What is the diagnosis and management for a 43-year-old female with macrocytic anemia, elevated uric nitrogen, and a positive ENA panel?

Diagnosis and Management of Macrocytic Anemia with Elevated Urea Nitrogen and Positive ENA

This patient requires immediate workup for vitamin B12 and folate deficiency as the first priority, followed by evaluation for autoimmune connective tissue disease given the positive ENA, while also investigating the elevated urea nitrogen for potential renal involvement or dehydration. 1, 2

Initial Diagnostic Workup

The MCV of 98 fL represents borderline macrocytosis (threshold is 100 fL), suggesting early megaloblastic changes or a mixed picture that warrants full evaluation 3. The positive ENA at 1.40 indicates possible autoimmune disease, which can coexist with nutritional deficiencies and complicate the clinical picture 1.

Essential first-line laboratory tests include:

• Serum vitamin B12 level (deficiency defined as <150 pmol/L or <203 ng/L; if borderline, obtain methylmalonic acid >271 nmol/L to confirm deficiency) 1, 3
• Serum folate and RBC folate levels (deficiency: serum folate <10 nmol/L or RBC folate <305 nmol/L) 1, 3
• Reticulocyte count to differentiate megaloblastic (low/normal) from non-megaloblastic causes (elevated suggests hemolysis or hemorrhage) 1, 2, 3
• TSH and free T4 to exclude hypothyroidism as a cause of macrocytosis 2, 3
• Comprehensive metabolic panel to further evaluate the elevated urea nitrogen (UN 24) and assess renal function 1
• Red cell distribution width (RDW) to identify coexisting iron deficiency, which can mask itself when combined with macrocytosis 1, 2

Autoimmune Disease Evaluation

The positive ENA requires further characterization:

• Specific ENA antibody panel (anti-Ro, anti-La, anti-Sm, anti-RNP, anti-Scl-70, anti-Jo-1) to identify the specific autoimmune condition 1
• CRP and creatinine to assess for inflammatory anemia or renal involvement from connective tissue disease 1
• Important caveat: In inflammatory conditions, ferritin may be falsely elevated despite concurrent iron deficiency, so check transferrin saturation and RDW if inflammation is present 1, 3

Treatment Algorithm

Critical treatment principle: Never initiate folate supplementation before ruling out and treating vitamin B12 deficiency, as this can precipitate subacute combined degeneration of the spinal cord, an irreversible neurological complication. 1, 3

If Vitamin B12 Deficiency is Confirmed:

• Without neurological symptoms: Cyanocobalamin 1 mg intramuscularly three times weekly for 2 weeks, followed by 1 mg every 2-3 months for life 1, 3
• With neurological symptoms: Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then 1 mg every 2 months 1

If Folate Deficiency is Confirmed (after excluding B12 deficiency):

• Oral folic acid 5 mg daily for a minimum of 4 months 1

If Hypothyroidism is Identified:

• Thyroid hormone replacement as per endocrine guidelines 1

Monitoring Response

• Repeat complete blood count within 4 weeks of treatment initiation 1, 3
• An acceptable response is defined as hemoglobin increase of at least 2 g/dL within 4 weeks 1, 3

When to Refer to Hematology

Refer to hematology if:

• The cause of anemia remains unclear after extensive evaluation 1
• Myelodysplastic syndrome is suspected, especially with concurrent leukopenia and/or thrombocytopenia 1, 4
• The patient is elderly with unexplained macrocytosis, as MDS and myeloid neoplasms commonly affect this population 4

Common Pitfalls to Avoid

• Do not assume normal B12 levels exclude deficiency: If clinical suspicion remains high despite normal serum B12, test methylmalonic acid and homocysteine levels, as functional B12 deficiency can occur with normal serum levels 2
• Do not overlook medication review: Drugs such as hydroxyurea, methotrexate, and azathioprine can cause macrocytosis and should be reviewed 1
• Do not miss mixed deficiency states: Multiple causes of macrocytosis can coexist, particularly in patients with chronic conditions and autoimmune disease 2
• Do not ignore the elevated urea nitrogen: This requires evaluation for dehydration, renal disease, or potential renal involvement from the underlying autoimmune condition 1