What is the most likely diagnosis and appropriate work‑up for anemia with elevated lactate dehydrogenase, high ferritin, normal reticulocyte count, and low hemoglobin/hematocrit?

Differential Diagnosis and Work-Up

The combination of elevated LDH, high ferritin, normal reticulocyte count, and low hemoglobin points most strongly toward anemia of chronic disease, myelodysplastic syndrome, or a mixed deficiency state—not hemolysis—because hemolysis would produce reticulocytosis. 1, 2, 3

Initial Diagnostic Algorithm

Step 1: Confirm Anemia and Classify by MCV

• Obtain a complete blood count with MCV, MCH, and red cell distribution width (RDW) to determine whether the anemia is microcytic, normocytic, or macrocytic. 1, 2, 3
• Measure absolute reticulocyte count to differentiate production failure (low/normal count) from destruction or loss (elevated count). 1, 2, 3
• A normal or low reticulocyte count with anemia excludes hemolysis as the primary mechanism, despite elevated LDH, and instead suggests bone marrow failure, nutritional deficiency, or chronic disease. 1, 3, 4, 5

Step 2: Assess Inflammation and Iron Status

• Measure C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) immediately, because ferritin is an acute-phase reactant and can be falsely elevated in inflammation. 1, 2
• Calculate transferrin saturation (TSAT) as (serum iron × 100) ÷ total iron-binding capacity; a TSAT < 20 % confirms iron deficiency even when ferritin is elevated up to 100 µg/L in the setting of inflammation. 1, 2
• Ferritin > 100 µg/L with TSAT < 20 % and elevated CRP/ESR defines anemia of chronic disease with functional iron deficiency. 2
• Ferritin 30–100 µg/L with TSAT < 20 % and elevated CRP/ESR indicates a mixed picture of true iron deficiency plus anemia of chronic disease. 2

Step 3: Evaluate for Nutritional Deficiencies

• Measure serum vitamin B12 and folate (or red blood cell folate) to exclude megaloblastic anemia, especially if MCV is elevated or high-normal. 1
• Vitamin B12 < 150 pmol/L (≈203 pg/mL) confirms deficiency; if borderline (180–350 pg/mL), measure methylmalonic acid (MMA > 271 nmol/L confirms functional B12 deficiency). 1
• Always treat vitamin B12 deficiency before or simultaneously with folate supplementation to prevent irreversible subacute combined degeneration of the spinal cord. 1, 6

Step 4: Rule Out Myelodysplastic Syndrome and Bone Marrow Pathology

• If no obvious nutritional or inflammatory cause is identified, proceed with bone marrow aspiration and biopsy with cytogenetic analysis to evaluate for myelodysplastic syndrome (MDS), especially if there is pancytopenia, macrocytosis, or refractory anemia. 1
• Refer to hematology if leucopenia and/or thrombocytopenia are present alongside unexplained anemia, as this raises suspicion for primary marrow disease. 1

Step 5: Consider Medication-Induced Macrocytosis

• Review the medication list for hydroxyurea, methotrexate, azathioprine, or PARP inhibitors, which can cause macrocytic anemia with normal or low reticulocyte count. 1
• PARP inhibitors may produce MCV > 105 fL independent of vitamin B12 status; management includes temporary discontinuation, dose reduction, and hematology consultation if cytopenias persist. 1

Step 6: Assess Thyroid and Renal Function

• Check TSH (and free T4 if TSH is abnormal) to exclude hypothyroidism, which can cause macrocytic anemia. 1
• Measure serum creatinine and estimated glomerular filtration rate (eGFR) to identify chronic kidney disease, which typically causes normocytic anemia but can coexist with other deficiencies. 1, 2

Why Hemolysis Is Unlikely Despite Elevated LDH

• Hemolysis characteristically produces reticulocytosis (elevated reticulocyte count), decreased haptoglobin, increased unconjugated bilirubin, and often schistocytes on peripheral smear. 4, 5
• A normal reticulocyte count effectively excludes active hemolysis as the primary cause of anemia, even when LDH is elevated. 1, 3, 4, 5
• LDH can be elevated in tissue breakdown, malignancy, liver disease, and ineffective erythropoiesis (as in MDS or megaloblastic anemia) without hemolysis. 7
• Rare cases of autoimmune hemolytic anemia with normal LDH have been reported, but these still present with reticulocytosis and low haptoglobin. 8

Critical Pitfalls to Avoid

• Do not assume elevated ferritin indicates adequate iron stores when inflammation is present; always calculate TSAT to assess functional iron availability. 1, 2
• Do not attribute anemia solely to chronic disease when ferritin is 30–100 µg/L and TSAT < 20 %; true iron deficiency may coexist and require treatment. 2
• Do not start folate supplementation before confirming and treating vitamin B12 deficiency, as folate can correct the anemia but allow irreversible neurological damage to progress. 1, 6
• Do not overlook MDS in older adults with unexplained macrocytic or normocytic anemia and normal or low reticulocyte count; bone marrow evaluation is indicated when nutritional causes are excluded. 1
• Do not rely on LDH alone to diagnose hemolysis; reticulocyte count, haptoglobin, and peripheral smear are essential to confirm red cell destruction. 4, 5

Recommended Laboratory Panel

Test	Purpose
Complete blood count with MCV, MCH, RDW	Classify anemia and detect coexisting deficiencies [1,2,3]
Absolute reticulocyte count	Differentiate production failure from hemolysis [1,3,4,5]
Serum ferritin	Assess iron stores (interpret with CRP) [1,2]
Transferrin saturation (TSAT)	Confirm iron deficiency when ferritin is 30–100 µg/L [1,2]
C-reactive protein (CRP) and ESR	Identify inflammation that elevates ferritin [1,2]
Serum vitamin B12 and folate	Exclude megaloblastic anemia [1]
Methylmalonic acid (if B12 borderline)	Confirm functional B12 deficiency [1]
TSH (and free T4 if abnormal)	Rule out hypothyroidism [1]
Serum creatinine and eGFR	Assess chronic kidney disease [1,2]
Peripheral blood smear	Identify dysplastic cells, schistocytes, or abnormal morphology [1,4,5]
Haptoglobin, unconjugated bilirubin (if hemolysis suspected)	Confirm hemolysis only if reticulocytes are elevated [4,5]