When we look at the causes of iron deficiency anemia, we can count three main causes; inadequate intake of iron from food, conditions with iron malabsorption (imperfect absorption), and iron loss more than iron intake.

In adults in developed countries, dietary intake is usually adequate and it is important to assume that the cause is blood loss until proven otherwise and to investigate this as a priority. However, this is not the case for underprivileged populations. As in the diagnosis of many diseases, a good history is the most important factor in determining the cause of iron deficiency anemia. Nutritional status, the presence of diarrhea in terms of possible malabsorption, previous gastrointestinal surgery, medications, and the presence of any bleeding foci should be questioned in detail. 

Reduced iron absorption

Iron is absorbed in the upper gastrointestinal tract, with the duodenum being the site of highest absorption [3]. Reduced iron absorption is a rare cause of iron deficiency, especially in healthy individuals and in parts of the world where there is access to an iron-rich diet.

Disorders affecting mucosal cells responsible for iron absorption such as celiac disease, atrophic (autoimmune*) gastritis, Helicobacter pylori infection, and bariatric surgery (surgery for obesity that cannot be treated with diet and exercise) are important causes of malabsorption (imperfect absorption). 

In people with gastrointestinal symptoms or inadequate response to oral iron supplementation, sources of reduced iron absorption may be considered. A source of bleeding should be excluded, whether or not reduced iron absorption has been documented. 

*Autoimmune: A situation in which a person creates an immune response against his or her own cells and tissues as a result of a disorder in the immune system.

Dietary

Heme iron (iron from meat rather than plant sources) is better absorbed than non-heme iron, but both sources are important. A review of published studies assessing vegetarians and non-vegetarians found that those who consumed a vegetarian diet were more likely to develop iron deficiency [4].

Some foods can impair iron absorption, such as tannins (found in tea), phosphates, phytates (mineral-binding compounds found in whole grains and seeds), and foods high in calcium 

One case report described iron deficiency in an individual who drank excessive amounts of tea (more than 1500 mL per day for 20 years). Upper and lower endoscopies showed no pathological conditions and hemoglobin increased with cessation of tea drinking and decreased with continued tea drinking [5]. 

Celiac disease (gluten-sensitive enteropathy)

Celiac disease (gluten-sensitive enteropathy) is a small intestinal malabsorption disorder triggered by exposure to gluten in susceptible individuals. Iron may contribute to anemia through several mechanisms, including malabsorption (imperfect absorption) of other nutrients required for red blood cell (RBC) production, including vitamin B12, folic acid, and copper [6].

Autoimmune gastritis or Helicobacter pylori

Autoimmune gastritis or Helicobacter pylori (H. pylori); gastritis due to an autoimmune mechanism (e.g., anti-parietal cell antibodies) or H. pylori has also been shown to be an important cause of iron deficiency [7,8]. 

Bariatric surgery

Iron requires to be conjugated with vitamin C, amino acids, or sugars in the presence of gastric acid to protect it from alkaline (in a base pH) secretions in the proximal jejunum; otherwise, iron is converted to ferric hydroxide and cannot be absorbed. Bariatric surgery involves a number of procedures that promote weight loss by limiting the reservoir capacity of the stomach and/or shortening the length of the functional small intestine, leading to malabsorption (imperfect absorption). The risk of causing iron deficiency is highest as it reduces the absorption area.  Monitoring iron status is recommended after most bariatric surgeries with routine iron supplementation or iron supplementation as needed.

Drugs

An acidic gastric environment facilitates the absorption of iron, especially non-heme iron. Reduced gastric acidity alone is unlikely to cause clinically significant iron deficiency in an individual with adequate dietary iron intake and a normally functioning gastrointestinal tract.

Drugs that reduce gastric acidity, especially proton pump inhibitors (PPIs, stomach protector), have been suggested to decrease iron absorption [9,10].

Inherited disorders that interfere with iron absorption

Inherited disorders that interfere with iron absorption are very rare. IRIDA (iron therapy-resistant iron deficiency anemia) due to a TMPRSS6 mutation is a rare inherited disorder in which oral iron absorption is markedly impaired. IRIDA is caused by loss-of-function mutations of the TMPRSS6/matriptase 2 gene, which encodes a serine protease that cleaves membrane-bound hemojuvelin [11,20].  It causes iron deficiency due to inappropriately high levels of hepcidin, markedly decreased iron absorption, and increased iron uptake in macrophages* [17, 21-26]. Patients present with mild hypochromic*, microcytic anemia*** with very low serum iron levels and low transferrin saturation. Serum ferritin levels are usually in the normal range or slightly elevated following intravenous iron therapy [17].

*Macrophage: These are white blood cells that protect the body against diseases.

**Hypochromia: The amount of hemoglobin in the red blood cell is below the reference range of 32 - 36 grams/deciliter (g/dL).

***Microcytic anemia: It suggests a type of anemia in which red blood cells are smaller than normal.

Iron deficiency anemia due to iron loss

Menstrual bleeding is the most important cause of iron deficiency anemia in premenopausal women. Gastrointestinal bleeding in postmenopausal women and adult men is an important cause of IDA. Further investigations are absolutely necessary. Upper and lower gastrointestinal endoscopy is recommended to rule out the bleeding focus and possible malignancy (types of tumors that can be considered cancer). Bleeding disorders such as Von Willebrand Disease should also be kept in mind, especially in prolonged menstrual bleeding.