Why Iron Is More Complicated Than Just Taking a Supplement

 

I am very interested in iron as I have had iron deficiency most of my life. I was diagnosed with Celiac disease at the age of 35, but even after 13 years on the gluten-free diet, I continue to experience nutritional deficiencies, iron being one of them. I believe I am unfortunately one of the few who continue to experience malabsorption issues to the microvilli never returning to full height. However, there are many other factors one can explore even if you don’t have celiac disease and this article will cover them.

Iron deficiency is one of the most common nutrient deficiencies, yet understanding iron balance is more complex than simply increasing iron intake. Iron is essential for oxygen transport, energy production, brain function, immune health, and many cellular processes. However, the body tightly controls iron because both too little and too much iron can cause problems. Many people are told they are iron deficient and are advised to take an iron supplement, but the underlying reason for low iron is not always addressed.

Iron status depends on:

• How much iron you consume
• How well your gut absorbs it
• The balance between iron storage and transport
• Hormones such as hepcidin that regulate iron movement
• Nutrients such as copper, vitamin C, B12, and folate
• Factors such as inflammation, gut health, thyroid function, and blood loss

This article explores how iron works in the body, how it is absorbed and regulated, what iron tests actually show, and why some people struggle to improve their iron levels despite supplementation.

Let’s dive in…

What does iron do in the body?

Iron is needed to make haemoglobin, the molecule in red blood cells that carries oxygen. It supports energy production and helps cells grow and repair.

 

Sources of iron

Dietary iron exists in two major forms: Heme iron in meat, poultry, and fish and Non-heme iron such as in plants, grains, and legumes.

Absorption is influenced by enhancers  like vitamin C and inhibitors such Phytates, Calcium, polyphenols.

The body does not absorb all the iron you consume. Usually, only about 1–2 mg of dietary iron is absorbed. Unlike many minerals, the body has no active pathway to excrete excess iron. Because of this, iron balance is maintained primarily through regulation of absorption, recycling, storage and transport. We need approximately 24 mg of elemental iron a day.

 

Symptoms of iron deficiency

Symptoms of iron deficiency can occur even before anemia develops. These symptoms include:

• Fatigue
• Reduced exercise tolerance
• Poor concentration
• Brain fog
• Headaches
• Irritability
• Restless legs
• Hair shedding
• Brittle nails
• Feeling cold
• Reduced immune resilience
• Shortness of breath with exertion

• Some people develop pica, especially cravings for ice, starch, or non-food substances.

The complexities of Iron absorption

Iron absorption is a carefully controlled process involving the stomach, small intestine, transport proteins, and hormones.

Step 1: The role of stomach acid

First, stomach acid helps release iron from food and helps convert it into a form that can be absorbed. This is one reason why low stomach acid production may influence iron absorption.

Step 2: Absorption in the duodenum

The iron then reaches the first section of the small intestine called the duodenum. This is where most iron absorption occurs. Specialised cells called enterocytes (cells lining the intestinal wall) control how much iron enters the body. (note that in celiac disease, this is the part of the intestine that is damaged!)

Most non-heme iron exists as ferric iron (Fe³⁺). Before it can enter intestinal cells, it needs to be converted into ferrous iron (Fe²⁺). This conversion is helped by stomach acid, Vitamin C and Enzymes on the surface of intestinal cells. Once converted, Fe²⁺ can enter the intestinal cell through a transporter called DMT1.

Heme iron is absorbed through a separate pathway. Once inside the intestinal cell, the heme structure is broken down and iron is released. The iron can then enter the body’s iron pool. Because heme iron is packaged differently, it is generally less affected by dietary inhibitors compared with non-heme iron.

Moving iron into the bloodstream

Once inside the enterocyte, iron has two possible pathways: It can be stored inside the intestinal cell as ferritin. or it can exit the enterocyte through a transporter called ferroportin which is the only known iron export channel that moves iron from cells into the bloodstream.

Once iron enters the blood, it binds to a transport protein called transferrin that carries iron to tissues that need it, including the bone marrow for making red blood cells, the muscles for making myoglobin and cells involved in energy production.

 

Hepcidin: The Gatekeeper of Iron Absorption

The liver produces a hormone called hepcidin, which controls how your body absorbs and uses iron. Think of it like a gate. It tells your body when to open the gate to let iron go through and when to close the gate to keep iron inside. When hepcidin is low, it can indicate iron deficiency. When hepcidin is high, it can indicate infectiom, inflammation or iron overload.

When iron levels are sufficient, hepcidin increases and ferroportin is blocked. This means that taking more iron does not always mean you are absorbing more iron. The body actively adjusts iron absorption depending on its needs.

Hepcidin can take about 24 hours to reduce, which is why it is often better to take iron every alternate day so that you are taking it when the “gate” is open again. Taking too much iron can increase hepcidin levels, which can contribute to inflammation. Too much iron can also lead to increased reactive oxygen species (ROS), which damages cells, proteins and DNA. This drives oxidative stress.

 

The Role of Ceruloplasmin and Copper in Iron Metabolism

Ceruloplasmin is a protein made by the liver that carries most of the copper in your blood. More importantly for iron metabolism, it acts as a ferroxidase.

This means it converts iron from the ferrous form (Fe²⁺) to the ferric form (Fe³⁺), allowing it to be properly loaded onto transferrin and transported out of storage cells. Ceruloplasmin also acts as an active antioxidant because of its ability to oxidise highly toxic ferrous iron into the relatively non-toxic ferric form. This helps prevent oxidative damage to Proteins, lipids and DNA.

If ceruloplasmin is deficient or not functioning properly, iron transport becomes impaired and iron may become “trapped” in certain tissues instead of being efficiently utilised. Even with iron supplementation, iron may not effectively replenish iron stores and ferritin may remain low or increase much more slowly than expected.

This can manifest as diabetes mellitus, retinal degeneration and also severe progressive neurological problems, such as ataxia and involuntary movements.

When Should You Test Ceruloplasmin and Copper?

Testing may be useful when there is:

• Ferritin that stays low despite months of appropriate iron therapy
• Iron deficiency that seems resistant to treatment
• Anemia that does not improve with iron
• Neurological symptoms suggestive of copper deficiency
• Low white blood cell counts

Risk factors for copper deficiency include:

• Gastric bypass surgery
• Malabsorption disorders such as celiac disease
• Excess zinc supplementation, which can interfere with copper absorption

It is important to test both ceruloplasmin and copper, because copper deficiency can cause secondary problems with iron transport and contribute to anaemia.

Iron-Refractory Iron Deficiency Anemia (IRIDA)

Iron-refractory iron deficiency anemia (IRIDA) is a rare hereditary microcytic anemia characterised by partial or complete resistance to oral iron supplementation. It is caused by elevated plasma hepcidin levels resulting from pathogenic variants in the TMPRSS6 gene. [PMC11985374]

In IRIDA, elevated hepcidin levels impair iron absorption from the intestine and iron release from macrophages. This occurs because hepcidin interacts with ferroportin and prevents iron from leaving cells. An IV iron infusion can bypass this barrier.

The main features of IRIDA include:

• Low circulating iron levels
• Low serum iron
• Low transferrin saturation
• No evidence of inflammation
• Minimal response to oral iron after approximately 4 weeks

 

Iron Combined With B12 or Folate Deficiency

Another complication occurs when iron deficiency exists alongside low vitamin B12 or folate. Vitamin B12 and folate are connected to iron utilisation through their role in red blood cell production.

Iron is required for haemoglobin synthesis, while B12 and folate are required for DNA synthesis. If B12 or folate is deficient, the bone marrow cannot properly mature red blood cell precursors. This leads to ineffective red blood cells and megaloblastic anaemia.

In this situation, iron may be present but not used as it should because red blood cell production is impaired.On the other hand, after treatment of B12 or folate deficiency, previously “hidden” iron deficiency may emerge because marrow activity increases and iron demand rises.

If treating a combined B12 and iron deficiency, ferritin can drop even further as red blood cell production improves and iron is used. It is also important to note that a complete blood count can mask a combined deficiency. Iron deficiency produces microcytic cells (small red blood cells) while B12 deficiency produces macrocytic cells (large red blood cells). Because the MCV shows the average size of red blood cells, the result may appear “normal” even when both deficiencies are present.

 

Why Iron Can Cause Digestive Issues

Some unabsorbed iron stays in the intestine, where it can encourage the growth of harmful bacteria.

Some forms of iron, such as ferrous bisglycinate, can lower beneficial bacteria like Bifidobacteria and increase harmful bacteria such as Enterobacteriaceae. Good bacteria like Bifidobacteria and Lactobacillus do not rely on free iron to grow. Because of this, they can compete with iron-loving harmful bacteria.

Probiotics may help restore the balance and can bind iron, reducing how much free iron is available for harmful bacteria. Examples include bifidobacterium longum and lactobacillus acidophilus.

Why “Just Increasing the Dose” Is Not Always the Solution

In celiac disease or when other gut issues are present, doubling the dose is not always the solution because the gut may be the limiting step. Iron still needs to be absorbed through the intestinal lining, and hepcidin regulation can block iron export into the bloodstream. As a result, excess iron may remain unabsorbed and contribute to gastrointestinal side effects.

In celiac disease, it is important to give the gut time to heal by supporting nutrient intake, taking supporting supplements that encourage growth and repair, such as L-glutamine and limiting gut disruptors such as sugar, alcohol, certain medications like PPIs, and antibiotics. If ferritin is very low and oral iron is not effective, intravenous iron may be considered.

Factors Affecting Iron Absorption

1.Low stomach acid

Iron needs an acidic environment to be broken down and absorbed. Low stomach acid means iron may pass through the gastrointestinal tract largely intact without being absorbed.

Symptoms of low stomach acid may include:

• Bloating after meals
• Undigested food in stool
• Feeling full quickly
• Burping
• Acid reflux
• Heartburn

Testing: serum gastrin

At-home test: First thing in the morning on an empty stomach, drink ¼ teaspoon of baking soda mixed into 180 ml of cold water. If you burp within 3 minutes, your stomach contains enough ambient hydrochloric acid to react with the alkaline soda and create carbon dioxide gas.

 HCL betaine may be helpful.

2.Gut inflammation, dysbiosis, or intestinal damage

Iron needs to cross the gut lining to enter the bloodstream. If the gut lining is damaged in any way, less iron can be absorbed. This is common in people with celiac disease and can remain an ongoing issue even many years after gluten has been removed from the diet. This is because iron is absorbed mainly in the duodenum, which is the area of the intestine that is often most damaged in celiac disease.

3. H. pylori

This bacterial infection affects the stomach lining and can impair iron absorption.

4. SIBO

Small intestinal bacterial overgrowth (SIBO) occurs when bacteria overgrow in the small intestine and compete for nutrients, including iron.

5. The wrong form, dosage, and timing of iron

Not all iron is equal. Taking too much iron can be harmful to gut balance. Taking iron alongside certain foods or supplements can also reduce absorption.

 

Other Factors That Can Affect Iron Levels

Other factors that may affect iron status include:

• Bariatric surgery
• Blood transfusions
• Pancreatic insufficiency
• NSAID use
• Use of PPIs
• Heavy menstruation
• Endometriosis
• Gastric or duodenal ulcers
• Colon polyps

 

Nutrient Cofactors Needed for Iron Metabolism

Iron does not work alone. Important cofactors include:

• Vitamin C
• Vitamin A
• Vitamin B12
• Vitamin B9 (folate)
• Vitamin B2
• Vitamin B6
• Copper

 

Other Metabolic Factors Affecting Iron Utilisation: 

Poor liver function

GST and CYP genes can contribute, along with diet and lifestyle factors.

Poor estrogen detoxification

Slow COMT and certain CYP450 genes can contribute.

Poor bile flow

This is connected to liver function. PEMT can contribute.

Poor thyroid function

Hypothyroidism can impact iron metabolism and utilisation.

Not enough protein

Iron travels bound to transferrin, which is a protein, and it is stored in ferritin, which is also protein-based. Low protein intake can impair iron transport and utilisation. A general guideline is to aim for approximately 1 g of protein per kilogram of body weight.

 

Understanding Your Iron Test

An iron test usually refers to a group of blood markers used to evaluate:

• Your body’s iron status
• Iron transport
• Iron storage
• How well your bone marrow is using iron to make red blood cells

No single marker tells the full story, so iron markers are usually interpreted together.

 

 

A New Type of Iron May Be the Answer

According to new research, sucrosomial iron is a newer type of iron supplement designed to deliver iron to the body with fewer side effects. Ferric pyrophosphate is wrapped in a protective coating made up of a phospholipid layer and a sugar-based matrix that protects the iron while it travels through the gut.

Sucrosomial iron keeps the iron enclosed until it reaches the duodenum, where it is absorbed through Enterocytes (intestinal cells) and M cells in the gut lining. Traditionally, many iron supplements release free iron in the gastrointestinal tract. This can irritate the gut lining and leave available iron for gut bacteria to feed on. 

Think of traditional iron as walking through the main entrance, while sucrosomial iron arrives in an armoured vehicle and can use alternative entry routes.

Treatment of Iron Deficiency

Treatment should address both iron replacement and the underlying cause.

Oral iron is often the first-line therapy. Many people tolerate lower or alternate-day dosing better than traditional high daily dosing because hepcidin rises after iron ingestion and can temporarily reduce absorption. Taking iron away from substances that reduce absorption may improve uptake. These include Calcium, black tea, caffeine, High-phytate meals (such as legums, beans etc) and some medications such as PPIs and thyroid meds.

Vitamin C or acidic beverages may help absorption. If oral iron is ineffective, poorly tolerated, or malabsorption is present, intravenous iron may be appropriate under medical supervision.

When to Take Iron

Iron is usually absorbed best on an empty stomach. Ideally 1 hour before food or 2 hours after food. However, many people experience nausea or stomach discomfort when taking iron this way. If this happens, taking iron with a small meal is reasonable. Even though absorption may be slightly reduced, tolerable treatment is better than stopping treatment completely.

 

Iron deficiency is not always simply a matter of “not getting enough iron”

 

Iron balance depends on many factors:

• How much iron you consume
• The type of iron you consume
• Stomach acid production
• Gut health and absorption
• Hepcidin regulation
• Iron transport through ferroportin and transferrin
• Copper and ceruloplasmin function
• Vitamin and mineral cofactors
• Thyroid and liver function
• Protein intake
• Blood loss or increased demand

This is why some people continue to have low ferritin despite taking iron supplements. The answer is not always to increase the dose. Sometimes the missing piece is understanding why the body is not absorbing, transporting, or using iron effectively.

 

The ADHD connection

Iron is a cofactor in dopamine and norepinephrine synthesis. This affects attention and behaviour. Many studies have shown how lower ferritin levels lead to increased symptom severity in ADHD. Iron deficiency leads to poor myelination of the nervous system and disruption in the metabolism of neurotransmitters. These changes not only affect memory, learning abilities, and motor skills but also cause psychological and mental disorders, especially in children. [PMC8553]

 

Key Takeaways

Iron deficiency is not always caused by simply not eating enough iron. To improve iron status, it is important to understand the full picture:

✓ Iron needs to be absorbed through a healthy gut before it can be used.

✓ Hepcidin acts as the body’s iron “gatekeeper” and determines when iron can enter circulation.

✓ Ferritin reflects iron storage, but it should always be interpreted alongside other markers such as transferrin saturation, serum iron, haemoglobin, and inflammatory markers.

✓ Low ferritin that does not improve with supplementation may indicate issues with absorption, transport, inflammation, copper status, or other underlying factors.

✓ Iron works together with other nutrients, including vitamin C, vitamin A, B12, folate, and copper.

✓ Taking more iron is not always the answer. Sometimes the focus needs to shift toward improving absorption, identifying the root cause, and choosing the right form and dose of iron.

Understanding your iron status is about more than a single number on a blood test. It is about understanding how your body absorbs, transports, stores, and uses iron.

 

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