12-phase flow (12)

1. 1FRAME
   Establish macrocytic/megaloblastic anaemia frame — partition B12 vs folate vs both vs non-megaloblastic macrocytosis; flag pernicious anaemia and subacute combined degeneration as the high-stakes phenotypes (BSH Devalia 2014 PMID 24942828)
   inputs: age, pregnancy_status
   advance: Megaloblastic frame and candidate aetiology assigned
2. 2ENTRY
   Triggered by macrocytosis on CBC, low/borderline B12 or folate, anaemia symptoms, neuro/cognitive change, N2O use, or chronic metformin/PPI surveillance (Stabler NEJM 2013 PMID 23301732)
   inputs: cbc_with_indices
   advance: Entry trigger confirmed; engine launched
3. 3CONTEXT
   Capture diet (vegan/vegetarian), alcohol, malabsorption history (atrophic/pernicious gastritis, bariatric, ileal resection/Crohn, pancreatic insufficiency, fish tapeworm), offending drugs (metformin/PPI/MTX/trimethoprim/phenytoin), N2O exposure, pregnancy/preconception, prior NTD, autoimmune comorbidity (BSH Devalia 2014 PMID 24942828)
   inputs: age, pregnancy_status, malabsorption_risk, b12_folate_offenders
   actions: panel.cmp
   advance: Aetiologic context captured
4. 4RED_FLAGS
   LOAD-BEARING PIVOTS: (1) NEVER give folate without measuring/correcting B12 — folate-alone in B12 deficiency can precipitate/worsen subacute combined degeneration (BSH Devalia 2014 PMID 24942828; Stabler NEJM 2013 PMID 23301732). (2) Neuro deficits (paraesthesia, gait ataxia, dorsal-column signs, optic atrophy, cognitive change) may be IRREVERSIBLE if treatment delayed → treat empirically with B12 if high suspicion, do NOT wait for confirmatory MMA. (3) Pancytopenia / very low Hb with hypersegmented neutrophils can mimic acute leukaemia — bone-marrow only if no response. (4) Rapid repletion → hypokalaemia + rebound thrombocytosis → monitor K+. (5) N2O myeloneuropathy: functional B12 deficiency with NORMAL serum B12 — elevated MMA/Hcy + dorsal-column MRI signal (PMID 34427020)
   inputs: neuro_signs
   actions: workup.peripheral_neuropathy
   advance: Folate-alone risk excluded; neuro emergency triaged; empiric B12 started if indicated
5. 5INITIAL_WORKUP
   CBC + indices (MCV >100 fL), reticulocyte count (low — ineffective erythropoiesis), peripheral smear (oval macrocytes + hypersegmented neutrophils ≥5 lobes), serum B12, serum/red-cell folate, LDH (markedly elevated) + indirect bilirubin (intramedullary haemolysis), CMP + LFT (BSH Devalia 2014 PMID 24942828; Stabler NEJM 2013 PMID 23301732)
   inputs: cbc_with_indices, serum_b12, serum_folate, reticulocyte_count
   actions: panel.cbc, panel.lft, cascade.labs_command
   advance: First-line megaloblastic panel resulted
6. 6BRANCHING_WORKUP
   Reflex when B12 borderline or clinic-test discordant: MMA + total homocysteine + holotranscobalamin (elevated MMA+Hcy = B12 deficiency; isolated Hcy = folate; normal-B12 + high MMA/Hcy = functional/N2O). If B12 deficiency confirmed → anti-intrinsic-factor Ab (high specificity ~92%, low sensitivity ~50–70%), anti-parietal-cell Ab (sens ~68%, spec ~92%), gastrin + pepsinogen, consider gastroscopy for autoimmune gastritis + gastric cancer/carcinoid surveillance (~7× gastric-cancer RR, PMID 23216458). Coexistent iron deficiency (dimorphic anaemia normalises MCV) → iron studies. Route neuro complications to peripheral-neuropathy workup; cognitive change → cognitive screen (BSH Devalia 2014 PMID 24942828; PMID 32089757)
   inputs: mma_homocysteine
   actions: workup.macrocytic_anemia, workup.peripheral_neuropathy, panel.iron, calc.phq9
   advance: B12-vs-folate partitioned; pernicious-anaemia status determined; aetiology assigned
7. 7DIFFERENTIAL
   Terminal aetiologies: pernicious anaemia (autoimmune atrophic gastritis); dietary B12 (vegan); B12 malabsorption (atrophic gastritis, bariatric, ileal resection/Crohn, pancreatic insufficiency, Diphyllobothrium); drug-induced (metformin/PPI/H2RA → B12; methotrexate/trimethoprim/phenytoin → folate); N2O functional B12 deficiency; folate — dietary, alcohol, increased demand (pregnancy/haemolysis), MTHFR; combined B12+folate; non-megaloblastic macrocytosis (alcohol, liver disease, hypothyroidism, MDS, reticulocytosis) (BSH Devalia 2014 PMID 24942828)
   advance: Terminal aetiology assigned
8. 8RISK_STRATIFICATION
   Severity tiers: severe symptomatic anaemia (high-output failure / angina); neurologic involvement / subacute combined degeneration (treat-now — irreversibility risk); pancytopenia mimicking leukaemia; hypokalaemia on replacement; N2O myeloneuropathy. Lifelong-replacement determinants: pernicious anaemia, irreversible malabsorption (bariatric/ileal resection), continued N2O. Pregnancy + prior NTD → high-dose folate tier (BSH Devalia 2014 PMID 24942828; MRC Vitamin Study PMID 1677062)
   inputs: cbc_with_indices
   actions: calc.ckd_epi_2021
   advance: Severity tier + chronicity-of-replacement decided
9. 9TREATMENT
   B12: IM hydroxocobalamin 1 mg alternate-day x1–2 wk (or until no further neuro improvement) then 1 mg every 2–3 months for life in pernicious anaemia/irreversible malabsorption; OR high-dose oral cyanocobalamin 1000–2000 mcg/day (passive absorption; Cochrane Wang 2018 non-inferior haematologically/neurologically for short term, PMID 29543316) for dietary/borderline/reversible cause without severe neuro disease. ALWAYS correct/replace B12 before or with folate (SCD safety). Folate 1–5 mg PO daily x ~4 months (lifelong if chronic haemolysis/malabsorption). N2O-induced: stop N2O + high-dose B12 ± methionine. Expected response: reticulocytosis day 5–7, Hb rises ~1 g/dL/wk, normalises by ~8 wk; hypersegmentation resolves ~2 wk. Treat-underlying: deprescribe/monitor metformin-PPI, manage Crohn (route gi.crohns.core.v1), bariatric lifelong supplementation (BSH Devalia 2014 PMID 24942828; Stabler NEJM 2013 PMID 23301732)
   inputs: serum_b12, serum_folate
   advance: Repletion regimen + chronicity + underlying-cause plan executed
10. 10DISPOSITION
    Outpatient for most (oral or community IM repletion). Inpatient/urgent for severe symptomatic anaemia, neurologic emergency / progressive subacute combined degeneration, pancytopenia requiring exclusion of leukaemia, or symptomatic hypokalaemia on replacement (BSH Devalia 2014 PMID 24942828)
    advance: Disposition set
11. 11MONITORING
    Reticulocyte count day 5–7 (response confirmation); repeat CBC + MCV at ~2 and ~8 weeks (MCV normalises ~8 wk); serum K+ during early rapid repletion (hypokalaemia risk); platelet count (rebound thrombocytosis); B12/folate not routinely re-checked post-loading on adequate replacement; ferritin/iron studies if MCV fails to normalise (unmasked iron deficiency); neuro re-assessment for SCD recovery (BSH Devalia 2014 PMID 24942828)
    inputs: cbc_with_indices, reticulocyte_count, potassium
    actions: panel.cbc, panel.renal
    advance: Haematologic + biochemical response documented; K+ stable
12. 12FOLLOWUP
    Pernicious anaemia: lifelong B12 + endoscopic gastric surveillance per local pathway (gastric adenocarcinoma/carcinoid risk, ~7× RR, PMID 23216458); annual FBC + thyroid (autoimmune association — panel.thyroid). Drug-induced: periodic B12 on continued metformin/PPI (Aroda DPPOS PMID 26900641). Pregnancy: periconceptional folate 400 mcg standard, 4–5 mg if prior NTD/high-risk, continue through 12 wk; B12 in vegans/post-bariatric; infants of B12-deficient mothers screened. Geriatric: re-screen cognition if dementia-mimic. Bariatric/ileal resection: lifelong supplementation + monitoring (BSH Devalia 2014 PMID 24942828; MRC Vitamin Study PMID 1677062)
    actions: panel.thyroid
    advance: Lifelong/interval plan + surveillance documented