What are the causes of decreased hemoglobin in patients with various medical histories, including heavy menstrual bleeding, cancer, or chronic kidney disease?

Causes of Decreased Hemoglobin

Decreased hemoglobin results from three primary mechanisms: deficient red blood cell production, excessive destruction, or blood loss, with the specific etiology varying by patient population and clinical context. 1

Production Defects

Nutritional Deficiencies

• Iron deficiency is the most common cause of microcytic anemia globally, resulting from inadequate dietary intake, malabsorption (celiac disease, post-bariatric surgery, atrophic gastritis), or chronic blood loss 2, 3
• Iron deficiency affects approximately 38% of nonpregnant reproductive-age women without anemia and 13% with anemia in high-income countries 3
• Vitamin B12 and folate deficiencies impair DNA synthesis in rapidly dividing erythroid precursors, causing macrocytic anemia 4, 2
• These deficiencies commonly occur with alcohol use, thyroid disease, malabsorption syndromes, and certain medications (hydroxyurea, antiretrovirals) 2

Chronic Kidney Disease

• CKD causes anemia primarily through decreased erythropoietin production by damaged kidneys, with prevalence ranging from 24-85% depending on disease severity 4, 3
• The anemia of CKD is typically normochromic and normocytic 4
• Anemia prevalence increases as glomerular filtration rate declines, though this reflects disease pathology rather than normal aging 4

Bone Marrow Disorders

• Bone marrow infiltration by cancer cells directly suppresses hematopoiesis, affecting red blood cell production 5
• Myelodysplastic syndromes cause ineffective production of multiple cell lines 5, 1
• Aplastic anemia represents complete bone marrow failure 1
• Hematologic malignancies (leukemia, lymphoma, myeloma) suppress normal marrow function 5, 2

Anemia of Chronic Disease

• Chronic inflammatory conditions (inflammatory bowel disease, rheumatologic disorders, cancer) cause anemia through inflammatory cytokines that sequester iron and suppress erythropoiesis 4, 6
• This is the second most common type of anemia worldwide after iron deficiency 6
• Characterized by low iron and transferrin but elevated ferritin, distinguishing it from iron deficiency anemia 6

Blood Loss

Menstrual Bleeding

• Heavy menstrual bleeding causes iron losses averaging 0.3-0.5 mg/day and represents a leading cause of iron deficiency in reproductive-age women 4
• Severe anemia (hemoglobin <5 g/dL) from chronic menstrual blood loss occurs when women fail to recognize the severity or delay seeking treatment, with two-thirds experiencing heavy bleeding for more than 6 months before presentation 7
• Leiomyomas account for 47.9% of cases requiring transfusion for menstrual bleeding 7

Gastrointestinal Bleeding

• A gastrointestinal bleeding source is identified in 60-70% of patients with iron deficiency anemia referred for endoscopy 2
• Nonsteroidal anti-inflammatory drug use increases bleeding risk 3
• Occult bleeding should be excluded before attributing anemia solely to other causes 8

Hemolysis and Destruction

• Autoimmune hemolytic anemia causes accelerated red blood cell destruction 1
• Hereditary conditions include spherocytosis, enzyme deficiencies, hemoglobinopathies, and thalassemia 2, 1
• Paroxysmal nocturnal hemoglobinuria represents complement-mediated hemolysis 1
• Hypersplenism causes sequestration and destruction of red blood cells 4

Cancer-Related Causes

• Cancer causes anemia through multiple mechanisms: bone marrow infiltration, inflammatory cytokines causing iron sequestration, and treatment-related myelosuppression 4, 5, 9
• Chemotherapy directly impairs bone marrow hematopoiesis, with anemia rates increasing from 19.5% in cycle 1 to 46.7% by cycle 5 9
• Platinum-based regimens are particularly myelosuppressive due to combined bone marrow and kidney toxicity 9
• Cancer affects 18-82% of patients with iron deficiency, depending on tumor type 3

Special Populations

Pregnancy

• Hemoglobin decreases during first and second trimesters primarily from dilutional effects of expanding blood volume, with iron deficiency affecting up to 84% of pregnant women in the third trimester 4, 3
• Hemoglobin cutoffs for anemia in pregnancy are lower: 11.0 g/dL in first trimester, 10.5 g/dL in second trimester, and 11.0 g/dL in third trimester 4

Inflammatory Bowel Disease

• IBD causes anemia in 13-90% of patients through chronic inflammation, malabsorption, and occult bleeding 3

Heart Failure

• Heart failure is associated with anemia in 37-61% of patients, worsening symptoms and prognosis 3

Diagnostic Approach

Begin with complete blood count including mean corpuscular volume to classify anemia as microcytic, normocytic, or macrocytic 2, 1

For Microcytic Anemia

• Measure serum ferritin (typically <30 ng/mL indicates iron deficiency in non-inflammatory states) and transferrin saturation (<20% suggests iron deficiency) 4, 3
• In inflammatory conditions, ferritin may be falsely elevated; use transferrin saturation as primary marker 4, 6

For Normocytic Anemia

• Check reticulocyte count: low count suggests production defect, elevated count suggests hemolysis or blood loss 4, 1
• Evaluate renal function (creatinine, estimated GFR) to assess for CKD 4
• Consider bone marrow examination if hematologic malignancy suspected 4

For Macrocytic Anemia

• Measure vitamin B12 and folate levels 2, 1
• Review medication list for causative agents 2

Critical Pitfalls

• Do not assume anemia is a normal consequence of aging in elderly men; it reflects underlying disease and increased mortality risk 4
• Correct or exclude all reversible causes (vitamin deficiency, bleeding, inflammatory conditions) before initiating erythropoiesis-stimulating agents 8
• In patients with CKD not responding to iron supplementation over 12 weeks, increasing doses further is unlikely to help and may increase cardiovascular risks 8
• Always evaluate iron stores before and during treatment, as the majority of CKD patients require supplemental iron during erythropoiesis-stimulating agent therapy 8
• Consider medication review as a potentially reversible cause before pursuing extensive workup 5