What are the causes and treatment options for low hemoglobin in a patient?

Causes of Low Hemoglobin

Low hemoglobin results from three primary mechanisms: decreased red blood cell production, increased red blood cell destruction, or blood loss—with iron deficiency being the most common cause globally, followed by chronic disease/inflammation, nutritional deficiencies, bone marrow disorders, and bleeding. 1, 2, 3

Primary Mechanisms and Specific Causes

Decreased Red Blood Cell Production

Nutritional Deficiencies:

• Iron deficiency is the most common cause of microcytic anemia, affecting approximately 2 billion people worldwide and 14% of US adults 3
• Vitamin B12 and folate deficiency cause macrocytic anemia and should be measured when mean corpuscular volume (MCV) is elevated 4, 2
• In inflammatory bowel disease, vitamin B12 and folate levels should be measured at least annually, especially after ileal resection 4

Chronic Disease/Inflammation:

• Anemia of chronic disease occurs with inflammatory conditions including chronic kidney disease (24-85% prevalence), heart failure (37-61%), inflammatory bowel disease (13-90%), and cancer (18-82%) 3
• This anemia is characterized by low serum iron (<60 μg/dL) but elevated ferritin (>50 ng/mL), distinguishing it from iron deficiency 5
• Renal insufficiency causes anemia through blunted erythropoietin production and should be suspected when creatinine >1.5 g/dL 4

Bone Marrow Disorders:

• Bone marrow infiltration by malignancy directly suppresses hematopoiesis 4, 1
• Myelodysplastic syndromes and multiple myeloma can cause anemia 4, 2
• Drug-induced bone marrow toxicity, particularly from azathioprine and 6-mercaptopurine, can cause pancytopenia, leukopenia, and pure red cell aplasia 4

Increased Red Blood Cell Destruction (Hemolysis)

• Autoimmune hemolytic anemia should be evaluated with Coombs testing, particularly in patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or autoimmune disease history 4
• Drug-induced hemolysis can occur with certain medications 4, 1
• Hemolysis from cardiac valve replacements or formaldehyde exposure can cause dramatic resistance to treatment 4

Blood Loss

• Gastrointestinal bleeding is found in 60-70% of patients with iron deficiency anemia referred for endoscopy 2
• Menstrual bleeding is a leading cause in women of reproductive age, with 38% having iron deficiency without anemia and 13% having iron-deficiency anemia 3
• Heavy menstrual bleeding (menometrorrhagia) can lead to critically severe anemia 6
• Occult blood loss should be assessed through stool and urine examination 4

Diagnostic Thresholds

Anemia is diagnosed when hemoglobin falls below:

• <13.5 g/dL in adult males 4
• <12.0 g/dL in adult females 4

Severity classification:

• Mild: Hb ≤11.9 and ≥10 g/dL 4
• Moderate: Hb ≤9.9 and ≥8.0 g/dL 4
• Severe: Hb <8.0 g/dL 4

Essential Diagnostic Workup

Initial laboratory evaluation must include:

• Complete blood count with reticulocyte count and MCV 4, 1
• Peripheral blood smear examination 4
• Iron studies: serum iron, total iron binding capacity, ferritin, and transferrin saturation 4, 1
• Vitamin B12 and folate levels 4, 1
• Renal function assessment (creatinine, GFR) 4
• C-reactive protein to assess for inflammation 4

Additional testing when indicated:

• Coombs test for suspected hemolysis in lymphoproliferative disorders 4
• Endogenous erythropoietin levels in myelodysplasia 4
• Stool guaiac and endoscopy for gastrointestinal bleeding 4
• Bone marrow examination if malignancy or infiltrative process suspected 4

Treatment Approach Based on Cause

Iron Deficiency Anemia

Oral iron is first-line therapy:

• Ferrous sulfate 325 mg daily (containing 65 mg elemental iron) or on alternate days 7, 3
• Do not crush or chew tablets 7

Intravenous iron is indicated for:

• Oral iron intolerance or malabsorption (celiac disease, post-bariatric surgery) 3
• Chronic inflammatory conditions (CKD, heart failure, IBD, cancer) 3
• Ongoing blood loss 3
• Second and third trimesters of pregnancy 3
• Inflammatory bowel disease patients should receive IV iron supplementation following blood transfusions 4

Vitamin Deficiencies

• Vitamin B12 and folate deficiencies must be treated to avoid anemia, with oral vitamin B12 being as effective as intramuscular administration 4, 2

Anemia of Chronic Disease

• Optimize treatment of the underlying inflammatory condition first before considering erythropoiesis-stimulating agents (ESAs) 4
• ESAs may be considered for patients with insufficient response to IV iron and optimized disease therapy, targeting hemoglobin not above 12 g/dL 4

Severe Anemia Requiring Transfusion

Red blood cell transfusion should be considered when:

• Hemoglobin <7 g/dL 4
• Hemoglobin >7 g/dL if symptoms or particular risk factors present 4
• Hemodynamic instability or severe acute anemia 4

Critical caveat: Blood transfusions should be followed by subsequent intravenous iron supplementation, as transfusions do not correct underlying pathology and have no lasting effect 4

Common Pitfalls to Avoid

• Do not assume normal ferritin excludes iron deficiency in inflammatory states—inflammation falsely elevates ferritin; use transferrin saturation <20% as additional criterion 4, 3
• Do not overlook renal insufficiency—it was present in 31% of anemia of chronic disease patients and 20% of other anemic patients in one series 5
• Do not use ESAs in cancer patients not receiving chemotherapy—increased risk of death when targeting Hb of 12 g/dL 4
• Do not neglect to identify and treat underlying causes before initiating ESA therapy 4