What are the recommended diagnostic workup and treatment plan for an adult with pernicious anemia?

Pernicious Anemia: Diagnostic Workup and Treatment

Diagnostic Workup

For suspected pernicious anemia, confirm the diagnosis through fasting gastrin levels, anti-intrinsic factor antibodies (IFBA), and anti-parietal cell antibodies (PCA), followed by esophagogastroduodenoscopy (EGD) with gastric pH measurement and biopsies of the fundus and antrum to identify atrophic gastritis and rule out premalignant/malignant lesions. 1

Initial Laboratory Assessment

• Measure serum vitamin B12 levels alongside complete blood count showing macrocytic anemia 2, 3
• Check anti-intrinsic factor antibodies (IFBA), which are present in approximately 52% of PA patients and are highly specific for the diagnosis 1
• Measure anti-parietal cell antibodies (PCA), detected in 97% of PA patients 1
• Obtain fasting gastrin levels, which are markedly elevated (mean >1,500 pg/mL) in PA due to achlorhydria 1
• Measure chromogranin A levels, which are typically elevated (mean >500 ng/mL) and help monitor for gastric neuroendocrine tumors 1
• Assess plasma homocysteine and methylmalonic acid (MMA) concentrations, which are elevated in vitamin B12 deficiency and normalize with treatment 4

Endoscopic Evaluation

• Perform EGD with gastric pH measurement to confirm achlorhydria (pH >5) 1
• Obtain biopsies from both fundus and antrum to document atrophic gastritis and intestinal metaplasia 1, 2
• Screen for celiac disease during gastroscopy with duodenal biopsies, as it coexists in 3-5% of cases 5, 6
• Evaluate for high-risk gastric pathology, as premalignant or malignant lesions occur in 76% of PA patients, including gastric neuroendocrine tumors (GNETs) in 18% and adenocarcinoma 1

Additional Investigations

• Screen for concurrent autoimmune diseases, present in 94% of PA patients, including thyroid disease, type 1 diabetes, and vitiligo 1
• Assess iron status with serum ferritin and transferrin saturation, as iron deficiency commonly coexists due to achlorhydria impairing iron absorption 7, 1
• Perform urinalysis to exclude urinary tract bleeding as a contributor to anemia 7

Clinical Examination Findings

• Look for angular stomatitis, glossitis, and koilonychia as specific signs of chronic iron and B12 deficiency 8, 1
• Assess for neurologic symptoms including peripheral neuropathy, posterior column dysfunction (subacute combined degeneration), and cognitive impairment 1, 3
• Evaluate for restless legs syndrome and pagophagia (ice craving), which may indicate concurrent iron deficiency 8

Treatment Plan

Initiate vitamin B12 replacement therapy immediately upon diagnosis, with oral cyanocobalamin 1000 μg daily as an effective first-line option, or intramuscular B12 if neurologic symptoms are present or oral therapy fails. 4

Vitamin B12 Replacement

• Prescribe oral cyanocobalamin 1000 μg daily, which corrects B12 deficiency in 88.5% of PA patients within 1 month through passive absorption 4
• Consider intramuscular B12 initially if severe neurologic symptoms are present, as some neurologic sequelae may become irreversible without prompt treatment 3, 9
• Continue lifelong B12 supplementation, as PA is a chronic condition requiring permanent replacement therapy 2, 9

Iron Replacement (if deficient)

• Administer intravenous iron as first-line therapy when iron deficiency coexists, as oral iron is poorly absorbed due to achlorhydria and may worsen gastrointestinal symptoms 6
• Choose IV iron formulations that replace deficits in 1-2 infusions rather than multiple doses 6
• Continue iron therapy for 3 months after correction to replenish iron stores 6

Monitoring Strategy

• Measure plasma B12, homocysteine, and MMA at 1 month to confirm biochemical response (expect normalization of B12 and significant reduction in homocysteine and MMA) 4
• Monitor complete blood count every 3 months for the first year, then every 6 months thereafter 6
• Reassess iron parameters every 3 months initially, then every 6 months after normalization 6
• Expect hemolysis to resolve within 1 month and mucosal symptoms within 4 months of adequate B12 replacement 4

Endoscopic Surveillance

• Perform surveillance EGD every 3-5 years in all PA patients due to increased risk of gastric adenocarcinoma and GNETs 1, 2
• Increase surveillance frequency to annually if high-grade dysplasia, extensive intestinal metaplasia, or GNETs are identified 1, 2
• Do not halt investigation after identifying PA, as dual pathology occurs in 1-10% of cases; complete bidirectional endoscopy if age-appropriate 5

Common Pitfalls to Avoid

• Do not delay treatment while awaiting confirmatory tests if clinical suspicion is high, as neurologic damage may become irreversible 3
• Do not assume oral B12 is ineffective in PA—recent evidence demonstrates 1000 μg daily oral cyanocobalamin is highly effective through passive absorption 4
• Do not overlook iron deficiency, which commonly coexists and requires separate treatment with IV iron due to impaired absorption 7, 1
• Do not skip endoscopic surveillance, as 76% of PA patients develop premalignant or malignant gastric lesions requiring monitoring 1
• Do not miss concurrent autoimmune diseases, present in 94% of PA patients and requiring separate evaluation and management 1