Iron Deficiency: Symptoms, Causes, and Treatment Guide

What Is Iron and What Does It Do in Our Body?

Hello, I am Dr. Emre Gecer. Iron is a trace element indispensable for life. The total amount of iron in our body is approximately 3-4 grams, and most of this amount is in hemoglobin. Iron plays critical roles in transporting oxygen from the lungs to the tissues, in energy production, in DNA synthesis, and in immune function.

To understand iron metabolism, we need to know three fundamental processes:

Iron Absorption

Dietary iron is found in two forms:

• Heme iron: The form of iron found in animal-source foods (red meat, liver, fish) bound to hemoglobin and myoglobin. Its absorption rate is quite high at 15-35%, and it is very little affected by other nutrients.
• Non-heme iron: The form found in plant sources (spinach, lentils, dried legumes) and in iron supplements. Its absorption rate varies between 2-20% and is markedly affected by factors such as stomach acid, vitamin C, phytate, and tannins.

Iron absorption takes place mainly in the duodenum and proximal jejunum. The DMT1 (Divalent Metal Transporter 1) protein on the enterocyte surface brings non-heme iron (Fe2+) into the cell. Heme iron is absorbed via HCP1 (Heme Carrier Protein 1).

Iron Transport

Absorbed iron crosses into the blood through the ferroportin channel on the basolateral enterocyte membrane and is transported to the tissues bound to the protein transferrin. Each transferrin molecule can carry two iron atoms. Transferrin saturation is the ratio of iron being carried to the transferrin's capacity, and it is an important parameter in assessing iron status.

Iron Storage

Excess iron is stored in the cells of the reticuloendothelial system, mainly in the liver, spleen, and bone marrow, in the form of ferritin and hemosiderin. The serum ferritin level is the most reliable indicator of body iron stores. The master regulator of iron metabolism is the hormone hepcidin, secreted by the liver. Hepcidin blocks ferroportin and regulates intestinal absorption and iron release from macrophages.

Stages of Iron Deficiency

Iron deficiency does not appear suddenly; it develops as a stepwise process. Recognizing these stages is critical for early diagnosis and treatment:

Stage 1: Iron Depletion

When iron loss exceeds iron intake, the stores begin to decrease first. Serum ferritin falls but hemoglobin is still normal. The patient is usually asymptomatic. Bone marrow aspiration shows depleted iron stores. This stage is the first laboratory sign of a negative iron balance.

Stage 2: Iron-Deficient Erythropoiesis

Once stores are depleted, there is not enough iron for erythrocyte production. Transferrin saturation falls (below 16%), TIBC (Total Iron Binding Capacity) rises, and serum iron falls. Erythrocyte protoporphyrin levels rise. Hemoglobin may still be normal or slightly low. Reticulocyte hemoglobin content is reduced. At this stage fatigue, difficulty concentrating, and decreased exercise capacity may begin.

Stage 3: Iron Deficiency Anemia (IDA)

The most advanced stage. Hemoglobin falls markedly (men <13 g/dL, women <12 g/dL). Erythrocytes become microcytic (small) and hypochromic (pale). MCV (Mean Corpuscular Volume) falls. The peripheral blood smear shows target cells, elliptocytes, and anisopoikilocytosis. Clinical signs become prominent.

Causes of Iron Deficiency

1. Blood Loss (The Most Common Cause)

In adults, the most important cause of iron deficiency is chronic blood loss:

• Menstrual bleeding: The most common cause in women of reproductive age. Menorrhagia (heavy menstrual bleeding) is particularly high risk — an average of 30-40 mL of blood is lost per period; in menorrhagia this amount exceeds 80 mL.
• Gastrointestinal bleeding: The first cause to consider in men and postmenopausal women. Peptic ulcer, gastritis, NSAID use, colon polyps, colorectal cancer, angiodysplasia, inflammatory bowel disease, and celiac disease are the leading causes of GI bleeding.
• Urogenital bleeding: Hematuria, frequent blood donation
• Parasitic infections: Hookworms (Necator americanus, Ancylostoma duodenale) are an important cause in developing countries

2. Inadequate Iron Intake

Vegetarian/vegan diets, unbalanced diets, and low socioeconomic conditions can cause inadequate iron intake. Early introduction of cow's milk in infants (which is low in iron and can cause intestinal microbleeding) is an important risk factor.

3. Iron Malabsorption

• Celiac disease: Duodenal villous atrophy impairs absorption — it must always be investigated in unexplained iron deficiency
• Helicobacter pylori infection: Reduces stomach acid and impairs non-heme iron absorption
• Atrophic gastritis and stomach acid deficiency: Prevents reduction of non-heme iron from Fe3+ to Fe2+, reducing absorption
• Gastrectomy or bariatric surgery: Reduction in gastric acid and duodenal absorption surface
• Inflammatory bowel disease: Especially when Crohn's disease involves the duodenum

4. Increased Iron Requirement

• Pregnancy: Iron requirements increase significantly because of fetal development, the placenta, and increased blood volume — approximately 1000 mg of additional iron is required in total
• Lactation period
• Periods of rapid growth: Infancy, adolescence

Symptoms of Iron Deficiency

Iron deficiency symptoms develop slowly and insidiously. Because the body gradually adapts to anemia, patients may sometimes report minimal symptoms despite very low hemoglobin levels.

General Symptoms

• Fatigue and weakness: The most common complaint — a direct consequence of inadequate oxygen delivery to tissues
• Pallor: Noticeable in skin, mucous membranes (inside of the eyelid, inside the mouth), palms, and nail beds
• Exertional dyspnea: Shortness of breath even with light exercise
• Palpitations and tachycardia: The heart beats faster to compensate for the decreased oxygen carrying capacity
• Headache and dizziness
• Difficulty concentrating and decreased cognitive performance
• Cold intolerance: Due to effects on thyroid function

Symptoms Specific to Iron Deficiency

• Pica: The desire to eat non-nutritive substances — ice (pagophagia), dirt (geophagia), starch (amylophagia) are the most common forms. Pagophagia in particular is quite specific for iron deficiency.
• Koilonychia (spoon nails): Concave, spoon-shaped depression of the nails — a classic finding of advanced iron deficiency
• Restless legs syndrome: Uncomfortable sensations in the legs with the urge to move them, especially in the evening and at night — strongly associated with iron deficiency
• Plummer-Vinson syndrome: The triad of iron deficiency anemia + dysphagia (difficulty swallowing) + esophageal web — rare but of high diagnostic value
• Angular stomatitis and glossitis: Cracks at the corners of the mouth and an atrophic, shiny, red appearance of the tongue
• Hair loss: Diffuse hair loss in the form of telogen effluvium

Diagnosis: Laboratory Evaluation

The basic tests used in the diagnosis of iron deficiency:

• Serum ferritin: The most reliable indicator of iron stores. A value of <15 ng/mL is quite specific for iron deficiency. However, ferritin is also an acute-phase reactant; it can be falsely elevated in infection, inflammation, liver disease, and malignancy. In inflammatory states a threshold of <30 ng/mL should be used. In chronic disease, the combination of <100 ng/mL with transferrin saturation <20% is diagnostic.
• Serum iron: The amount of iron circulating in the blood bound to transferrin. It falls in iron deficiency. It shows diurnal variation (high in the morning, low in the evening) and is affected by diet.
• TIBC (Total Iron Binding Capacity): Reflects the iron-binding capacity of transferrin. It rises in iron deficiency — the body prepares to carry more iron.
• Transferrin saturation: Serum iron / TIBC × 100. <16% indicates iron deficiency.
• Peripheral blood smear: Microcytic hypochromic erythrocytes, target cells, elliptocytes (pencil cells), and anisopoikilocytosis are seen.
• Reticulocyte hemoglobin content (CHr or Ret-He): Reflects the iron status of erythrocytes produced in the last 1-2 days — useful for evaluating early response to iron therapy.
• Soluble transferrin receptor (sTfR): Not affected by inflammation and helps distinguish iron deficiency from anemia of chronic disease.

Treatment of Iron Deficiency

Oral Iron Therapy

Oral iron is the first-line treatment for iron deficiency:

• Ferrous sulfate: The most commonly used and cheapest form — a 325 mg tablet contains 65 mg of elemental iron. Recommended 2-3 times a day on an empty stomach.
• Ferrous gluconate and ferrous fumarate: Alternative forms for patients who cannot tolerate ferrous sulfate
• Iron polymaltose complex: Can be taken with food, with fewer GI side effects

Points to pay attention to in oral iron therapy:

• Take with vitamin C: A glass of orange juice or 250 mg of vitamin C increases non-heme iron absorption 2-3 fold
• Stay 2 hours away from tea, coffee, milk, and calcium supplements: These substances significantly reduce iron absorption
• Prefer empty-stomach intake: Absorption is highest on an empty stomach. However, if GI intolerance develops (nausea, abdominal pain, constipation), try taking it with food or every other day
• Alternate-day dosing: Recent studies suggest that alternate-day intake may optimize the hepcidin cycle and improve absorption
• Treatment duration: After hemoglobin normalizes, treatment should continue for at least 3-6 more months to replenish stores
• Treatment response: Reticulocyte count rises within 7-10 days, hemoglobin starts to rise within 2 weeks, and is expected to normalize within 6-8 weeks

Intravenous (IV) Iron Therapy

IV iron is preferred in the following situations:

• Inability to tolerate oral iron (severe GI side effects)
• Malabsorption states (celiac, after bariatric surgery)
• Ongoing severe blood loss (where oral treatment is inadequate)
• Chronic kidney failure and dialysis patients
• Inflammatory bowel disease
• Situations requiring rapid iron replacement (late pregnancy, preoperative preparation)

The IV iron preparations used today (iron sucrose, ferric carboxymaltose, iron isomaltoside) have a high safety profile. The serious anaphylaxis risk seen with older preparations has been significantly reduced with modern formulations.

Nutrition Recommendations

Diet is important in preventing iron deficiency and supporting its treatment:

• Heme iron sources: Red meat, liver, turkey, chicken (especially dark meat), fish, seafood
• Non-heme iron sources: Lentils, chickpeas, dried beans, spinach, dried apricots, raisins, tahini, molasses (pekmez), dark green leafy vegetables, whole grains
• Pair with vitamin C: Consume plant iron sources with vitamin C-rich foods such as lemon, orange, tomato, and pepper
• Avoid factors that reduce absorption: Reduce tea and coffee consumption with meals; these contain tannins and polyphenols that can reduce non-heme iron absorption by 60-70%

Special Populations

Iron Deficiency in Pregnancy

In pregnancy, plasma volume rises faster than red cell mass, creating a physiologic dilutional anemia. In addition, fetal and placental iron requirements increase. The WHO recommends that all pregnant women take 30-60 mg of elemental iron supplementation per day from the second trimester onward.

Iron Deficiency in Children

Iron deficiency in children negatively affects cognitive development, attention span, and school performance. Term infants are born with 4-6 months of iron stores, so iron intake should be provided through complementary feeding after 6 months. Preterm infants are born with less iron reserve and require early supplementation.

Conclusion

Iron deficiency is the most common nutritional deficiency in the world, affecting approximately 2 billion people. This insidiously progressing condition causes a wide range of symptoms from fatigue to cognitive impairment, from hair loss to restless legs syndrome. In diagnosis, ferritin is the most valuable test, and in treatment, oral iron is first line. However, the success of treatment depends on identifying and correcting the underlying cause. In unexplained iron deficiency — especially in men and postmenopausal women — gastrointestinal bleeding causes must always be investigated.

Wishing you healthy days.
Dr. Emre Gecer

References

• Harrison's Principles of Internal Medicine, 22nd Edition — Chapter: Iron Deficiency and Other Hypoproliferative Anemias
• Williams Hematology, 10th Edition — Chapter: Iron Deficiency and Overload
• WHO Guideline: Daily Iron Supplementation in Adult Women and Adolescent Girls, 2016