Lucan · Conditions

Vitamin B12 deficiency

Australian guidance: eTG Endocrinology — B12 + RACGP

1. Definition and epidemiology

Vitamin B12 (cobalamin) deficiency is a state of inadequate cellular cobalamin supply resulting in impaired DNA synthesis, megaloblastic haematopoiesis, and, distinctively, demyelination of the nervous system. In Australia, the most common cause is pernicious anaemia, an autoimmune condition destroying gastric parietal cells and therefore intrinsic factor, which is required for ileal B12 absorption. Population prevalence rises sharply with age; estimates suggest 5 to 15% of adults over 65 years have suboptimal B12 levels, and strict vegetarians and vegans are at high risk across all age groups.

2. Pathophysiology

Cobalamin enters the body bound to dietary protein, is liberated by gastric acid and pepsin, and then bound to haptocorrin before transfer to intrinsic factor in the duodenum. The cobalamin-intrinsic factor complex binds cubilin receptors in the terminal ileum for absorption. Inside cells, cobalamin functions as a cofactor for two reactions. First, methylcobalamin is required by methionine synthase to convert homocysteine to methionine and to regenerate tetrahydrofolate (THF) from 5-methyltetrahydrofolate; deficiency therefore traps folate in a form unusable for thymidylate and purine synthesis, producing the megaloblastic picture identical to folate deficiency. Second, adenosylcobalamin is required by methylmalonyl-CoA mutase to convert methylmalonyl-CoA to succinyl-CoA; impairment leads to accumulation of methylmalonic acid (MMA) and abnormal fatty acid incorporation into myelin. This second reaction is specific to B12 and not affected by folate, which explains why subacute combined degeneration of the spinal cord is a feature of B12 deficiency and not folate deficiency. Megaloblastic erythropoiesis results from arrested nuclear maturation with continued cytoplasmic growth; the resulting macro-ovalocytes and hypersegmented neutrophils (five or more lobes) are the hallmark on peripheral blood film (Robbins Ch 14). Ineffective erythropoiesis causes intramedullary haemolysis and elevated lactate dehydrogenase (LDH) and indirect bilirubin.

3. Clinical presentation and diagnostic criteria

Presentation is insidious and spans haematological, neurological, and psychiatric domains. Haematological features include fatigue, exertional dyspnoea, pallor, mild jaundice, and a smooth sore tongue (glossitis). Neurological features, collectively termed subacute combined degeneration (SCD), arise from demyelination of the dorsal and lateral columns: patients report symmetric distal paraesthesiae (stocking-glove), proprioceptive and vibration loss, Romberg sign, and, in advanced disease, spastic paraparesis, urinary incontinence, and optic neuropathy. Psychiatric manifestations include cognitive slowing, depression, and, rarely, frank psychosis. Importantly, neurological disease may precede anaemia by months, particularly when folate intake is high enough to partially correct haematological indices while failing to prevent demyelination. Diagnosis is clinical plus biochemical: a serum B12 below 148 pmol/L is consistent with deficiency; levels 148 to 221 pmol/L are borderline and require reflex MMA or homocysteine testing for confirmation. A full blood count showing macrocytosis (mean corpuscular volume above 100 fL) with or without anaemia, plus characteristic film findings, supports the diagnosis.

4. Investigations and AU-specific cutoffs

The recommended investigation sequence in Australian practice follows eTG and RACGP guidance. First-line: serum B12 (reference range laboratory-dependent; deficiency generally below 148 pmol/L); full blood count and blood film (macro-ovalocytes, hypersegmented neutrophils); reticulocyte count; serum folate (to identify concurrent deficiency); LDH and indirect bilirubin (elevated in haemolysis from ineffective erythropoiesis). Second-line when B12 is borderline (148 to 221 pmol/L): serum or urine MMA (elevated specifically in B12 deficiency, not folate deficiency; normal less than 0.28 micromol/L serum) and total plasma homocysteine (elevated in both B12 and folate deficiency; normal 5 to 15 micromol/L). Third-line to establish cause: anti-intrinsic factor antibodies (specificity above 95% for pernicious anaemia, but sensitivity only 60%; positive result is diagnostic); anti-parietal cell antibodies (sensitive but non-specific); gastroscopy with biopsy if malabsorption or gastric pathology is suspected; consideration of Helicobacter pylori testing (associated with atrophic gastritis and reduced acid-dependent B12 release). Serum B12 can be falsely normal in the presence of high transcobalamin-bound fractions in liver disease; clinical suspicion should override borderline results when symptoms are present.

5. Management

eTG recommends treatment without delay once deficiency is confirmed clinically and biochemically, and before results of autoantibody testing, to prevent irreversible neurological injury. For pernicious anaemia or confirmed malabsorption: intramuscular (IM) cyanocobalamin or hydroxocobalamin is standard. The RACGP and eTG loading regimen is hydroxocobalamin 1 mg IM on alternate days for two weeks (6 to 7 injections) to replete stores, followed by 1 mg IM every three months for life. Hydroxocobalamin is preferred over cyanocobalamin in Australia as it has a longer half-life and achieves higher tissue concentrations with less frequent dosing. For dietary deficiency (strict veganism, inadequate intake with normal absorption): high-dose oral cyanocobalamin 1000 micrograms daily is effective; passive absorption across the gut mucosa is sufficient at this dose even in the absence of intrinsic factor, making oral replacement a validated alternative when adherence to injections is problematic. eTG notes that oral B12 1000 micrograms daily achieves serum normalisation in most patients within 8 weeks and is acceptable first-line for dietary deficiency. When folate deficiency coexists, folate must not be replaced without concurrent B12 replacement to avoid precipitating or worsening neurological disease.

6. Pharmacology and AU PBS notes

Hydroxocobalamin injection 1 mg/mL (1 mL ampoule) is listed on the PBS under streamlined authority for pernicious anaemia and other conditions causing B12 malabsorption (PBS item codes within the Blood and blood-forming organs group; prescribers should confirm current item numbers via the PBS online formulary as these are subject to revision). The AU brand name is Hydroxocobalamin Injection BP. Cyanocobalamin tablets 50 micrograms and 100 micrograms are available over the counter; 1000 microgram tablets (e.g. Cytamen, generic brands) are available for therapeutic use and are not PBS-listed for dietary deficiency. Methylcobalamin sublingual preparations are sold as supplements and are not PBS-listed. No specific drug interactions alter B12 metabolism at conventional doses, but long-term metformin use reduces ileal B12 absorption by approximately 30% and warrants annual B12 monitoring per RACGP guidance. Proton pump inhibitor use over several years reduces acid-dependent liberation of protein-bound B12 and is a recognised iatrogenic cause in the elderly.

7. Complications and monitoring

Untreated deficiency leads to irreversible neurological damage; SCD may progress to paraplegia if diagnosis is delayed beyond 12 to 18 months of symptom onset. Haematological complications include severe megaloblastic anaemia with haemoglobin sometimes below 60 g/L, thrombocytopaenia, and pancytopaenia in advanced disease, raising the differential of a myelodysplastic syndrome. Rebound hypokalaemia may occur within the first 48 hours of treatment as rapidly proliferating erythroid precursors consume potassium; serum potassium monitoring is recommended in the first week of treatment for patients with pre-treatment haemoglobin below 80 g/L. Monitoring schedule: check serum B12 and full blood count at 8 weeks after starting treatment to confirm haematological response (reticulocyte count should rise within 7 to 10 days, haemoglobin should normalise within 8 weeks). Neurological recovery is slower and incomplete if axonal degeneration has occurred; physiotherapy input is appropriate for patients with established SCD. For patients on lifelong IM replacement, serum B12 monitoring is not required once on maintenance dosing, as levels will be supraphysiological post-injection. Annual serum B12 measurement is appropriate for patients on oral replacement, metformin, or long-term proton pump inhibitors to confirm adequacy. Patients with pernicious anaemia carry a two to threefold increased risk of gastric adenocarcinoma and gastric carcinoid; RACGP guidance supports surveillance gastroscopy at the time of diagnosis and every three to five years thereafter in those with confirmed atrophic gastritis.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.