What is the appropriate diagnostic workup and treatment for a patient with a history of vitamin B12 deficiency suspected of having pernicious anemia, presenting with anemia, elevated alkaline phosphatase, and arthralgia?

Pernicious Anemia Workup

Initial Diagnostic Testing

For suspected pernicious anemia presenting with anemia, elevated alkaline phosphatase, and arthralgia, begin with serum vitamin B12, complete blood count with MCV and RDW, reticulocyte count, and serum ferritin to establish the diagnosis and rule out concurrent iron deficiency. 1

First-Line Laboratory Tests

• Serum vitamin B12: If <180 pg/mL (<150 pmol/L), this confirms deficiency and warrants immediate treatment 2, 3
• Complete blood count: Look for macrocytic anemia (MCV elevated), though hematologic abnormalities may be absent in one-third of cases 2
• Reticulocyte count: Low or "normal" reticulocytes indicate inappropriate erythropoiesis, consistent with B12 deficiency 1
• Serum ferritin and transferrin saturation: Essential because iron deficiency commonly coexists with B12 deficiency and must be addressed separately 1

Confirmatory Testing for Pernicious Anemia

Once B12 deficiency is established, confirm pernicious anemia specifically:

• Anti-intrinsic factor antibodies: Highly specific for pernicious anemia when positive 1, 2
• Anti-parietal cell antibodies: Supportive but less specific; present in 28-68% of autoimmune gastritis cases 2
• Serum gastrin: Markedly elevated levels (>1000 pg/mL) indicate pernicious anemia due to achlorhydria 3

Critical pitfall: Standard B12 assays can yield false-normal results in pernicious anemia due to interfering anti-intrinsic factor antibodies 4. If clinical suspicion remains high despite "normal" B12 (180-350 pg/mL), proceed to functional markers.

Functional Markers When B12 Results Are Indeterminate

• Methylmalonic acid (MMA): MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity 2
• Homocysteine: Elevated levels >15 μmol/L support B12 deficiency, though less specific than MMA 2

MMA testing is particularly valuable because standard serum B12 misses functional deficiency in up to 50% of cases 2. In patients with polyneuropathy, 44% had B12 deficiency based solely on abnormal metabolites despite normal serum B12 2.

Endoscopic Evaluation

Patients with confirmed pernicious anemia who have not had recent endoscopy should undergo upper endoscopy with topographical biopsies to confirm corpus-predominant atrophic gastritis, stratify gastric cancer risk, and rule out type 1 gastric neuroendocrine tumors. 1

• Obtain biopsies from gastric body and antrum/incisura in separately labeled jars 1
• Look for endoscopic features of atrophic gastritis: increased visibility of vasculature, loss of gastric folds, light blue crests, and white opaque fields 1
• Screen for type 1 gastric neuroendocrine tumors, which occur in autoimmune gastritis 1

Addressing Concurrent Conditions

Iron Deficiency Assessment

Your patient's elevated alkaline phosphatase may reflect bone marrow activity responding to anemia. Evaluate iron status because:

• In the absence of inflammation, serum ferritin <30 μg/L indicates iron deficiency 1
• With inflammation present, ferritin up to 100 μg/L may still represent iron deficiency 1
• Transferrin saturation <16-20% supports iron deficiency 1

Autoimmune Comorbidities

• Screen for autoimmune thyroid disease: This coexists commonly with pernicious anemia; check TSH, free T4, and thyroid peroxidase antibodies 2
• Consider celiac disease testing: Tissue transglutaminase antibodies and total IgA are positive in 13.3% of B12-deficient patients with autoimmune thyroid disease 2

Arthralgia Evaluation

While arthralgia is not a classic feature of pernicious anemia, consider:

• Concurrent autoimmune conditions that may cause joint symptoms
• Bone marrow expansion from severe anemia potentially causing bone pain
• Evaluate inflammatory markers (CRP) as part of the anemia workup 1

Treatment Initiation

Do not delay treatment while awaiting confirmatory antibody tests if B12 deficiency is established, especially with neurological symptoms present. 5

Immediate Treatment Protocol

For pernicious anemia with neurological involvement (which may include arthralgia if neuropathic):

• Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement 3, 5
• Then hydroxocobalamin 1 mg intramuscularly every 2 months for life 3, 5

For pernicious anemia without neurological involvement:

• Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks 6
• Then hydroxocobalamin 1 mg intramuscularly every 2-3 months lifelong 6, 5

Critical warning: Never administer folic acid before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage (subacute combined degeneration) to progress 2, 3, 6.

Alternative Oral Therapy

While intramuscular therapy is standard for pernicious anemia, oral vitamin B12 at 1000-2000 μg daily is effective for most patients and costs less 2, 7. However, given your patient's confirmed malabsorption (pernicious anemia), parenteral therapy is preferred initially 5, 8.

Monitoring Strategy

• Recheck B12 and complete blood count at 3 months, then at 6 and 12 months in the first year 6
• Annual monitoring thereafter once levels stabilize 6
• Monitor MMA and homocysteine if available; target homocysteine <10 μmol/L for optimal outcomes 2, 6
• Assess neurological symptoms regularly: Improvement indicates effective therapy, though some damage may be irreversible if treatment was delayed 2, 3

Common Diagnostic Pitfalls

• Relying solely on serum B12: Up to 50% of functional deficiencies are missed with serum B12 alone 2
• Missing false-normal B12 results: Anti-intrinsic factor antibodies can interfere with competitive-binding assays 4
• Overlooking neurological symptoms: These often present before hematologic changes and can become irreversible 2, 3
• Stopping monitoring after one normal result: Patients require lifelong supplementation and can relapse 6
• Not screening for concurrent autoimmune conditions: Autoimmune thyroid disease and celiac disease frequently coexist 1, 2