What is the most likely diagnosis for a patient with an elevated red‑blood cell count (RBC), borderline‑high hemoglobin, low mean corpuscular hemoglobin (MCH), borderline‑elevated serum creatinine, hyperchloremia, low total carbon dioxide (metabolic acidosis), borderline hypercalcemia, and low alkaline phosphatase?

Differential Diagnosis: Polycythemia Vera vs. Iron Deficiency Anemia with Metabolic Acidosis

The most likely diagnosis is iron deficiency anemia (IDA) with concurrent non-anion gap metabolic acidosis (likely renal tubular acidosis), rather than polycythemia vera, because the low MCH indicates hypochromic red cells characteristic of iron deficiency, not the true erythrocytosis of PV. 1

Critical Laboratory Pattern Analysis

The Microcytic Picture Points Away from Polycythemia Vera

• Low MCH is the key discriminating feature - this reflects hypochromic cells resulting from severe iron restriction during red blood cell production, which is pathognomonic for iron deficiency 2
• Polycythemia vera produces normocytic or slightly macrocytic red cells with normal MCH, not microcytic hypochromic cells 1
• The "high RBC count" with borderline-high hemoglobin likely represents relative polycythemia from hemoconcentration (dehydration, diuretics) superimposed on underlying iron deficiency 1, 3

The Metabolic Acidosis Pattern

• High chloride with low total CO2 indicates non-anion gap metabolic acidosis - this is consistent with renal tubular acidosis (RTA), particularly Type 1 (distal RTA) 2
• The borderline-high creatinine suggests mild renal dysfunction that could explain both the acidosis and contribute to anemia 2
• Borderline hypercalcemia with low alkaline phosphatase raises concern for hypophosphatasia or vitamin D-related disorders, which can coexist with RTA 4

Essential Diagnostic Workup Required

Confirm Iron Deficiency Immediately

• Serum ferritin is the single most powerful test - ferritin <12 μg/dL is diagnostic of iron deficiency, though values <30 μg/dL confirm it in the absence of inflammation 1, 5, 2
• Transferrin saturation <15-20% supports iron deficiency and is less affected by inflammation than ferritin 5, 2
• Red cell distribution width (RDW) should be elevated in iron deficiency, reflecting the heterogeneous population of microcytic and normocytic cells 1, 2
• Reticulocyte count to assess bone marrow response - expect low or normal count indicating impaired red cell production 5, 6

Evaluate the Metabolic Acidosis

• Calculate anion gap: Na - (Cl + HCO3) - normal is 8-12 mEq/L 2
• If non-anion gap acidosis confirmed, check urine pH, urine anion gap, and serum potassium to classify RTA type 2
• Assess renal function with BUN, creatinine, and eGFR 2

Address the Low Alkaline Phosphatase

• Persistently low ALP may indicate hypophosphatasia - measure pyridoxal phosphate (vitamin B6), which accumulates when ALP is deficient 4
• Consider nutritional deficiencies (zinc, magnesium) or medication effects (bisphosphonates) as acquired causes 4
• If hypophosphatasia suspected, genetic testing for ALPL gene variants may be warranted 4

Critical Red Flags to Exclude

Rule Out Polycythemia Vera Despite High RBC

• Serum erythropoietin (EPO) level is the next step - PV shows low EPO (<4 mU/mL), while iron deficiency with hemoconcentration shows normal or elevated EPO 1
• If EPO is low, bone marrow examination with cytogenetic studies is mandatory to evaluate for myeloproliferative neoplasm 1
• However, the low MCH makes PV extremely unlikely - this pattern is incompatible with true erythrocytosis 1, 2

Gastrointestinal Investigation for Iron Loss

• All adult men and post-menopausal women with confirmed iron deficiency require both upper endoscopy (with small bowel biopsy for celiac disease) and colonoscopy to exclude malignancy 1, 2
• This applies even without overt bleeding, as occult GI blood loss is the most common cause in these populations 1, 2, 7
• For pre-menopausal women, detailed menstrual history is essential, but GI evaluation is still warranted if menstrual losses don't explain severity 5, 6

Management Algorithm

Step 1: Confirm Iron Deficiency (Immediate)

• Order serum ferritin, transferrin saturation, and complete iron panel 5, 2
• Check C-reactive protein to identify inflammation that might falsely elevate ferritin 2

Step 2: Initiate Iron Replacement if Confirmed

• Ferrous sulfate 325 mg (65 mg elemental iron) 1-3 times daily between meals 5, 6
• Expect hemoglobin increase of 1-2 g/dL every 2-4 weeks 5, 6
• Continue iron for 3-6 months after hemoglobin normalizes to replenish stores 5, 6

Step 3: Investigate Underlying Causes Simultaneously

• Pursue GI evaluation (endoscopy/colonoscopy) to identify bleeding source 1, 2, 7
• Evaluate renal function and acid-base status comprehensively 2
• Assess for celiac disease with tissue transglutaminase antibodies and small bowel biopsy 1, 2

Step 4: Address Metabolic Acidosis

• If RTA confirmed, treat underlying cause and consider alkali therapy (sodium bicarbonate or citrate) 2
• Optimize renal function and discontinue nephrotoxic medications 2

Step 5: Follow-Up Monitoring

• Recheck CBC, iron studies, and metabolic panel after 3 months of therapy 6
• If no response to iron, evaluate for malabsorption, ongoing blood loss, or chronic disease 1, 7

Common Pitfalls to Avoid

• Do not assume polycythemia vera based on high RBC alone - the low MCH excludes this diagnosis and indicates iron deficiency 1, 2
• Do not attribute iron deficiency to diet or menstruation without excluding GI malignancy - mild anemia is equally indicative of serious disease as severe anemia 1, 2
• Do not overlook the metabolic acidosis - this requires separate evaluation and may indicate significant renal pathology 2
• Do not ignore low alkaline phosphatase - while often benign, it may indicate hypophosphatasia or nutritional deficiency requiring specific treatment 4
• Do not rely on ferritin alone if inflammation present - use transferrin saturation to confirm iron deficiency when ferritin is 12-100 μg/dL 1, 2