What is the diagnosis and management plan for a 51-year-old post-cholecystectomy (gallbladder removal surgery) woman with jaundice, anemia, splenomegaly (enlarged spleen), hemolytic anemia (elevated indirect bilirubin, reticulocytosis, and anisocytes on peripheral blood smear (PBS)), normal liver function tests (LFTs), and a negative direct Coombs test?

Diagnosis: Hereditary Red Blood Cell Enzymopathy (Most Likely Pyruvate Kinase Deficiency)

This patient's presentation of microcytic anemia with hemolysis, negative Coombs test, splenomegaly, and post-cholecystectomy status strongly suggests hereditary red blood cell enzymopathy, specifically pyruvate kinase (PK) deficiency, which requires confirmatory enzyme assays and specialist hematology evaluation. 1

Key Diagnostic Features Supporting Enzymopathy

The combination of findings points away from acquired causes:

• Negative direct Coombs test definitively excludes autoimmune hemolytic anemia, which would be the primary consideration in most hemolytic cases 1, 2
• Microcytic anemia (MCV 70) with hemolysis is highly unusual and characteristic of PK deficiency rather than typical hemolytic anemias 1
• Indirect hyperbilirubinemia (17 mg/dl) with normal direct bilirubin and normal LFTs confirms extravascular hemolysis without hepatocellular dysfunction 1, 3
• Reticulocytosis (6%) with anisocytes indicates active bone marrow compensation for hemolysis 3, 4
• Splenomegaly reflects chronic extravascular hemolysis through the mononuclear-phagocytic system 4
• Post-cholecystectomy status suggests chronic hemolysis leading to pigment gallstone formation, a known complication of hereditary hemolytic anemias 5

Essential Immediate Investigations

Confirm Hemolysis (Priority 1)

• Lactate dehydrogenase (LDH) - expect elevation with predominance of LDH1 1, 6, 3
• Haptoglobin - expect decreased or undetectable levels 1, 3, 4
• Peripheral blood smear review by hematopathologist - look for specific red cell morphology beyond anisocytes 1, 3

Identify Specific Enzymopathy (Priority 2)

• Pyruvate kinase enzyme activity assay by spectrophotometry - this is the reference standard, with activity typically <20% of normal in PK deficiency 1
• Glucose-6-phosphate dehydrogenase (G6PD) assay - though less likely given microcytosis, G6PD deficiency can cause hemolysis 3, 5
• Complete red blood cell enzyme panel if initial tests are negative 1

Exclude Hemoglobinopathies (Priority 3)

• Hemoglobin electrophoresis at pH 7.1 - to exclude hemoglobin M variants and unstable hemoglobin variants 1
• High-performance liquid chromatography (HPLC) - for comprehensive hemoglobin analysis 5

Rule Out Acquired Causes (Priority 4)

• Viral hepatitis serologies (HAV IgM, HBsAg, anti-HCV, HEV) - hepatitis A can rarely cause acute hemolysis with similar presentation 6
• Autoimmune markers (ANA, anti-smooth muscle antibody) - though Coombs negative, some autoimmune conditions can present atypically 2

Differential Diagnoses in Order of Likelihood

1. Pyruvate kinase deficiency - microcytic hemolytic anemia with negative Coombs, splenomegaly, and history of gallstones is pathognomonic 1, 5

2. Other red blood cell enzymopathies - less common but possible (hexokinase deficiency, phosphofructokinase deficiency) 5

3. Unstable hemoglobin variants - can present with chronic hemolysis and methemoglobinemia 1

4. Hereditary spherocytosis - though typically normocytic, can occasionally present with microcytosis; family history would be supportive 3, 5

5. Acute viral hepatitis with hemolysis - hepatitis A can cause hemolysis with negative Coombs, but normal LFTs make this unlikely 6

Management Plan

Immediate Supportive Care

• Folic acid supplementation (1-5 mg daily) to support increased erythropoiesis from chronic hemolysis 1
• Monitor hemoglobin closely - transfuse packed red blood cells if hemoglobin drops below 7 g/dl or patient becomes symptomatic 7
• Screen for iron overload with ferritin and transferrin saturation, as chronic hemolysis and potential transfusions increase risk 1

Specialist Referral

• Urgent hematology consultation for definitive diagnosis and long-term management planning 1
• Genetic counseling once diagnosis is confirmed, as these are inherited conditions 5

Definitive Treatment Considerations (After Diagnosis)

• Splenectomy may be curative or significantly reduce transfusion requirements in PK deficiency, though this requires specialist evaluation of risks versus benefits 1, 5
• Avoid oxidative stressors if G6PD deficiency is identified (certain drugs, fava beans) 3, 5
• Consider emerging therapies such as PK activators or gene therapy if available through clinical trials 1

Critical Pitfalls to Avoid

• Do not assume this is autoimmune hemolytic anemia despite hemolysis - the negative Coombs test and microcytosis exclude this diagnosis 1, 2
• Do not attribute jaundice to post-cholecystectomy complications - the cholecystectomy was likely performed for pigment stones from chronic hemolysis, not the cause of current presentation 1, 5
• Do not delay enzyme assays - these must be performed before transfusion, as transfused cells will dilute the patient's abnormal enzyme levels and cause false-negative results 1
• Do not overlook viral hepatitis - though less likely with normal LFTs, hepatitis A can cause acute hemolysis superimposed on chronic hemolytic anemia 6