Jason Freed, MD 

Oral Versus IV Iron, Populations That Warrant Upfront Escalation, the Implementation Gap, and Always Finding the Underlying Cause 

Freed outlines which patients should proceed directly to IV iron without a trial of oral therapy and why oral iron follow-up is inadequately practiced in the United States.

The decision between oral and IV iron is not a single binary choice but a clinical stratification that begins before the prescription is written. Certain populations can be identified prospectively as unlikely to derive meaningful benefit from oral iron and should proceed directly to IV iron: patients with gastrointestinal conditions that impair absorption, including gastric bypass surgery, inflammatory bowel disease, and celiac disease; patients whose rate of iron loss exceeds the capacity of oral absorption to keep pace, most commonly women with heavy menstrual bleeding that has not yet been adequately addressed and patients with chronic gastrointestinal blood loss; patients with advanced chronic kidney disease, in whom elevated hepcidin levels — accumulated due to impaired renal clearance — suppress intestinal iron absorption and render oral supplementation largely ineffective, a problem that begins well before dialysis initiation; patients with congestive heart failure, for whom a substantial evidence base supports IV iron as the preferred route; and patients with chronic inflammatory diseases broadly, in whom inflammation-driven hepcidin upregulation similarly suppresses oral iron absorption. For patients who do not fall into these categories, an appropriate trial of oral iron is reasonable, but it must be followed: the hemoglobin should be rechecked at 4 to 6 weeks, and failure to improve is the indication for conversion to IV iron. Multiple studies have documented that this follow-up is not occurring in the majority of cases in the United States, meaning patients who fail oral iron are frequently not identified as having done so and are not escalated.

The forward-looking challenge in iron deficiency is not primarily scientific but operational. The tools and treatments needed to dramatically reduce the burden of iron deficiency in the United States already exist. The priority question is how to close the gap between what is known and what is practiced — fixing reference ranges at the health system level through institutional advocacy; creating rapid-access pathways for IV iron in appropriate patients; ensuring that women of reproductive age are screened and treated for iron deficiency before they become pregnant, so that clinicians are not encountering severely iron-deficient patients at the first prenatal visit. On the horizon, new IV iron formulations are expected to enter the market with the potential to reduce infusion costs and expand the number of agents capable of delivering full replacement doses in a single short session with a favorable reaction profile. These are meaningful incremental advances, but they are secondary to the implementation work already warranted by the agents available today.

In this final segment of the video discussion on iron deficiency anemia, Jason Freed, MD, closes with what he describes as the principle most important to carry into practice: iron deficiency is never a complete diagnosis. Identifying that a patient is iron deficient is the beginning of the clinical workup, not the end of it, and the underlying cause must always be sought and addressed — repletion without source control produces temporary benefit and inevitable recurrence. In premenopausal women, structured assessment of menstrual blood loss — including questions about the number of saturated pads or tampons used per day, nocturnal changes, missed work or school, and clot size — reveals heavy menstrual bleeding far more frequently than a single unstructured inquiry. In men, iron deficiency should not be explained away by secondary factors such as proton pump inhibitor use; 90% of men with unexplained iron deficiency will have a gastrointestinal cause identified on upper endoscopy and colonoscopy, and the workup should not be deferred. Freed frames this emphasis on source identification not as an additional burden on the clinician but as the necessary condition for any treatment intervention to produce durable benefit — a principle that applies as much to the individual patient as it does to the field's broader effort to reduce the health burden of a condition that is, by every available measure, being massively undertreated.

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Oral Versus IV Iron, Populations That Warrant Upfront Escalation, the Implementation Gap, and Always Finding the Underlying Cause

Intravenous Iron — Formulation Selection, Patient Counseling, Infusion Reactions, and Dosing Principles 

Freed discusses how to select among IV iron formulations based on practical and access considerations.

When IV iron has been determined to be the appropriate route of repletion, formulation selection in clinical practice is driven by 2 considerations: which formulation can deliver a full replacement dose in a single infusion setting, and which formulation the patient's insurance will cover without burdensome prior authorization. All IV iron formulations are equivalent in efficacy on a milligram-per-milligram basis — the milligrams of elemental iron are directly comparable across products, and there is no plausible mechanistic basis for preferring 1 formulation over another for a specific indication. Among the agents capable of delivering 1,000 mg in a single session, low-molecular-weight iron dextran satisfies both criteria for most patients: it has been available since the 1990s, is inexpensive, and is covered by nearly all payers without requiring additional authorization. Ferric derisomaltose offers the advantage of a 15-minute infusion time for a 1,000 mg dose but remains on patent and is not universally covered. Where insurance will support it, the shorter infusion time is a meaningful practical benefit; where it will not, iron dextran is an effective and appropriate alternative. The priority from the patient's perspective is minimizing the number of clinic visits required, not the duration of any single infusion — a distinction that should anchor formulation discussions.

Patient counseling before a first IV iron infusion warrants deliberate attention and is best supported by a standardized written information sheet. Patients should be explicitly advised to take all their usual medications on the day of the infusion and eat breakfast normally, as a surprising proportion will otherwise fast or hold medications in the absence of specific instruction. The most important anticipatory guidance concerns Fishbane reactions — infusion-related reactions involving flushing, chest tightness, and back pain that affect approximately 1 in 20 patients and are rate-dependent rather than immunologically mediated. These reactions are not life-threatening when properly managed but are dramatic in presentation and frightening to patients who have not been forewarned. The appropriate response is to pause the infusion, allow the reaction to self-resolve over several minutes, and resume at 50% of the prior rate after a 15-minute observation window; the full infusion can typically be completed in the same setting. True anaphylaxis to IV iron is rare — occurring in approximately 1 in 200,000 infusions — and is distinguished from Fishbane reactions by the presence of bronchospasm and other systemic manifestations; the rate of true anaphylaxis is lower than that associated with IV antibiotics, a comparison that usefully contextualizes the risk for patients. Post-infusion arthralgias and myalgias occur in a small percentage of patients, typically resolve within 1 to 2 days, and can be managed with acetaminophen; patients should be counseled about this possibility so that they do not present for urgent evaluation when it occurs. Diphenhydramine premedication should be avoided, as its side effects — flushing, chest tightness — can mimic infusion reactions and complicate clinical assessment. The safety profile of IV iron during pregnancy is well established in the second and third trimesters; first-trimester safety data are insufficient, and IV iron should not be administered during the first trimester. Given that iron deficiency disproportionately affects women of reproductive age, pregnancy status should be confirmed before infusion in all patients for whom this is clinically relevant.

In this segment of the video discussion on iron deficiency anemia, Jason Freed, MD, describes how he applies the Ganzoni to individualize iron dosing. The equation accounts for the severity of anemia — lower hemoglobin requires more iron to support red blood cell production — and the patient's body weight, since blood volume and therefore total iron requirements scale with body size. In practice, Freed uses the equation primarily to determine whether a patient's needs are approximately 1,000 mg, in which case a single infusion is scheduled, or closer to 2,000 mg, in which case a second infusion is scheduled proactively rather than waiting to recheck labs. In diagnostically uncertain cases — such as patients with chronic kidney disease or anemia of inflammation where the iron-attributable component of anemia is unclear — he uses a lower test dose of 200 to 500 mg and rechecks hemoglobin in 2 to 3 weeks: a response of approximately 1 g/dL per week confirms that iron was the limiting factor, while absence of response indicates that additional iron will not be productive. Freed also notes that patients who are actively losing iron — through ongoing heavy menses or uncontrolled gastrointestinal bleeding — should receive an intentionally higher dose to account for continued losses during and after repletion.

Treating Before Anemia — Non-Anemic Iron Deficiency, Symptom Recognition, and Completing the Diagnostic Picture 

Freed discusses the evidence supporting treatment of iron deficiency before anemia develops, the symptom burden of non-anemic iron deficiency including fatigue, restless legs syndrome, and pica.

The clinical teaching that iron deficiency and anemia are inseparable — that one does not meaningfully exist without the other — has persisted in medical training despite more than 3 decades of evidence to the contrary. Iron is essential to mitochondrial function and cellular metabolism across virtually every tissue in the body, and iron deficiency can produce clinically significant symptoms well before red blood cell parameters become abnormal. The paradox is that symptom sensitivity to iron deficiency varies substantially and unpredictably between individuals: some patients experience profound fatigue and reduced exercise tolerance with no measurable anemia, while others present with a hemoglobin of 7.5 g/dL and describe only vague, mild worsening. This variability is not yet understood mechanistically, but its clinical implication is clear — the decision to treat iron deficiency should not be gated on the presence of anemia. It should be informed by the probability that a given patient will benefit from iron repletion, which depends on symptom burden, ferritin level, and clinical context.

3 symptom domains are particularly important for clinicians to recognize as iron-related and act on accordingly. The first is fatigue: randomized trials of IV iron versus IV placebo in nonanemic women with iron deficiency have demonstrated that iron repletion produces meaningful improvement in fatigue, independent of any change in hemoglobin. The second is restless legs syndrome, which is among the most consequential and underreported manifestations of iron deficiency — patients often do not seek care for it because they do not recognize it as a medical problem rather than an unchangeable feature of their lives, and iron deficiency as an etiology is frequently not considered. The third is pica, the craving for non-food substances, most commonly ice — a behavioral manifestation of iron deficiency with a probable evolutionary basis in the drive to obtain minerals from environmental sources. In severe cases, patients consume 4 or more large cups of ice per day and can sustain dental damage as a result; IV iron repletion typically resolves the craving within days. Together, these symptom domains represent a large population of patients whose quality of life is being significantly affected by iron deficiency that is neither recognized nor treated.

In this segment of the video discussion on iron deficiency anemia, Jason Freed, MD describes how he constructs the complete diagnostic picture beyond ferritin alone. Transferrin saturation (TSAT) is the most useful complementary test, particularly in patients with chronic kidney disease or chronic inflammatory disease in whom ferritin may be falsely elevated and a low TSAT identifies iron-deficient states that ferritin alone would miss. The CBC is interpreted not merely as a binary anemic or nonanemic result but as a longitudinal trend: hemoglobin is a highly stable physiologic parameter in the absence of disease, and a decline of 1 g/dL or more — even if the absolute value remains within the labeled normal range — is a clinically meaningful signal. Mean corpuscular volume (MCV) is similarly stable over time, and the teaching that iron deficiency anemia equals microcytic anemia is, by Freed's characterization, wrong — more than half of patients with iron deficiency anemia have a normocytic MCV by absolute criteria, but nearly all show a relative decline from their personal baseline. Freed frames the diagnostic approach not as identifying a threshold that definitively establishes disease, but as assembling evidence for the likelihood that a given patient will benefit from iron — a probabilistic framework that better reflects the clinical reality of this condition than any single cutoff. structural flaw in how laboratory reference ranges are constructed. Reference ranges are developed locally: each institution validates its own normal range by measuring a parameter in approximately 120 healthy individuals from the surrounding community and defining normal as the central 95th percentile of that distribution. This approach works reasonably well for most laboratory values, but it fails catastrophically for iron and ferritin in populations where iron deficiency is endemic. When two-thirds of premenopausal women are iron deficient, those women constitute the healthy reference population — and iron deficiency becomes enshrined as normal by the mathematics of the method itself. The consequence is visible in hemoglobin reference ranges: many laboratories use a lower limit of approximately 10.7 g/dL for women compared with 13.5 g/dL for men, a gap of nearly 3 g/dL that cannot be explained by the physiologic effects of testosterone alone, which accounts for approximately 1 g/dL of true sex-based difference. The remainder reflects under-recognized, under-treated iron deficiency that has been absorbed into the definition of normal.

In this video discussion on iron deficiency anemia, Jason Freed, MD, an assistant professor of medicine at Harvard Medical School, examines what the ASH draft guidelines — issued for public comment in 2025 — propose to address this problem. The draft recommends a ferritin cutoff of 30 µg/dL for general healthy adults, with consideration for a threshold of 50 µg/dL, representing a meaningful departure from the World Health Organization's longstanding cutoff of 15 µg/dL and from the local reference ranges most clinicians encounter in their electronic health records. Freed notes that the debate between 30 and 50 reflects a legitimate concern about over-medicalizing iron deficiency in asymptomatic individuals, but argues that for any patient presenting with a symptom attributable to iron deficiency — anemia, fatigue, restless legs syndrome — a ferritin below 50 µg/dL is an actionable finding. He emphasizes that correcting reference ranges at the health system level will ultimately require institutional advocacy and committee action, not just individual clinician awareness, and that the finalization of the ASH guidelines is a necessary prerequisite for that broader implementation effort to begin in earnest.

Treating Before Anemia — Non-Anemic Iron Deficiency, Symptom Recognition, and Completing the Diagnostic Picture

The Underdiagnosis Crisis — Ferritin Thresholds, Reference Range Failures, and What Clinicians Are Missing 

Freed explains why iron deficiency anemia is being missed at an alarming rate in clinical practice and what the ASH draft guidelines propose to correct this systemic failure.

Iron deficiency is among the most prevalent nutritional deficiencies in the world, yet it is being underdiagnosed at a scale that most clinicians would find surprising. Data from the National Health and Nutrition Examination Survey (NHANES) — a nationally representative cohort of approximately 10,000 healthy adults — illustrate the magnitude of the problem. Using a ferritin cutoff of 15 µg/dL, a threshold applied by many laboratories, 17% of premenopausal women meet criteria for iron deficiency. At a cutoff of 30 µg/dL, that proportion rises to 39%. At 50 µg/dL — a threshold with strong physiologic and clinical justification — 62% of premenopausal women are iron deficient. Most of those women are not receiving iron supplementation, meaning the gap between prevalence and treatment is not marginal but structural. A national cohort analysis of more than 120,000 patients found that among the roughly 12,000 who presented to primary care with a chief complaint of fatigue, only half had a complete blood count (CBC) performed, and only approximately 10% had ferritin testing — despite iron deficiency being one of the most common and correctable causes of that symptom. Of those who did have ferritin measured, two-thirds were found to be iron deficient.

The root cause of this underdiagnosis is not clinical inattention but a structural flaw in how laboratory reference ranges are constructed. Reference ranges are developed locally: each institution validates its own normal range by measuring a parameter in approximately 120 healthy individuals from the surrounding community and defining normal as the central 95th percentile of that distribution. This approach works reasonably well for most laboratory values, but it fails catastrophically for iron and ferritin in populations where iron deficiency is endemic. When two-thirds of premenopausal women are iron deficient, those women constitute the healthy reference population — and iron deficiency becomes enshrined as normal by the mathematics of the method itself. The consequence is visible in hemoglobin reference ranges: many laboratories use a lower limit of approximately 10.7 g/dL for women compared with 13.5 g/dL for men, a gap of nearly 3 g/dL that cannot be explained by the physiologic effects of testosterone alone, which accounts for approximately 1 g/dL of true sex-based difference. The remainder reflects under-recognized, under-treated iron deficiency that has been absorbed into the definition of normal.

Jason Freed, MD

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