What is the cause of elevated B12 levels in a patient with leukocytosis, a psychiatric condition, and potential lithium use, with no apparent supplement use and otherwise unremarkable lab results?

Elevated B12 in Psychiatric Patient with Leukocytosis and Potential Lithium Use

Primary Cause: Lithium-Induced Leukocytosis with Incidental B12 Elevation

The most likely explanation for this clinical picture is lithium-induced leukocytosis, which is a well-established pharmacologic effect occurring in the majority of patients on lithium therapy, while the elevated B12 is likely a secondary phenomenon related to increased white blood cell turnover or production. 1, 2, 3

Understanding Lithium's Hematologic Effects

Lithium carbonate consistently causes leukocytosis in psychiatric patients, with this effect persisting throughout long-term treatment:

• Lithium induces significant leukocytosis in all patients during the first few weeks of therapy, with elevations persisting throughout the course of treatment 2
• The mean increase in WBC count is approximately 2,237 cells/mm³ above baseline values (p < 0.001), with mean counts reaching 11,950 ± 4,028 cells/mm³ 3
• This leukocytosis is drug-related but not dose-dependent or correlated with serum lithium levels 2, 3
• The FDA label confirms that lithium affects sodium reabsorption and has multiple systemic effects, though leukocytosis is not listed as a contraindication 1

Mechanism of B12 Elevation in This Context

Elevated B12 levels in the setting of leukocytosis and psychiatric illness likely reflect:

Increased white blood cell production and turnover releases stored B12 from leukocytes into the serum, creating falsely elevated or truly elevated circulating levels that do not reflect functional B12 status 4. This is particularly relevant because:

• Standard total B12 tests may not accurately reflect the biologically active form of vitamin B12 available for cellular use 4
• Serum B12 measures total B12, not the biologically active form, and up to 50% of patients with "normal" serum B12 have metabolic deficiency when measured by methylmalonic acid 4
• Leukocytosis itself can elevate serum B12 through release from white blood cells 2, 3

Diagnostic Algorithm for This Patient

Step 1: Confirm Lithium Use and Review Medication History

• Verify current lithium therapy and duration of use 1
• Check for other medications that can cause leukocytosis (carbamazepine can also cause this, though less commonly) 5
• Review for NSAIDs, diuretics, or ACE inhibitors that interact with lithium 1

Step 2: Assess the Leukocytosis

• Obtain complete blood count with differential to characterize the leukocytosis 3
• Check serum lithium level to ensure therapeutic range (0.6-1.0 mEq/L) and rule out toxicity 1, 6
• Rule out infection, though lithium-induced leukocytosis typically shows neutrophil predominance without left shift 2, 3

Step 3: Evaluate True B12 Status Despite Elevated Serum Level

• Measure methylmalonic acid (MMA) as the primary test to assess functional B12 status, as this reflects actual cellular B12 availability regardless of serum levels 4
• MMA >271 nmol/L confirms functional B12 deficiency even with elevated serum B12 4
• Consider active B12 (holotranscobalamin) measurement, which is more accurate than total B12 4
• Check homocysteine levels (>15 μmol/L suggests functional deficiency) 4

Step 4: Screen for Underlying Conditions

• Assess for autoimmune thyroid disease, as patients with psychiatric conditions may have concurrent autoimmune disorders affecting B12 metabolism 4
• Check thyroid function (TSH, free T4, TPO antibodies), as hypothyroidism can affect nutrient utilization despite normal serum levels 4
• Consider testing for pernicious anemia with intrinsic factor antibodies if MMA is elevated 4

Critical Clinical Pitfalls to Avoid

Do not assume elevated B12 means adequate B12 status in a patient with leukocytosis - the elevated serum level may be artifactual from white blood cell turnover, while functional deficiency exists at the cellular level 4. This is particularly important because:

• Relying solely on serum B12 levels misses functional deficiency in up to 50% of cases 4
• In patients with psychiatric conditions, B12 deficiency can worsen cognitive symptoms, memory problems, and neurological manifestations 4
• Lithium therapy itself does not cause B12 deficiency, but the psychiatric population has higher rates of nutritional deficiencies 7

Do not discontinue lithium based solely on leukocytosis - this is an expected pharmacologic effect, not toxicity, unless the WBC count is extremely elevated or the patient shows signs of lithium toxicity (diarrhea, vomiting, tremor, ataxia, drowsiness, muscular weakness) 1, 2, 3

Monitor for lithium-drug interactions that could affect both the leukocytosis and overall clinical picture:

• NSAIDs can increase lithium levels significantly and should be monitored closely 1
• Diuretics and ACE inhibitors reduce renal clearance of lithium, increasing toxicity risk 1
• Combined use with haloperidol or other antipsychotics requires close monitoring for encephalopathic syndrome 1

When to Treat Despite Elevated B12

Treat with B12 supplementation if MMA is elevated (>271 nmol/L) or homocysteine is elevated (>15 μmol/L), regardless of serum B12 level 4. Use:

• Hydroxocobalamin 1000 mcg IM monthly for maintenance, or
• Oral methylcobalamin 1000-2000 mcg daily if no malabsorption 4, 8
• Never use cyanocobalamin in psychiatric patients who may have renal impairment from lithium, as it increases cardiovascular risk 8

Monitoring Strategy

• Recheck MMA and homocysteine at 3 months after initiating B12 treatment if functional deficiency was confirmed 4, 8
• Continue monitoring lithium levels and renal function every 3-6 months, as lithium affects sodium reabsorption and can impact kidney function long-term 1, 6
• Annual B12 screening is reasonable in patients on long-term lithium therapy, using MMA rather than serum B12 for accurate assessment 4