What is the most likely diagnosis and recommended work‑up for a patient with mild‑to‑moderate anemia (hematocrit 36.2%), high reticulocyte count (~119 % or 119 ×10⁹/L), borderline macrocytosis (mean corpuscular volume 99 fL), mean corpuscular hemoglobin concentration 307 g/L, red cell distribution width 14.7 %, low serum iron (8 µmol/L), low transferrin saturation (13 %), low‑normal ferritin (44 µg/L), low‑normal total iron‑binding capacity (61 µmol/L), elevated aspartate aminotransferase (94 U/L) and alanine aminotransferase (77 U/L), and normal platelets (169 ×10⁹/L)?

Hemolytic Anemia with Possible Underlying Iron Deficiency or Chronic Liver Disease

This patient has an elevated reticulocyte count (119 ×10⁹/L) indicating active red‑cell production or destruction, combined with borderline macrocytosis (MCV 99 fL), low iron parameters (serum iron 8 µmol/L, transferrin saturation 13 %), and elevated transaminases (AST 94 U/L, ALT 77 U/L), pointing most likely to hemolytic anemia with concurrent iron deficiency or anemia of chronic disease related to liver dysfunction. 1

Interpretation of Key Laboratory Findings

Reticulocyte Count and Bone‑Marrow Response

• An elevated absolute reticulocyte count signals either active hemolysis or recent blood loss with an appropriate marrow response, distinguishing this presentation from pure iron‑deficiency anemia, which typically shows a low or inappropriately normal reticulocyte count. 2
• The reticulocyte elevation here (~119 ×10⁹/L) is the single most important clue that red‑cell destruction or acute bleeding is driving the anemia, rather than impaired erythropoiesis alone. 2

Iron Studies in the Context of Inflammation or Hemolysis

• Serum iron 8 µmol/L and transferrin saturation 13 % confirm insufficient circulating iron for erythropoiesis, meeting the threshold of < 16–20 % that indicates iron deficiency. 1, 3
• Ferritin 44 µg/L sits in the borderline range (30–100 µg/L); in the presence of inflammation or liver disease, ferritin can be falsely elevated, so this value does not exclude true iron deficiency. 4, 1
• Total iron‑binding capacity (TIBC) 61 µmol/L is low‑normal, which is atypical for pure iron deficiency (where TIBC is usually elevated) and instead suggests anemia of chronic disease or a mixed picture. 1, 3

Elevated Transaminases and Liver Involvement

• AST 94 U/L and ALT 77 U/L indicate hepatocellular injury; chronic liver disease is a well‑recognized cause of anemia through multiple mechanisms, including hemolysis, splenic sequestration, and impaired erythropoietin production. 5
• Ferritin is synthesized in the liver and rises as an acute‑phase reactant in hepatic inflammation, so the ferritin of 44 µg/L may underestimate the severity of iron depletion. 1, 3

Borderline Macrocytosis (MCV 99 fL) and RDW 14.7 %

• MCV 99 fL is at the upper limit of normal and can reflect early vitamin B12 or folate deficiency, alcohol‑related macrocytosis, or reticulocytosis itself (reticulocytes are larger than mature red cells). 2
• RDW 14.7 % is mildly elevated, suggesting a mixed population of red cells—consistent with concurrent iron deficiency (which produces microcytes) and reticulocytosis (which produces larger cells). 1, 6

Most Likely Diagnosis

The combination of elevated reticulocyte count, low iron/transferrin saturation, borderline‑low ferritin, elevated transaminases, and borderline macrocytosis points to hemolytic anemia (or recent acute blood loss) with underlying iron deficiency and possible chronic liver disease. 1, 2, 5

Alternative or coexisting diagnoses include:

• Anemia of chronic disease secondary to liver dysfunction, where ferritin > 100 µg/L and transferrin saturation < 20 % would be expected; however, this patient's ferritin is only 44 µg/L, making pure anemia of chronic disease less likely. 3, 5
• Combined iron and vitamin B12/folate deficiency, which can normalize the MCV but produce an elevated RDW; the borderline macrocytosis here warrants checking B12 and folate levels. 2

Recommended Diagnostic Work‑Up

Immediate Laboratory Tests

1. Hemolysis panel:

   • Measure haptoglobin (low in hemolysis), lactate dehydrogenase (LDH; elevated in hemolysis), and indirect bilirubin (elevated in hemolysis). 2
   • Examine a peripheral blood smear for schistocytes, spherocytes, or other morphologic clues to red‑cell destruction. 2
   • Perform a direct antiglobulin (Coombs) test to identify autoimmune hemolytic anemia. 2

2. Vitamin B12 and folate levels:

   • Measure serum B12 and folate to exclude megaloblastic anemia, which can coexist with iron deficiency and produce a mixed micro‑ and macrocytic picture. 2
   • Chronic liver disease and alcohol use are both risk factors for folate deficiency. 2

3. C‑reactive protein (CRP):

   • Obtain CRP to assess for inflammation, which can falsely elevate ferritin and confound the interpretation of iron stores. 1, 3
   • If CRP is elevated, a ferritin up to 100 µg/L may still indicate iron deficiency. 4, 1

4. Reticulocyte hemoglobin content (CHr) if available:

   • CHr is an early marker of iron‑deficient erythropoiesis, less affected by inflammation than ferritin, and can confirm functional iron deficiency even when ferritin appears borderline. 7

Evaluation of Liver Disease

• Obtain a complete hepatic panel (including albumin, bilirubin fractionation, prothrombin time/INR, and gamma‑glutamyl transferase) to assess the severity and chronicity of liver dysfunction. 5
• Consider abdominal ultrasound or other imaging to evaluate for cirrhosis, portal hypertension, and splenomegaly, all of which can contribute to hemolysis and anemia. 5

Investigation for Blood Loss

• Even with an elevated reticulocyte count suggesting hemolysis, occult gastrointestinal bleeding must be excluded, especially given the low iron and transferrin saturation. 1
• In adults with confirmed iron deficiency (transferrin saturation < 16 %), upper endoscopy with duodenal biopsies and colonoscopy are mandatory to rule out GI malignancy, celiac disease, and other sources of chronic blood loss. 1
• The elevated transaminases and possible liver disease raise the risk of portal hypertensive gastropathy or esophageal varices as bleeding sources. 5

Additional Testing if Initial Work‑Up Is Nondiagnostic

• If the hemolysis panel is negative and no bleeding source is identified, consider flow cytometry for paroxysmal nocturnal hemoglobinuria, a disseminated intravascular coagulation panel, and screening for viral hepatitis or other infections. 2
• Bone‑marrow examination may be warranted if pancytopenia develops or if the diagnosis remains unclear after comprehensive testing. 2

Treatment Approach Pending Diagnostic Confirmation

Iron Supplementation

• Initiate oral iron therapy (e.g., ferrous sulfate 325 mg once to three times daily) immediately while the diagnostic work‑up proceeds, because transferrin saturation < 16 % confirms iron‑deficient erythropoiesis. 1, 2
• Monitor hemoglobin after 2 weeks; a rise of ≥ 10 g/L confirms that iron deficiency is contributing to the anemia. 1
• If oral iron is not tolerated or malabsorption is suspected (e.g., celiac disease, inflammatory bowel disease), switch to intravenous iron (iron sucrose or ferric gluconate) with an expected hemoglobin increase of at least 2 g/dL within 4 weeks. 1

Management of Hemolysis

• If autoimmune hemolytic anemia is confirmed by a positive Coombs test, corticosteroids are first‑line therapy. 2
• If hemolysis is secondary to liver disease (e.g., hypersplenism, Zieve syndrome), treatment focuses on managing the underlying hepatic condition. 5

Vitamin Supplementation

• If B12 or folate deficiency is identified, initiate appropriate replacement therapy; however, high‑dose folic acid can mask B12 deficiency, so always check both before starting folate alone. 2

Critical Pitfalls to Avoid

• Do not attribute the anemia solely to iron deficiency when the reticulocyte count is elevated; an elevated reticulocyte count mandates evaluation for hemolysis or acute bleeding. 2
• Do not rely on ferritin alone in the setting of liver disease or inflammation; transferrin saturation < 16 % is a more reliable marker of iron deficiency in this context. 1, 3
• Do not overlook combined deficiencies—iron deficiency can coexist with B12 or folate deficiency, and the borderline macrocytosis here (MCV 99 fL) with elevated RDW suggests a mixed picture. 2
• Do not delay gastrointestinal investigation in an adult with confirmed iron deficiency (transferrin saturation 13 %); occult GI bleeding, including from portal hypertensive sources, must be excluded. 1
• Do not assume that elevated transaminases are incidental; chronic liver disease is a well‑recognized cause of anemia through hemolysis, splenic sequestration, and impaired erythropoietin production. 5