Iron Deficiency: Beyond the CBC

By Amanda Queen, PA-C

A normal CBC does not rule out iron deficiency. Yet many people are told their "bloodwork looks fine" after nothing more than a complete blood count, and never have an iron panel checked at all.

Here's the problem: your hemoglobin can sit perfectly in the normal range while your iron stores are running on empty. Anemia is the end of a long slide, not the beginning. By the time your CBC notes a problem, you may have been iron deficient for months or years. In fact, when common CBC-based markers like mean corpuscular volume were compared against serum ferritin in reproductive-age women, MCV caught only a fraction of true iron deficiency, with sensitivity as low as ~32% in nonpregnant women (Williams et al., Journal of Nutrition, 2025). A "normal" CBC is reassuring only if you never look deeper.

This is more common than you think

In high-income countries, roughly 38% of nonpregnant, reproductive-age women have iron deficiency without anemia, and about 13% have full iron-deficiency anemia (Auerbach et al., JAMA, 2025). Depending on the ferritin cutoff used, NHANES data in young females found iron deficiency in 38.6% at a ferritin threshold of 15 µg/L and 77.5% at a threshold of 50 µg/L (Allen, New England Journal of Medicine, 2025). During the third trimester of pregnancy, iron deficiency affects up to 84% of women.

And yet routine iron panels still aren't standard for every patient, even many who are planning a pregnancy. Screening tends to happen only once anemia appears, which means the window to catch and correct low iron before symptoms and pregnancy demands set in is routinely missed.

Why iron matters even when you're not anemic

Iron isn't just about red blood cells. It's a component of hemoglobin and myoglobin and is essential for neurotransmitter synthesis and mitochondrial energy production (Auerbach et al., JAMA, 2025). In other words, it touches oxygen transport, cellular energy, brain chemistry, and muscle function.

So it's no surprise that low iron, with or without anemia, is associated with:

• Fatigue

• Exercise intolerance and reduced stamina

• Brain fog and difficulty concentrating

• Hair shedding

• Restless legs syndrome (reported in roughly 32–40% of iron-deficient patients)

• Poor sleep

• Headaches and lightheadedness

• Feeling cold

• Irritability and low mood

• Shortness of breath with exertion

• Pica (craving ice or non-food items), reported in up to 40–50%

You do not have to be anemic for your iron status to affect how you feel and function (Auerbach et al., JAMA, 2025).

So what's an "optimal" ferritin?

Serum ferritin is the single best indirect marker of total body iron stores, and it's the first-line test because iron deficiency is the only thing that makes ferritin low. Most guidelines define iron deficiency as a ferritin below 30 ng/mL in people without inflammation, and some use thresholds up to 45 ng/mL to catch more true cases (Auerbach et al., JAMA, 2025; Ko et al., Gastroenterology/AGA, 2020).

From a functional standpoint, we often aim a bit higher than the bare-minimum, targeting roughly the 50–80 ng/mL range so there's a comfortable buffer, rather than sitting right at the edge of depletion. A personalized approach is key, as those with certain conditions will continue to have symptoms at any level under 100 ng/mL.

Iron in excess catalyzes the formation of reactive oxygen species and can cause oxidative tissue damage, which is exactly why the body regulates it so tightly (Koleini et al., Journal of Clinical Investigation, 2021). More is emphatically not better. Chasing a high ferritin is its own mistake.

One caveat: ferritin is also an acute-phase reactant, so inflammation can falsely raise it. If iron deficiency is still suspected despite a ferritin above 30–50 ng/mL, transferrin saturation (TSAT <20%) helps clarify the picture (Auerbach et al., JAMA, 2025).

If you're deficient, we care about WHY

Low iron is a clue, not a diagnosis. The common culprits:

1. Blood loss — heavy menstrual bleeding, frequent blood donation, or GI bleeding. Recurrent blood loss accounts for the large majority of iron-deficiency anemia cases (Latimer et al., American Family Physician, 2025).

   
   

2. Not enough coming in — low intake of iron-rich foods, or restrictive/low-heme diets.

   
   

3. Poor absorption — GI conditions and certain medications interfere with uptake.

   
   

4. Increased demand — pregnancy, postpartum, growth, and endurance training.

   
   

Often, it comes back to the gut

Because most iron is absorbed in the duodenum and proximal jejunum, the gut is frequently where the story lives:

• H. pylori — reduces stomach acidity and causes atrophic gastritis, impairing iron absorption. It's associated with both iron-deficiency anemia (odds ratio ~1.72) and iron deficiency without anemia (Auerbach et al., JAMA, 2025). Treating it improves the response to iron (Latimer et al., American Family Physician, 2025).

  
  

• Celiac disease — a recognized and common cause, through villous atrophy, occult blood loss, and inflammation-driven hepcidin. In one series, 46% of adults with celiac disease had iron-deficiency anemia (Auerbach et al., JAMA, 2025). Serologic screening is recommended in iron deficiency.

  
  

• SIBO / intestinal dysbiosis — bacterial overgrowth and atrophic gastritis are listed among malabsorptive contributors to iron deficiency (Lopez et al., Lancet, 2016), and worth considering when nutrient deficiencies cluster together.

  
  

• Inflammatory bowel disease — contributes through both impaired absorption and chronic blood loss; iron deficiency affects anywhere from 13% to 90% of IBD patients (Auerbach et al., JAMA, 2025).

  
  

Worth noting: chronic proton pump inhibitor use also raises gastric pH and roughly doubles the risk of iron deficiency (Auerbach et al., JAMA, 2025).

What about supplements?

• Ferrous bisglycinate — a chelated form that tends to be gentler on the gut. A meta-analysis found fewer GI side effects and, in pregnant women, higher hemoglobin versus other iron supplements (Fischer et al., Nutrition Reviews, 2023). 

  
  

• Alternate-day dosing — taking oral iron raises hepcidin for up to ~48 hours, which blocks further absorption. So dosing every other day can improve absorption and tolerance versus daily dosing — often the smarter strategy (DeLoughery et al., AGA, 2024; Latimer et al., American Family Physician, 2025).

  
  

• Heme iron — animal-source heme iron is well absorbed and can serve as an alternative or adjunct, and pairing iron with meat protein or vitamin C improves uptake (DeLoughery et al., AGA, 2024).

  
  

• Lactoferrin — an iron-binding milk glycoprotein. The evidence here is genuinely mixed: a Cochrane-reviewed set of trials in pregnancy found oral bovine lactoferrin raised hemoglobin and dramatically reduced GI side effects versus ferrous iron (da Silva Lopes et al., Cochrane Database, 2021), but a large 2026 randomized trial in nonpregnant women found lactoferrin inferior to ferrous sulfate for raising hemoglobin (Huda et al., Journal of Nutrition, 2026). It may have a role for tolerance in select patients, but it's not a proven substitute for iron.

  
  

Small practical tips: take iron on an empty stomach when tolerated, add Vitamin C, and avoid tea and coffee within about an hour (DeLoughery et al., AGA, 2024).

Why more iron isn't the answer

Taking high-dose iron indefinitely without monitoring is not a strategy. Doses of 45 mg or more per day increase constipation and nausea (Allen, New England Journal of Medicine, 2025), and side effects — constipation, nausea, abdominal discomfort, dark stools — drive roughly half of patients to reduce adherence (Latimer et al., American Family Physician, 2025).

And if ferritin isn't climbing despite supplementation, that's information. It may mean:

• The dose or form isn't right, or

• You're still losing iron somewhere, or

• You're not absorbing it, or

• The underlying cause was never addressed.

  
  

The functional bottom line

Low ferritin? Don't just replace it, investigate it.

The questions worth answering:

• Is dietary iron intake adequate?

• Is there ongoing blood loss?

• Is absorption impaired?

• Is there an underlying GI issue?

• Is inflammation distorting the ferritin?

• Is the current supplement actually working?

  
  

Restoring iron stores is only half the job. Finding out why they were depleted is the other half. Reassessing response at 2–4 weeks — and rechecking ferritin over time — closes the loop (Latimer et al., American Family Physician, 2025).

Need help navigating iron deficiency? We would be honored to partner with you. 

BECOME A PATIENT

This article is educational and not a substitute for individualized medical care. Talk with your clinician before starting or changing supplements, and get an underlying cause evaluated.

1. Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults. JAMA. 2025.

2. Williams AM, Ford ND, Jefferds MED, Sharma AJ. Exploring the Use of Iron and Hematologic Indicators for Surveillance of Iron Deficiency in Pregnant and Nonpregnant Women in the United States. J Nutr. 2025.

3. Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults. JAMA. 2025.

4. Allen LH. Micronutrients — Assessment, Requirements, Deficiencies, and Interventions. N Engl J Med. 2025.

5. Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults. JAMA. 2025.

6. Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults. JAMA. 2025.

7. Latimer K, Baci G, Layne M. Iron Deficiency Anemia: Evaluation and Management. Am Fam Physician. 2025.

8. Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron Deficiency Anaemia. Lancet. 2016.

9. Fischer JAJ, Cherian AM, Bone JN, Karakochuk CD. The Effects of Oral Ferrous Bisglycinate Supplementation on Hemoglobin and Ferritin Concentrations in Adults and Children: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutr Rev. 2023.

10. Huda TM, Islam S, Ali NB, et al. Bovine Lactoferrin Compared With Ferrous Sulfate for Treating Iron-Deficiency Anemia in Bangladeshi Women — a Randomized Controlled Trial. J Nutr. 2026.

11. da Silva Lopes K, Yamaji N, Rahman MO, et al. Nutrition-Specific Interventions for Preventing and Controlling Anaemia Throughout the Life Cycle: An Overview of Systematic Reviews. Cochrane Database Syst Rev. 2021.

12. DeLoughery TG, Jackson CS, Ko CW, Rockey DC. AGA Clinical Practice Update on Management of Iron Deficiency Anemia: Expert Review. Clin Gastroenterol Hepatol. 2024.

13. Ko CW, Siddique SM, Patel A, et al. AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology. 2020.

14. Koleini N, Shapiro JS, Geier J, Ardehali H. Ironing Out Mechanisms of Iron Homeostasis and Disorders of Iron Deficiency. J Clin Invest. 2021.

15. Latimer K, Baci G, Layne M. Iron Deficiency Anemia: Evaluation and Management. Am Fam Physician. 2025.

16. Camaschella C. Iron-Deficiency Anemia. N Engl J Med. 2015.

17. Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults. JAMA. 2025.