Recurrent episodic blood loss from normal menstruation is not expected to result in anemia. But without treatment, chronic heavy periods will progress through the stages of low iron stores to iron deficiency and then to anemia. When iron storage levels are low, the bone marrow’s blood cell factory cannot keep up with continued losses. Every patient with heavy menstrual bleeding (HMB) or prolonged menstrual episodes should be tested and treated for iron deficiency and anemia.1,2
Particular attention should be paid to assessment of iron storage levels with serum ferritin, recognizing that low iron levels progress to anemia once the storage is depleted. Recovery from anemia is much slower in individuals with iron deficiency, so assessment for iron storage also should be included in preoperative assessments and following a diagnosis of acute blood loss anemia.
The mechanics of erythropoiesis, hemoglobin, and oxygen transport
Red blood cells (erythrocytes) have a short life cycle and require constant replacement. Erythrocytes are generated on demand in erythropoiesis by a hormonal signaling process, regardless of whether sufficient components are available.3 Hemoglobin, the main intracellular component of erythrocytes, is comprised of 4 globin chains, which each contain 1 iron atom bound to a heme molecule. After erythrocytes are assembled, they are sent out into circulation for approximately 120 days. A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.
Unless erythrocytes are lost from bleeding, they are decommissioned—that is, the heme molecule is metabolized into bilirubin and excreted, and the iron atoms are recycled back to the bone marrow or to storage.4 Ferritin is the storage molecule that binds to iron, a glycoprotein with numerous subunits around a core that can contain about 4,000 iron atoms. Most ferritin is intracellular, but a small proportion is present in serum, where it can be measured.
Serum ferritin is a good marker for the iron supply in healthy individuals because it has high correlation to iron in the bone marrow and correlates to total intracellular storage unless there is inflammation, when mobilization to serum increases. The ferritin level at which the iron supply is deficient to meet demand, defined as iron deficiency, is hotly debated and ranges from less than 15 to 50 ng/mL in menstruating individuals, with higher thresholds based on onset of erythropoiesis signaling and the lower threshold being the World Health Organization recommendation.5-7 When iron atoms are in short supply, erythrocytes still are generated but they have lower amounts of intracellular hemoglobin, which makes them thinner, smaller, and paler—and less effective at oxygen transport.
A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.
CASE Patient seeks treatment for HMB-associated symptoms
A 17-year-old patient presents with HMB, fatigue, and difficulty with concentration. She reports that her periods have been regular and lasting 7 days since menarche at age 13. While they are manageable, they seem to be getting heavier, soaking pads in 2 to 3 hours. The patient reports that she would like to start treatment for her progressively heavy bleeding and prefers lighter scheduled bleeding; she currently does not desire contraception. The patient has no family history of bleeding problems and self-reports no personal history of epistaxis or bleeding with tooth extraction or tonsillectomy. Laboratory tests confirm iron deficiency with a hemoglobin level of 12.5 g/dL (reference range, 12.0–17.5 g/dL) and a serum ferritin level of 8 ng/mL (reference range, 50–420 ng/mL). Results from a coagulopathy panel are normal, as are von Willebrand factor levels.
Untreated iron deficiency will progress to anemia
This patient has iron deficiency without anemia, which warrants significant attention in HMB because without treatment it eventually will progress to anemia. The prevalence of iron deficiency, which makes up half of all causes of anemia, is at least double that of iron deficiency anemia.3
Adult bodies usually contain about 3 to 4 g of iron, with two-thirds in erythrocytes as hemoglobin.8 Approximately 40 to 60 mg of iron is recycled daily, 1 to 2 mg/day is lost from sloughed cells and sweat, and at least 1 mg/day is lost during normal menstruation. These losses are balanced with gastrointestinal uptake of 1 to 2 mg/day until bleeding exceeds about 10 mL/day. In this 17-year-old patient, iron stores have likely been on a progressive decline since menarche.
For normally menstruating individuals to maintain iron homeostasis, the daily dietary iron requirement is 18 mg/day. Iron requirements also increase during periods of illness or inflammation due to hormonal signaling in the iron absorption and transport pathway, in athletes due to sweating, foot strike hemolysis and bruising, and during growth spurts.9
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