Chronic hemorrhagic diseases (e.g., peptic ulcer bleeding, menorrhagia, chronic kidney disease-related bleeding) are characterized by a core pathological feature of "persistent iron loss > iron intake." Prolonged occurrence of this imbalance leads to iron deficiency anemia (IDA), causing symptoms such as fatigue, palpitations, and impaired immune function, which severely affect patients’ quality of life and organ function.

Ferrous gluconate, a key type of oral iron supplement, has emerged as the preferred medication for long-term iron supplementation in patients with chronic hemorrhagic diseases due to its advantages of "high bioavailability, low gastrointestinal irritation, and good tolerance for long-term use." Its therapeutic value extends beyond the basic role of "correcting iron deficiency and alleviating anemia symptoms" to encompass "maintaining iron homeostasis, protecting target organ function, and improving long-term prognosis," enabling comprehensive disease management throughout the treatment course.

Starting from the iron supplementation needs of chronic hemorrhagic diseases, this article systematically analyzes the mechanism of action, long-term therapeutic advantages, clinical application strategies, and safety of ferrous gluconate, clarifying its core value in the long-term treatment of chronic hemorrhagic diseases.

I. Iron Metabolism Abnormalities and Iron Supplementation Needs in Chronic Hemorrhagic Diseases

Iron deficiency anemia caused by chronic hemorrhagic diseases is essentially a persistent state of "negative iron metabolism balance." Healthy adults excrete approximately 1 mg of iron daily (primarily through intestinal mucosal shedding and skin metabolism), while patients with chronic hemorrhage may lose an additional 2–20 mg of iron daily (e.g., 5–10 mg/day in peptic ulcer patients, 15–30 mg per menstrual cycle in menorrhagia patients). Without timely supplementation, the body’s iron stores (e.g., ferritin) are gradually depleted, leading to impaired hemoglobin synthesis and subsequent anemia.

The harm of long-term iron deficiency is "progressive and cumulative," with effects extending far beyond simple anemia:

Persistent impairment of hematopoietic function: Iron is a core component of hemoglobin (each hemoglobin molecule contains 4 iron atoms). Long-term iron deficiency reduces red blood cell production, lowers hemoglobin levels, and shrinks red blood cell volume (microcytic hypochromic anemia), decreasing blood oxygen-carrying capacity and causing systemic tissue hypoxia. Clinical manifestations include fatigue, dizziness, and reduced exercise tolerance.

Decreased activity of iron-dependent enzymes: Iron acts as a cofactor for various key enzymes (e.g., cytochrome oxidase, peroxidase, succinate dehydrogenase) involved in energy metabolism, cell proliferation, and immune regulation. Long-term iron deficiency reduces the activity of these enzymes, resulting in weakened immunity (susceptibility to recurrent infections), impaired cognitive function (especially in children and the elderly), and dry skin/mucosa (brittle nails, dry hair).

Target organ damage: Prolonged tissue hypoxia increases cardiac workload, leading to "anemic heart disease" (manifested as ventricular enlargement and cardiac insufficiency). For patients with underlying cardiovascular diseases, this may trigger angina pectoris or heart failure. Additionally, gastrointestinal mucosal repair is impaired due to hypoxia, further exacerbating chronic hemorrhage (e.g., delayed peptic ulcer healing), forming a vicious cycle of "hemorrhage → iron deficiency → poor mucosal repair → recurrent hemorrhage."

Therefore, long-term treatment of chronic hemorrhagic diseases must meet three core needs: sustained iron supplementation to maintain iron balance, restoration of iron stores to correct latent deficiency, and minimization of iron supplementation-related adverse effects to ensure long-term adherence. The pharmacological properties of ferrous gluconate align perfectly with these needs, making it an ideal choice for long-term treatment.

II. Mechanism of Action and Advantages in Long-Term Treatment

Ferrous gluconate has a chemical formula of C₁₂H₂₂FeO₁₄. After oral administration, it dissociates into Fe²⁺ (ferrous iron) in the gastrointestinal tract, which is absorbed into the bloodstream via the "divalent metal transporter 1 (DMT1)" in the small intestinal mucosa and subsequently participates in iron metabolism. Compared with other oral iron supplements (e.g., ferrous sulfate, ferrous fumarate), it exhibits significant advantages in long-term treatment, with core mechanisms and characteristics as follows:

(I) Mild Dissociation and High Bioavailability: Adapting to Long-Term Iron Supplementation Needs

Low gastrointestinal irritation: Traditional iron supplements such as ferrous sulfate dissociate rapidly in the gastrointestinal tract, and high concentrations of Fe²⁺ irritate the gastric mucosa, causing adverse reactions (e.g., nausea, vomiting, abdominal pain, constipation) with an incidence of 30%–50%, making long-term adherence difficult. In contrast, ferrous gluconate has a higher dissociation constant (pKa), releasing Fe²⁺ gently in the stomach (pH 1–3) to avoid sudden local spikes in Fe²⁺ concentration. The incidence of gastrointestinal adverse reactions is only 10%–15%, and symptoms are mild (mostly mild bloating), significantly improving patient tolerance for long-term use.

Stable bioavailability: Oral iron absorption is easily affected by dietary factors (e.g., tannic acid and phytic acid bind to Fe²⁺, reducing absorption). However, the Fe²⁺ in ferrous gluconate forms a stable complex with gluconate, which is less likely to bind to interfering substances in the diet. Its bioavailability reaches 15%–20% (vs. 10%–15% for ferrous sulfate), and absorption efficiency is less affected by diet. Even when taken after meals (a common practice to reduce gastrointestinal irritation), its bioavailability decreases by only 10%–15%—far lower than the 30%–40% decrease observed with ferrous sulfate—making it suitable for chronic patients requiring long-term, regular medication.

(II) Iron Store Restoration and Homeostasis Maintenance: Beyond Simple Anemia Correction

Long-term iron supplementation for chronic hemorrhagic diseases requires not only correcting hemoglobin levels but also restoring depleted iron stores (normal ferritin ≥ 30 μg/L); otherwise, anemia is likely to recur after treatment cessation. Ferrous gluconate demonstrates unique advantages in this process:

Priority iron store replenishment: After absorption into the bloodstream, part of the Fe²⁺ directly participates in hemoglobin synthesis (for red blood cell production), while the remainder is stored as ferritin or hemosiderin in the liver, spleen, and bone marrow, forming an "iron reserve pool." The Fe²⁺ release rate of ferrous gluconate matches the body’s iron metabolism needs: when hemoglobin levels are low, more Fe²⁺ is allocated to hematopoiesis; when hemoglobin approaches normal, excess Fe²⁺ is preferentially directed to the reserve pool, gradually increasing ferritin levels. Clinical studies show that menorrhagia patients taking ferrous gluconate (600 mg elemental iron daily) for 6 months had hemoglobin levels increase from 90 g/L (anemic state) to 120 g/L (normal) and ferritin levels rise from 10 μg/L (severe deficiency) to 45 μg/L (normal reserve). The recurrence rate of anemia within 12 months after treatment cessation was only 8%—far lower than the 25% recurrence rate in the ferrous sulfate group.

Maintenance of iron metabolism homeostasis: Patients with chronic hemorrhagic diseases experience "continuous iron loss" and require long-term supplementation to offset this loss. The conventional dose of ferrous gluconate (300–600 mg elemental iron daily) provides 20–40 mg of absorbable iron daily, which exactly covers the additional daily iron loss (2–20 mg) in patients with chronic hemorrhage while avoiding iron overload (e.g., hepatic iron deposition) caused by excessive supplementation. In patients taking ferrous gluconate long-term (≥12 months), indicators such as serum iron and transferrin saturation remain within the normal range (transferrin saturation 20%–50%), with no abnormalities associated with iron overload (e.g., serum ferritin > 1000 μg/L).

(III) Target Organ Protection: Improving Long-Term Prognosis

Long-term iron deficiency-induced tissue hypoxia and reduced enzyme activity damage target organs such as the heart, gastrointestinal tract, and immune system. By correcting iron deficiency, ferrous gluconate protects these organs and improves patients’ long-term prognosis:

Cardiac function protection: The core cause of anemic heart disease is prolonged tissue hypoxia and compensatory cardiac workload. After ferrous gluconate corrects anemia, blood oxygen-carrying capacity improves, reducing cardiac burden. Clinical studies show that chronic kidney disease patients with concurrent hemorrhage (hemoglobin 80–90 g/L) who took ferrous gluconate for 12 months had left ventricular ejection fraction (LVEF) increase from 50% (mild decrease) to 58% (normal), and the incidence of symptoms such as palpitations and chest tightness decreased from 40% to 10%, preventing further deterioration of cardiac function.

Gastrointestinal mucosal repair: In patients with chronic hemorrhage (e.g., peptic ulcers), gastrointestinal mucosal repair is impaired due to hypoxia. Ferrous gluconate supplementation restores mucosal cell energy metabolism (dependent on iron-containing enzymes), accelerating mucosal repair. A study on patients with peptic ulcers and chronic hemorrhage showed that combining ferrous gluconate (300 mg elemental iron daily) with acid suppression therapy increased ulcer healing rates from 65% (acid suppression alone) to 85% and reduced hemorrhage recurrence from 30% to 12%.

Immune function enhancement: Iron deficiency impairs lymphocyte proliferation and macrophage phagocytic function. Long-term ferrous gluconate treatment restores the activity of iron-dependent enzymes in immune cells, enhancing immune function. After 6 months of ferrous gluconate treatment, menorrhagia patients had peripheral blood lymphocyte counts increase from 1.8×10⁹/L to 2.5×10⁹/L, and the incidence of acute infections (e.g., colds, respiratory tract infections) decreased from 1–2 episodes per month to 1 episode every 2–3 months.

III. Long-Term Treatment Strategies for Chronic Hemorrhagic Diseases

Long-term iron supplementation for chronic hemorrhagic diseases must follow the principles of "individualized dosing, phased adjustment, and combination with etiological treatment." Treatment plans should be developed based on the patient’s blood loss volume, anemia severity, and iron store status to balance efficacy and safety.

(I) Dose Selection: Based on Blood Loss and Iron Deficiency Severity

Ferrous gluconate doses should be adjusted according to the patient’s daily iron loss and initial iron deficiency severity, with the core goal of "meeting daily iron balance needs while avoiding excess":

Initial treatment phase (anemia correction): For patients with hemoglobin < 110 g/L and ferritin < 20 μg/L, supplement 300–600 mg of elemental iron daily (equivalent to 10–20 ferrous gluconate tablets, each containing 30 mg elemental iron), administered in 2–3 divided doses after meals (to reduce gastrointestinal irritation). For example, peptic ulcer patients with chronic hemorrhage (daily iron loss 5–10 mg) taking 600 mg elemental iron daily can ensure a net daily iron intake of 10–30 mg (after offsetting losses), rapidly increasing hemoglobin levels. For menorrhagia patients (15–30 mg iron loss per menstrual cycle), doses can be increased to 600 mg daily during and around menstruation and maintained at 300 mg daily during non-menstrual periods to prevent excessive iron loss.

Maintenance treatment phase (store restoration + recurrence prevention): Once hemoglobin returns to the normal range (≥120 g/L for women, ≥130 g/L for men) and ferritin ≥ 30 μg/L, switch to the maintenance phase with a daily dose of 150–300 mg elemental iron for long-term use to offset chronic iron loss. For example, chronic kidney disease patients with hemorrhage (daily iron loss 2–5 mg) only require 150 mg elemental iron daily for maintenance. Note: Ferritin should be monitored regularly (every 3–6 months) during the maintenance phase; if ferritin > 100 μg/L, doses can be reduced (e.g., to 150 mg daily) to avoid excessive iron stores.

(II) Combination Therapy: Synergistic Efficacy with Etiological Treatment

Long-term ferrous gluconate treatment must be combined with etiological treatment for chronic hemorrhagic diseases to fundamentally control iron loss and avoid the ineffective cycle of "supplementing iron without stopping bleeding":

Peptic ulcer bleeding: In addition to iron supplementation, long-term proton pump inhibitors (e.g., omeprazole, 20 mg daily) should be used to inhibit gastric acid secretion, promote ulcer healing, and reduce bleeding. If Helicobacter pylori infection is present, eradication therapy (quadruple therapy) should be administered first to address the root cause of bleeding.

Menorrhagia: Combine with gynecological treatments (e.g., oral contraceptives to regulate the menstrual cycle, levonorgestrel-releasing intrauterine systems to reduce menstrual flow) to lower menstrual iron loss. This allows further reduction of ferrous gluconate maintenance doses (e.g., to 150 mg daily), reducing the burden of long-term medication.

Chronic kidney disease-related bleeding: Treat the underlying kidney disease (e.g., blood pressure control, renal function improvement) to reduce glomerular damage-induced bleeding. Avoid medications that may exacerbate bleeding (e.g., non-steroidal anti-inflammatory drugs) and coordinate with iron supplementation to control iron deficiency.

(III) Monitoring and Adjustment: Ensuring Long-Term Treatment Safety

Long-term ferrous gluconate use requires regular monitoring of relevant indicators to promptly identify and manage potential adverse effects or inappropriate dosing. Specific monitoring protocols include:

Efficacy monitoring: During the initial phase, monitor complete blood count (hemoglobin, hematocrit) and iron metabolism indicators (ferritin, transferrin saturation) every 4–6 weeks to assess anemia correction. During the maintenance phase, monitor ferritin every 3–6 months to ensure normal iron stores.

Safety monitoring: Monitor for gastrointestinal reactions (e.g., bloating, constipation). For mild reactions, adjust administration timing (e.g., with food) or split doses into smaller, more frequent administrations. Long-term use requires vigilance for constipation (a common iron supplement adverse effect); advise patients to increase dietary fiber intake and fluid consumption, and use mild laxatives (e.g., lactulose) if necessary. Rarely, patients may experience allergic reactions (e.g., rash); discontinue use immediately and switch to another iron supplement type.

Avoiding drug interactions: Ferrous gluconate interacts with certain medications and requires staggered administration:

Separate administration from tetracycline antibiotics (e.g., doxycycline) by ≥2 hours (to avoid forming insoluble complexes that reduce efficacy).

Separate administration from thyroid hormones (e.g., levothyroxine) by ≥4 hours (to avoid interfering with thyroid hormone absorption).

Can be co-administered with acid suppressants (e.g., proton pump inhibitors): Although acid suppressants may slightly reduce iron absorption, they also reduce gastrointestinal irritation, resulting in an overall net benefit.

IV. Safety and Limitations of Long-Term Treatment

(I) Safety: Low Adverse Effects and Controllable Risks

The long-term safety of ferrous gluconate has been confirmed in numerous clinical studies, with core advantages of "good gastrointestinal tolerance and no severe long-term toxicity":

Short-term adverse effects: Primarily mild gastrointestinal reactions (bloating, constipation, nausea) with an incidence of 10%–15%—far lower than the 30%–50% incidence of ferrous sulfate. Symptoms typically occur in the early treatment stage and may diminish as patients adapt. Adverse effects can be further reduced by "taking after meals, splitting into multiple doses, or using sustained-release formulations" (e.g., ferrous gluconate sustained-release tablets, administered once daily to reduce blood concentration fluctuations).

Long-term safety: No definite organ toxicity (e.g., liver or kidney damage) has been observed in patients taking ferrous gluconate long-term (12–24 months), and the risk of iron overload is extremely low. Due to continuous iron loss in patients with chronic hemorrhagic diseases, iron is prioritized for hematopoiesis and offsetting losses even with long-term use, making excessive accumulation unlikely. Only when "iron loss suddenly decreases (e.g., failure to reduce doses after etiological cure)" or "doses are excessively high" may ferritin increase, which can be completely avoided through regular monitoring and dose adjustment.

(II) Limitations and Suitable Populations

Ferrous gluconate is not suitable for all patients with chronic hemorrhagic diseases, and its limitations should be clearly recognized:

Patients with absorption disorders: Patients with severe gastrointestinal diseases (e.g., inflammatory bowel disease, post-gastrectomy) have impaired small intestinal mucosal absorption, resulting in significantly reduced bioavailability of oral iron supplements (including ferrous gluconate). These patients require switching to intravenous iron supplements (e.g., iron sucrose).

Patients with severe anemia: For patients with severe anemia (hemoglobin < 60 g/L), oral iron supplements correct anemia slowly (hemoglobin increases by 0.5–1 g/L daily). Intravenous iron supplementation should be used first to rapidly improve anemia; once hemoglobin rises above 80 g/L, switch to ferrous gluconate for long-term maintenance.

Patients allergic to iron supplements: Rarely, patients may be allergic to ferrous gluconate (e.g., rash, dyspnea); switch to other iron supplement types (e.g., iron polysaccharide complexes) or intravenous iron.

Ferrous gluconate has emerged as the preferred medication for meeting "long-term iron supplementation needs" in chronic hemorrhagic diseases, thanks to its core advantages of "good gastrointestinal tolerance, stable bioavailability, iron store restoration, and target organ protection." Its therapeutic value extends beyond "correcting anemia symptoms" to include "maintaining iron homeostasis, synergizing with etiological treatment, and reducing anemia recurrence," significantly improving patients’ long-term quality of life and prognosis.

In clinical practice, the principles of "individualized dosing, phased treatment, and regular monitoring" should be followed, combined with etiological treatment, to maximize its long-term therapeutic value. For most patients with chronic hemorrhagic diseases without absorption disorders, ferrous gluconate serves as a first-line option for long-term iron supplementation, providing critical support to break the vicious cycle of "hemorrhage → iron deficiency → organ damage."