What are the causes of low hemoglobin levels?

Causes of Low Hemoglobin

Low hemoglobin levels can be caused by decreased production of red blood cells, increased destruction of red blood cells, or blood loss, with specific etiologies requiring targeted evaluation and treatment. 1

Pathophysiologic Categories of Anemia

The causes of low hemoglobin can be grouped into three main categories:

1. Decreased Production of Red Blood Cells

   • Iron deficiency (ferritin <30 ng/mL, transferrin saturation <15%) 2
   • Vitamin B12 deficiency (may present with macrocytosis) 2, 3
   • Folate deficiency 2
   • Bone marrow suppression/infiltration (cancer, chemotherapy) 1
   • Chronic kidney disease (GFR <60 mL/min/1.73 m²) 1
   • Anemia of chronic disease/inflammation 1, 2
   • Myelodysplastic syndrome 2

2. Increased Destruction of Red Blood Cells

   • Hemolysis (elevated LDH, low haptoglobin) 1, 2
   • Sickle cell disease (HbS production) 4
   • Thalassemias and other hemoglobinopathies 5
   • Enzyme deficiencies (G6PD, pyruvate kinase) 1
   • Autoimmune hemolytic anemia (positive Coombs test) 1
   • Methemoglobinemia (congenital or acquired) 1

3. Blood Loss

   • Acute hemorrhage (trauma, surgery) 1
   • Chronic blood loss:
     • Gastrointestinal bleeding (positive stool guaiac) 1
     • Menstrual losses in women 1
     • Malignancy-related bleeding 1

Specific Causes and Diagnostic Considerations

Iron Deficiency Anemia

• Most common cause of anemia worldwide
• Diagnosed by low ferritin (<30 ng/mL) and low transferrin saturation (<15%) 2
• Common in pregnancy, menstruating women, and with chronic blood loss 6
• Presents with microcytic, hypochromic anemia (low MCV)

Anemia of Chronic Disease/Inflammation

• Second most common cause of anemia
• Associated with chronic infections, inflammatory disorders, and malignancies 7
• Characterized by normal/elevated ferritin with low transferrin saturation 2
• Cytokine-mediated impairment of iron utilization and erythropoiesis 7, 8

Vitamin B12 and Folate Deficiency

• Causes macrocytic anemia (elevated MCV)
• B12 deficiency can result from inadequate intake (strict vegetarians), malabsorption, or pernicious anemia 3
• Folate deficiency often due to poor dietary intake, increased requirements, or malabsorption 2
• May present with neurological symptoms in B12 deficiency 3

Chronic Kidney Disease

• Decreased erythropoietin production leads to anemia 1
• Severity correlates with degree of renal dysfunction
• Often normocytic, normochromic anemia

Hemoglobinopathies

• Inherited disorders affecting hemoglobin structure or production 5
• Include sickle cell disease, thalassemias
• More prevalent in malaria-endemic regions 5
• Can cause hemolytic anemia or impaired hemoglobin production

Cancer-Related Anemia

• Multifactorial: bone marrow infiltration, chronic inflammation, nutritional deficiencies, bleeding 1, 7
• Chemotherapy can cause myelosuppression 1
• Reduced erythropoietin production relative to degree of anemia 8

Special Considerations

Altitude Adjustment

• Hemoglobin levels increase with altitude (approximately 0.6 g/dL in women and 0.9 g/dL in men for each 1,000m above sea level) 1
• Threshold for defining anemia should be adjusted upward at high altitudes

Age and Sex Variations

• Lower normal hemoglobin values in women compared to men 1
• Children have age-dependent normal ranges 1
• Older adults should not have anemia attributed to age alone 1

Diagnostic Approach

Initial evaluation of low hemoglobin should include:

• Complete blood count with red cell indices (MCV, MCH, RDW)
• Reticulocyte count (to assess bone marrow response)
• Peripheral blood smear examination
• Iron studies (ferritin, transferrin saturation)
• Inflammatory markers (CRP)
• Additional tests based on clinical suspicion:
  • B12 and folate levels
  • Hemolysis panel (LDH, haptoglobin, bilirubin)
  • Renal function tests
  • Stool guaiac testing 1, 2

Common Pitfalls to Avoid

• Failing to investigate the cause of anemia, even if mild
• Overlooking iron deficiency when ferritin is falsely elevated due to inflammation
• Relying solely on MCV to rule out vitamin B12 deficiency (can miss up to 84% of cases) 2
• Neglecting to consider multiple concurrent causes of anemia
• Attributing anemia to age alone in elderly patients 1
• Missing macrocytosis in non-anemic patients, which may indicate early B12/folate deficiency 2

Understanding the specific cause of low hemoglobin is essential for appropriate management and preventing complications related to untreated anemia.