Low Hemoglobin: Causes, Diagnosis, and Evidence-Based Treatment

Low Hemoglobin Levels: Etiology, Diagnosis, and Management from a Modern Medical Perspective
Hemoglobin (Hb), an iron-containing protein in erythrocytes, is critical for oxygen transport from the lungs to tissues and carbon dioxide return to the lungs. A hemoglobin level below the reference range indicates anemia, a condition associated with diverse etiologies and clinical manifestations. According to the World Health Organization (WHO), reference hemoglobin values are:
  • Men: 130–180 g/L
  • Non-pregnant women: 120–160 g/L
  • Pregnant women: ≥110 g/L (depending on trimester)
  • Children: 110–140 g/L (age-dependent)

This article, grounded in current data from authoritative sources such as WHO, the National Institutes of Health (NIH), and peer-reviewed journals, explores the causes, clinical features, diagnostic approaches, treatment, and prevention of anemia due to low hemoglobin, tailored for medical professionals.
Etiology of Low Hemoglobin

Anemia is classified based on pathogenesis into three main categories:
  1. Reduced Erythrocyte or Hemoglobin Production
  • Iron Deficiency Anemia (IDA): The most prevalent form, accounting for approximately 50% of anemia cases globally (WHO, 2020). Iron deficiency may result from inadequate intake (low-iron diet, vegetarianism), impaired absorption (celiac disease, atrophic gastritis, gastric resection), or chronic blood loss (menorrhagia, gastrointestinal bleeding).
  • Megaloblastic Anemia: Caused by deficiencies in vitamin B12 (cyanocobalamin) or folate, leading to impaired DNA synthesis and formation of large, functionally immature erythrocytes. Etiologies include pernicious anemia, malabsorption, or prolonged use of proton pump inhibitors or metformin.
  • Anemia of Chronic Disease (ACD): Common in chronic kidney disease (reduced erythropoietin production), malignancies, rheumatoid arthritis, or chronic infections. Mechanisms involve dysregulated iron metabolism and elevated hepcidin levels.
  • Aplastic Anemia: A rare condition characterized by bone marrow failure due to radiation, chemotherapy, or autoimmune processes.
  • Hereditary Disorders: Thalassemias and other hemoglobinopathies impair globin chain synthesis.
  1. Hemolysis (Increased Erythrocyte Destruction)
  • Hemolytic anemias result from premature erythrocyte destruction. Causes include autoimmune disorders (autoimmune hemolytic anemia), infections (malaria, clostridial infections), toxins, hereditary membrane defects (spherocytosis), or hemoglobin abnormalities (sickle cell anemia).
  • Hypersplenism may exacerbate hemolysis through erythrocyte sequestration in the spleen.
  1. Blood Loss
  • Acute: Trauma, surgery, or massive gastrointestinal or obstetric hemorrhage.
  • Chronic: Peptic ulcer disease, erosive gastritis, colorectal cancer, parasitic infections (hookworm), menorrhagia, or hemorrhoidal bleeding.

Clinical Presentation
Low hemoglobin levels cause tissue hypoxia, manifesting as:
  • Generalized fatigue and weakness
  • Dyspnea on exertion or at rest (in severe cases)
  • Pallor of skin, mucous membranes, and conjunctiva
  • Tachycardia or palpitations
  • Dizziness or presyncope
  • Cognitive impairment (reduced concentration, memory)
Iron deficiency anemia may present with:
  • Koilonychia (spoon-shaped nails)
  • Cheilitis, glossitis
  • Pica (craving non-food items like chalk or clay)

Megaloblastic anemia may include neurological symptoms (paresthesia, ataxia) due to vitamin B12 deficiency. Hemolytic anemias are characterized by jaundice, splenomegaly, and dark urine.
In children, anemia may lead to growth retardation, poor academic performance, and behavioral issues. A study in The Lancet Global Health (2021) linked chronic anemia in children to impaired neurocognitive development.

Diagnosis
Diagnosis begins with a complete blood count (CBC), which confirms low hemoglobin, erythrocyte count, and hematocrit. Key parameters for differential diagnosis include:
  • Mean Corpuscular Volume (MCV):
  • Microcytic anemia (MCV <80 fL): IDA, thalassemia.
  • Normocytic anemia (MCV 80–100 fL): ACD, acute blood loss, hemolysis.
  • Macrocytic anemia (MCV >100 fL): B12/folate deficiency, myelodysplastic syndrome.
  • Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC) refine the anemia type.
  • Reticulocyte Count: Elevated in hemolysis or post-hemorrhagic recovery; low in hypoproliferative states.
Additional tests include:
  • Iron Deficiency Anemia: Low serum iron (<10 µmol/L), ferritin (<30 µg/L), and elevated total iron-binding capacity (TIBC).
  • Megaloblastic Anemia: Low vitamin B12 (<200 pg/mL) or folate, elevated homocysteine, and methylmalonic acid.
  • Hemolysis: Elevated lactate dehydrogenase (LDH), indirect bilirubin, low haptoglobin, and positive Coombs test in autoimmune cases.
  • Anemia of Chronic Disease: Normal or elevated ferritin, low transferrin, elevated C-reactive protein (CRP).
  • Bone Marrow Examination: Indicated for suspected aplastic anemia, myelodysplastic syndrome, or leukemia.
Differential diagnosis requires excluding thalassemia (hemoglobin electrophoresis), chronic infections, malignancies, and endocrine disorders (hypothyroidism, hypocortisolism).

Complications
Untreated anemia may lead to:
  • Cardiovascular Complications: Hypoxia and increased cardiac workload elevate the risk of heart failure, particularly in elderly patients (European Heart Journal, 2020).
  • Immune Dysfunction: Chronic anemia increases susceptibility to infections.
  • Pregnancy Complications: Anemia is associated with preterm delivery, low birth weight, and maternal mortality (American Journal of Obstetrics and Gynecology, 2021).
  • Neurological Impairment: Prolonged vitamin B12 deficiency may cause irreversible neuropathy.

Management
Treatment targets the underlying cause, restores hemoglobin levels, and prevents recurrence.
  1. Iron Deficiency Anemia
  • Iron Supplementation: Oral iron (ferrous sulfate, ferrous fumarate, or chelated forms) at 100–200 mg elemental iron daily. Parenteral iron (ferric carboxymaltose, iron sucrose) is indicated for malabsorption or intolerance to oral forms.
  • Dietary Recommendations: Include heme iron sources (red meat, liver) and non-heme iron (legumes, spinach) with vitamin C to enhance absorption.
  • Treatment duration: 3–6 months until ferritin normalizes.

Megaloblastic Anemia
  • Vitamin B12 Deficiency: Intramuscular cyanocobalamin (1000 µg/day for 1–2 weeks, then 1000 µg/month lifelong for pernicious anemia).
  • Folate Deficiency: Oral folic acid 1–5 mg/day for 1–4 months.

Anemia of Chronic Disease
  • Treat the underlying condition (anti-inflammatory therapy, chemotherapy).
  • Erythropoiesis-stimulating agents (epoetin alfa) are used in chronic kidney disease.
  • Iron metabolism correction with chelators may be considered.

Hemolytic Anemia
  • Immunosuppressive therapy (glucocorticoids, rituximab) for autoimmune causes.
  • Splenectomy for hypersplenism or hereditary spherocytosis.
  • Supportive care with folic acid supplementation.

Blood Loss
  • Address the bleeding source (endoscopic treatment of ulcers, gynecologic interventions).
  • Severe cases may require red blood cell transfusion.

Prevention
  • Diet: Ensure adequate intake of iron, vitamin B12, and folate.
  • Screening: Regular CBC in high-risk groups (pregnant women, children, patients with chronic diseases).
  • Management of Chronic Conditions: Timely treatment of gastrointestinal, gynecologic, or oncologic disorders.
  • Prophylactic Therapy: Iron or vitamin B12 supplementation for at-risk populations (pregnant women, post-bariatric surgery patients).

Recommendations for Clinicians
  1. Differential Diagnosis: Consider multiple etiologies and avoid empiric iron therapy without confirmed deficiency to prevent iron overload.
  2. Monitoring: Assess hemoglobin, ferritin, and reticulocyte counts 4–6 weeks after initiating therapy.
  3. Multidisciplinary Approach: Involve hematologists, gastroenterologists, or geneticists for complex cases (hemolysis, aplastic anemia).
  4. Patient Education: Emphasize adherence to treatment and dietary recommendations to prevent recurrence.

Conclusion
Low hemoglobin is a clinical marker requiring thorough investigation to identify the underlying cause. Modern management involves targeted therapy based on precise diagnostics, addressing the etiology, and preventing complications. Clinicians should employ evidence-based algorithms to ensure personalized care, improving patient outcomes and quality of life.

References:
  1. World Health Organization. Anaemia. (accessed: April 18, 2025).
  2. Kassebaum, N. J., et al. (2021). The global burden of anemia. The Lancet Global Health.
  3. Camaschella, C. (2019). Iron-deficiency anemia. New England Journal of Medicine, 380(19), 1832–1843.
  4. Bunn, H. F. (2020). Approach to the anemias. Harrison’s Principles of Internal Medicine, 20th ed.
  5. National Institutes of Health. Vitamin B12 Deficiency Anemia.
  6. Lopez, A., et al. (2021). Maternal anemia and adverse pregnancy outcomes. American Journal of Obstetrics and Gynecology.