is low. But in iron deficiency TfR1 level is high while tissue ferritin and ALA-S is low. ALA-S, DMT-1, TfR1, and Ferritin linkages are mediated by iron regulatory protein(IRP) binding to iron response elements (IREs) on ALA-S, DMT-1, TfR1,and ferritin, and. So in case iron overload the binding of IRP on IREs is decreased while in iron deficiency the binding ability is increased.
DMT-1 protein transfer iron from lumen of the guts, while Ferroportin protein transport the iron from inside the cell to plasma. The absorption of iron according to body need is regulated by changing DMT-1 and ferroprtin levels. This mechanism in DMT-1 is supported with the help of IRP/IREs binding and in ferroportin by hepcidin.
Hepcidin is the central regulator of systemic iron homeostasis and exerts its function by controlling the presence of ferroportin [4]. Homeostasis of iron is regulated by a major harmone known as hepcidin. The liver is the major source of circulating hepcidin that regulates systemic iron balance [2].It is a polypeptide produced by the liver cells. Inhibition of iron release from macrophages and intestinal cell is regulated by hepcidin with the help of ferrroportin, so when there is rise in hepcidin, there will be reduction of iron absorption from macrophages. The absorption of iron enterocytes, the efflux of recycled iron from macrophages and the efflux of stored iron by hepatocytes are all systemically controlled by 25 amino-acid peptide hormone hepcidin [5]. Iron is released in the acidic environment of the endosome, Fe3+ is reduced to Fe2+ by the ferrireductase [2].
Iron is converted from ferric?(Fe3+) to ferrous?(Fe2+) by an enzyme Ferrireductase presented at the apical surface, while another enzyme hephaestin at basal surface will convert Fe2+ to Fe3+ before it binds to transferrin. The release of ferrous iron from stores by ferroportin is assisted by the copper-containing ferroxidase enzyme caeruloplasmin or, in the intestine, by its membrane-bound counterpart hephaestin [3].
1.3.IRON DEFICIENCY
A diagnosis of iron deficiency anaemia should be considered in patients with low Hb levels (men <13 g/dL, women <12 g/dL, pregnant women and children <11 g/dL) [6]. A TfS below 20% and a ferritin level lower than 30 ng/mL are indicative of iron deficiency [7].
Haemosiderin and ferritin are reduced prior to anemia in process of iron deficiency. The patient will present general signs and symptoms of IDA.
There are microcytic, hpyochromic cells in the peripheral blood film. There is decrease in reticulocyte count relating degree of anemia. There is absence of iron in bone marrow. The size of erythroblast is small with irregular cytoplasm. Total iron-binding capacity (TIBC) is increased but serum iron, % saturation and serum ferritin decreases.
1.4.CLINICAL FEATURES:
There are many conditions, which increases the risk of IDA. IDA can be caused through bleeding in conditions such as heavy menstrual periods, cancer of esophagus, stomach and colon, GI bleeding due to chronic use of aspirin and PPI and peptic ulcer disease. While other causes of IDA are due to improper absorption of iron includes Celiac disease, and Crohn’s disease. Other causes are due to improper nutritional diet, where an individual may not get proper iron diet is increased at risk of IDA.
2.NEW FOUND CAUSES AND MECHANISM OF IDA:
2.1.PROTON PUMP INHIBITOR(PPI) INTERFERENCE WITH IRON ABSORPTION :
PPI are group of drugs which reduce the gastric acid secretion. Gastric acid helps in breakdown of food, which will release the micronutrients. Researchers found that PPI interfere with the absorption of iron.
Chronic use of PPI has been associated with IDA, malabsorption and increased risk of infections. Hypochlorhydria has been the common cause of IDA.
Fe2+ is absorbed by duodenum. Acidity or PH of luminal contents will reduce iron to Fe2+ . Reduction of gastric acid secretion by PPI will increase the PH, which will oxidize (oxidation) of Fe2+ to Fe3+ which cannot be absorbed. Ferric acid in food is delivered directly with help of iron replacement, while the ferrous form is more soluble and easily absorbed into the intestinal enterocyte.
PPI increases the gastric PH by inhibiting H+/K+ ATPase pump which will make the gastric alakine. Alkaline will facilitates oxidation of ferrous (Fe2+) iron to ferric state (Fe3+), which will affect the bioavilibilty of iron in duodenum. The research investigating the relationship between PPI use and iron absorption is not consistent. There is no effect on iron absorption with short term PPI therapy. Some studies suggest that prolonged omeprazole use for at least 3 to 4 years is unlikely to cause iron and ferritin malabsorption [8].
There is no evidence of IDA on short term use of PPI but on long term use of PPI the physicians should consider the prescription in anemic or IDA patients. Long-term PPI use has been associated with iron-deficiency anemia.
2.2.OBESITY CAUSING ELEVATION OF HEPCIDIN:
Obesity is a medical condition where a person has accumulated so much body fat that it might have a negative effect on their health. Obesity increases risks of diseases such as cardiovascular, diabetes, and sleep apnea. But recent studies proved that it may cause anemia. IDA and megaloblastic anemia of vitamin B12 are the main causes of anemia. Poor dietary intake of iron and lack of proper nutrional diet may cause IDA. IDA in obese individual may be also mediated by chronic inflammation. Iron absorption from guts depends on iron exporter ferroportin. Ferroportin is regulated by hepcidin, which can either inhibit intestinal iron absorption or mediate the iron absorption process. Hepicidin is produced by liver and fat tissues. Hepcidin is elevated in obese individual which will inhibit the iron absorption may cause iron deficiency. Elevation of hepcidin production in obese individual may be responsible for increase in serum ferritin and decrease in serum iron. In this regard, obesity can be associated with iron deficiency anemia
due to increased plasma volume, the consumption of high energetic agents, as well as chronic inflammatory reactions in response to excess adiposity. In obese individuals, the serum ferritin level can be increased due to iron metabolic disturbances [9].
2.3.CELIAC DISEASE (CD) CAUSING MALABSORPTION OF IRON:
IDA is often recorded in newly diagnosed celiac disease (CD) [10]. CD is a gluten-dependent, immune-mediated disorder primarily affecting small intestinal mucosa [11].
CD is an autoimmune disorder affecting the small intestine. Intestinal mucosal injury causing immunologic intolerance to gluten in person genetically suspectible to this condition. Normal mucosa of small intestine has finger like villi. In CD these villi are absent known as villoius atropy,which causes malabsorpion. Classic symptoms include gastrointestinal problems such as chronic diarrhea, abdominal distention, malabsorpion, loss of appetite, and failure of normal growth in children. Anemia may developed in several ways and iron malabsorption may cause iron deficiency anemia. IDA is common in CD because iron is absorbed in upper two parts of intestine, which is damaged by early stage of CD. While lower part of intestine may cause vitamin B12 deficiency.
CD may cause destruction, and inflammation of small intestine lining, and the portion of intestine affected is duodenum, where most of the nutrients are absorbed. CD will damages the duodenum by eliminating the villi which absorbs the nutrients, thus the elimination of absorptive villi on the surface of duodenum will inhibit the absorption of nutrients such as iron. Recently, more and more emphasis has been placed on micronutrient deficiency as a diagnostic clue to occult celiac disease, particularly for iron, and IDA [10].
2.4.CHRONIC KIDNEY DISEASE (CKD), A COMMON CAUSE OF IDA:
CKD is the loss of kidney function. This may cause several complications such as CVD, pericarditis, osteodystrophy and Anemia.CKD has anemia in common, IDA is the important cause.
A normal kidney produces hormone erythropoietin (EPO). EPO prompts the bone marrow to produce RBC, which carry oxygen all over the body. If the kidney functions to fail, there will be failure in producing EPO causing anemia, such as IDA, vitamin B12 or folic acid. Relative EPO deficiency is common, but also other factors that make the marrow less responsive to erythropoietin are prevalent. Inflammation and iron deficiency are most common among these factors [2].
2.5.CLONIC PSEUDOPOLYP CAUSING AN IMPAIRMENT OF IRON ABSORPTION AND LOSE OF BLOOD :
Pseudopolyps are fake or false polyps. These polyps are found in colon who has?Inflammatory Bowel Disease (IBD), CD or Ulcerative Colitis (UC). Malabsorption result in anemia or other deficiencies. Anemia is due to chronic inflammation, mucosal bleeding, IDA or vitamin B12 due to ileal inflammation. IDA is common in IBD due impaired iron absorption and secondary to chronic loss of blood from mucosal surface. Inflammatory pseudopolyps are common in patients with IBD and form during the regenerative phase of healing ulcerated gastrointestinal tissue. The extent and density of inflammatory pseudopolyps resulted in chronic microscopic bleeding and subsequent iron deficiency despite maximal therapy [12].
2.6.AUTOIMMUNE ATROPHIC GASTRITIS(AIG) INDUCES DESTRUCTION OF PARIETAL CELL:
Autoimmune gastritis (AIG) is an inflammatory condition of the stomach, typically restricted to the corpus and characterized by the presence of autoantibodies against the proton pump H+/K+ adenosine triphosphatase(present in gastric parietal cells), and to a lesser extent to intrinsic factor [13]. AIG is chronic inflammatory disease in which immune system destroys parietal cells in stomach. Parietal cells are special type of cells which makes gastric acid. Destruction of its parietal cells by immune system will impaired the absorption of iron and will cause iron deficiency. The cause of autoimmune gastric is unknown. AIG, first described by Faber in 1909 as?achlorhydric gastric atrophy, is a chronic progressive inflammatory condition leading to the decrease or disappearance of parietal cells, which results in reduced or absent acid production (hypochlorhydria or achlorhydria) [14].
2.7.HELICOBACTER PYLORI GASTRITIS:
H.pylori is a bacterium infecting the mucus lining of the stomach and duodenum. There are many GI diseases associated with H. pylori infection, such as peptic ulcer, gastritis, duodenal ulcer. H.pylori Infection may cause the loss of blood or may inhibit the iron absorption by altering iron metabolism. H.pylori-related IDA include occult chronic GI bleeding due to gastric mucosal microerosions,competition for dietary iron by the bacteria, reduced ascorbic acid concentration in the gastric juice, affecting the absorption of dietary iron and upregulation of proinflammatory cytokines and hepcidin, the key regulator of iron homeostasis [14].
Research on H.pylori shows that there is direct relationship between stomach acid secretion and colonization pattern of H.pylori. The acidity of lumen will determine if the ulcer is duodenal or gastric. When the H. pylori enters the stomach, it starts to colonize. The stomach acid will inhibit the H.pylori , it will enters the mucus lining of stomach epithelial cell layer which lines the stomach, where the PH environment is neutral. The low level of gastric acid makes it easy for bacteria to enter and infect the stomach. Once it enters and colonize it creates ammonia as waste product, which will reduce the acidity of the stomach.in chronic infection the acid production is inhibited by consuming hydrogen.
H.pylori infection increases gastric acid secretion, reducing the gastric acid. Infection releases certain cytokines such tumor necrosis factor and ammonia, release gastrin. The infection decreases the mucosal expression of somatostatin. These changes in gastrin and somatostatin increases acid secretion lead to duodenal ulceration. H.pylori also induces gastric atrophy, leading to loss of parietal cells.
Another mechanism by which H.pylori infection may contribute to iron deficiency is through alteration of gastric PH. H.pylori infection may progress to atrophic gastritis with loss of parietal cells, which results in hypochlorhydria or achlorhydria, potentially causing or exacerbating IDA. This occurs because the absorption of dietary iron is dependent upon an acidic gastric [15].
2.8.TEA INTERFERENCE WITH IRON ABSORPTION:
Tea interferes with iron absorption and can lead IDA. Drinking green tea may make anemia worse.?
Green tea is made of camellia senesis leaves. Polyphenols found in green tea, which is antioxidant and interfere with iron absorption, which can increase the risk of iron deficiency. Although traditional views hold that polyphenols affect non heme iron absorption only, recent experiments on human intestinal monolayer cells have provided evidence that dietary polyphenolic compounds could interfere with absorption of both heme and non heme iron across these cells and demonstrated a dose-dependent inhibitory effect of polyphenols on heme iron absorption [16].
Epigallocatechin is an antioxidant contains catechins in green tea. Epigallocatechin gallate, which constitutes more than 50% of the total amount of catechins contained in green tea, is considered a potent antioxidant substance [16]. It leads to cause lack of iron absorption.
2.9.INTESTINAL PARASITIC INFECTION:
Intestinal parasites can infect the intestinal wall of GI tract in humans. Hookworms, an intestinal parasite classified as roundworm. The symptoms of parasitic infection may be abdominal pain, diarrhea and weakness. Anemia is caused by parasitic infection. Several studies have shown parasitic infections, especially?T. trichiura?and hookworm infections, to be closely associated with IDA. Hookworm infections are associated with mucosal damage and endogenous loss of iron, while?T. trichiura?and?E. histolytica?cause bleeding and dysentery by invading the mucosa of the large intestine [14].
2.10.KAWASAKI DISEASE(KD):
Kawasaki disease is a rare disease of blood vessels inflammation in childhood. It is a long term sickness of blood vessels.Due to prolonged inflammation, inflammation induced hepcidin will inhibit iron metabolism due to increase in hepcidin level in KD patient. Hepcidin has a vital controlling influence on iron metabolism. Induced during infection and inflammation, it acts by binding to ferroportin, an iron exporter present on the absorptive surface of duodenal enterocytes, macrophages, and hepatocytes [17].
KD patient has impaired iron metabolism causing IDA and decrease in Hb.Anemia is the most common clinical feature in KD patients and is thought to have a more prolonged duration of active inflammation [18].
3.CONCLUSION & PROSPECTIVE REMARKS:
There should be need to assure that an individual takes proper nutritional diet. Dietary intake should be improved and make sure proper dietary intake of iron supplements, and folic acid to promote the iron absorption to prevent the IDA. There should be proper investigation to diagnose the cause of IDA.
There should be proper investigation to diagnose the cause of IDA. After the cause of IDA is known there must be proper management by oral medication or IV administration. The iron management therapy should be continued unless it is ensure that iron storage are up to normal level.
In CKD, due to increase in hepcidin secretion causes IDA. Iron administration should be considered as management in CKD.
GI diseases association with bleeding, malabsorption, inflammation, all these conditions may lead to IDA.
H pylori infection doesn’t survive in gastric acid environment. The need of medication to normalize the acidic environment to eradicate the H pylori infection.
Access intake of green tea should be avoided and give proper education to patient who are diagnosed with IDA.
Conflicts of Interest: There is no conflict of interest.
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论文作者:Authors: Ubaid Syed1, LuXin Zh
论文发表刊物:《医师在线》2018年5月下第10期
论文发表时间:2018/8/22
标签：期刊论文; 尽在论文; 文章分类论文; 图书馆论文; reticulocyte论文; count论文; relating论文; 《医师在线》2018年5月下第10期论文;