Iron, B12, and folate metabolism
The three haematinics
- The three haematinics. Each has a different absorption site, a different store size, and a different failure mode
| Absorbed | Store | Store lasts | Deficiency picture | |
|---|---|---|---|---|
| Iron | Duodenum + proximal jejunum | 3-4 g (~2/3 in Hb) | ~1-3 yr | Microcytic, hypochromic |
| B12 | Terminal ileum (needs IF) | 2-5 mg, liver | 2-4 years | Macrocytic + neurological |
| Folate | Jejunum (PCFT) | 10-20 mg | ~3-4 months | Macrocytic, no neurology |
- *Store size explains the tempo: folate deficiency appears within months of poor intake, B12 deficiency takes years - so new B12 deficiency is nearly always malabsorption, not diet* (except strict vegans)
- Iron has no regulated excretory route - balance is controlled entirely at absorption -> overload if absorption is unregulated
Epidemiology
- Iron deficiency is the commonest nutritional deficiency worldwide - ~50% of all anaemia
- Australia: ~1 in 8 menstruating women iron deficient
- B12 deficiency ~5-10% over 65; pernicious anaemia ~1-2% of older adults
- Folate deficiency now uncommon in Australia - mandatory folic acid fortification of bread-making flour since 2009
- HFE C282Y homozygosity ~1:200 in people of northern European ancestry (low clinical penetrance)
Iron
Daily flux
- Diet ~10-20 mg/day, of which only 1-2 mg absorbed - matching obligate losses (desquamation, GI)
- Menstruation adds ~1 mg/day averaged; pregnancy ~1000 mg total
- *Macrophage recycling of senescent red cells supplies ~20-25 mg/day - an order of magnitude more than diet. Diet is a top-up, not the supply*
Absorption - enterocyte
- Non-haem Fe3+ -> reduced to Fe2+ by DCYTB -> in via DMT1
- Haem iron via HCP1 - far better absorbed, hence red meat
- Out basolaterally via ferroportin -> oxidised by hephaestin -> bound to transferrin
- Enhancers: ascorbate, haem/meat. Inhibitors: phytate, tannin (tea), calcium, PPI/achlorhydria, coeliac disease
Delivery and storage
- Transferrin -> TfR1 on erythroblasts -> endocytosis -> STEAP3 reduces -> DMT1 releases into cytosol
- Stored as ferritin (24 subunits, up to ~4500 Fe atoms) and haemosiderin
Hepcidin - the master regulator
- 25-aa hepatic peptide; binds ferroportin -> internalisation and degradation
- inc hepcidin -> iron trapped inside enterocytes and macrophages -> low serum iron
- dec hepcidin -> absorption and macrophage release both increase
| Hepcidin UP | Hepcidin DOWN |
|---|---|
| Iron loading (BMP6/HJV/SMAD; HFE, TFR2) | Iron deficiency |
| Inflammation - IL-6 -> STAT3 | Hypoxia |
| High erythropoietic drive - erythroferrone from erythroblasts |
- Inflammation raising hepcidin = anaemia of chronic disease; teleologically, withholding iron from bacteria
- High erythropoietic drive suppressing hepcidin explains iron overload in ineffective erythropoiesis (thalassaemia, chronic haemolysis, MDS) even without transfusion
Hereditary haemochromatosis = functional hepcidin deficiency
- Hepcidin fails to rise despite iron loading -> ferroportin stays on the surface
- -> unregulated absorption (several-fold above normal) + macrophage iron egress
- -> inc transferrin saturation -> saturated transferrin -> non-transferrin-bound iron (NTBI)
- -> NTBI avidly taken up by hepatocytes, pancreatic islets, endocrine glands, cardiomyocytes - the organs that get damaged
---
Vitamin B12 (cobalamin)
Absorption - a four-step relay, and any step can fail
1. Saliva/stomach: B12 released from food by acid + pepsin, bound by haptocorrin (R-binder)
2. Duodenum: pancreatic proteases degrade haptocorrin -> B12 handed to intrinsic factor (gastric parietal cells)
3. Terminal ileum: IF-B12 bound by the cubam receptor (cubilin + amnionless) -> endocytosed
4. Portal blood: carried on transcobalamin II - the only bioavailable fraction (~20% of total serum B12; haptocorrin carries the inert ~80%)
- Step 4 is why serum B12 is a poor test - most of what is measured cannot be used by cells
Two cofactor roles
- Methylcobalamin -> methionine synthase: homocysteine + 5-methyl-THF -> methionine + THF
- Failure -> inc homocysteine and the methyl-folate trap
- Adenosylcobalamin -> methylmalonyl-CoA mutase: methylmalonyl-CoA -> succinyl-CoA
- Failure -> inc methylmalonic acid; implicated in the neurological disease - which is why folate cannot rescue it
- *cblC disease (MMACHC mutation) = commonest inherited* disorder of B12 metabolism -> combined methylmalonic acidaemia + homocystinuria
---
Folate
- Dietary polyglutamates deconjugated to monoglutamate -> absorbed in jejunum via PCFT (proton-coupled, acid pH)
- Requirement ~200 microgram/day; 500 microgram/day in pregnancy
- Role: one-carbon transfer -> purine and thymidylate (dTMP) synthesis
- Malabsorption: coeliac disease, chronic enteritis, tropical sprue, jejunal resection
- Drugs: methotrexate (DHFR), trimethoprim, sulfasalazine, phenytoin and phenobarbitone (reduced absorption), alcohol
The megaloblastic mechanism - shared final pathway
- dec B12 or dec folate -> dec dTMP -> impaired DNA synthesis with intact RNA/protein synthesis
- -> nuclear-cytoplasmic asynchrony: large immature nucleus in a mature cytoplasm
- -> ineffective erythropoiesis, intramedullary haemolysis (inc LDH, inc bilirubin, low retics)
Methyl-folate trap
- dec B12 -> methionine synthase stalls -> folate accumulates as 5-methyl-THF and cannot be converted to usable THF
- -> functional folate deficiency inside the cell despite a normal serum folate
- *This is why B12 deficiency produces a megaloblastic anaemia, and why giving folate alone partly corrects the blood count while the neurology worsens*
Iron - tests
Iron
- Ferritin - the best single test; acute phase reactant, so a normal ferritin does not exclude deficiency in inflammation
- Transferrin/TIBC inc, transferrin saturation dec in deficiency
- Soluble transferrin receptor rises in iron deficiency, normal in anaemia of chronic disease - the discriminator when ferritin is uninterpretable
- Overload: transferrin saturation >45% is the earliest and most sensitive marker (rises before ferritin)
- Then HFE genotype; ferritin >1000 microgram/L -> liver fibrosis risk, MRI T2\ / R2\ for hepatic and cardiac iron
B12 - tests
B12
- Serum B12 low, but a normal level does not exclude deficiency (haptocorrin fraction; falsely low in pregnancy, myeloma, oral contraceptive; falsely high in liver disease, myeloproliferative neoplasms)
- Methylmalonic acid - raised, and specific to B12
- Homocysteine - raised in BOTH B12 and folate deficiency (and in renal impairment, hypothyroidism, MTHFR variants)
- Anti-intrinsic factor antibody: specific (~95%) but only ~50% sensitive
- Anti-parietal cell antibody: sensitive but non-specific - positive in ~15% of normal older women
Folate - tests
Folate
- Red cell folate reflects the preceding ~3 months; serum folate reflects the last meal (rises after a single folate-rich meal or admission diet)
Film and marrow (either deficiency)
- Oval macrocytes + hypersegmented neutrophils (>5% with >=5 lobes)
- MCV often >110 fL; pancytopenia in severe deficiency
- Marrow: megaloblastic change, giant metamyelocytes
Iron deficiency - treatment
Iron deficiency
- Find the cause - in men and post-menopausal women, GI malignancy until proven otherwise -> gastroscopy + colonoscopy; coeliac serology in all
- Oral: ferrous salt, ~100-200 mg elemental iron, given on ALTERNATE DAYS
- A dose raises hepcidin for ~24 h and blocks the next day's absorption - alternate-day, single daily dosing absorbs more total iron than tds dosing, with fewer GI effects
- Take with vitamin C, away from food, tea, calcium and PPI
- Response: retics peak day 5-10; Hb rises ~10-20 g/L per 2-3 weeks
- Continue 3 months after Hb normalises to refill stores
- IV iron (ferric carboxymaltose, ferric derisomaltose, iron polymaltose) if malabsorption, intolerance, ongoing losses outpacing intake, CKD, IBD, or 3rd-trimester pregnancy
- Ferric carboxymaltose -> hypophosphataemia (FGF23-mediated), sometimes symptomatic/osteomalacic with repeat dosing; less with derisomaltose
- Skin staining at extravasation; check Hb + ferritin at 4-8 weeks, not earlier
- No response to iron -> reconsider: non-adherence, ongoing bleeding, anaemia of chronic disease, coeliac, copper deficiency, thalassaemia trait, congenital iron-handling defect (IRIDA)
B12 deficiency - treatment
B12 deficiency
- Hydroxocobalamin 1000 microgram IM alternate days until response (or x5-6 doses), then 3-monthly for life if the cause is irreversible
- High-dose oral (1000-2000 microgram daily) is effective even in pernicious anaemia - ~1% is absorbed by passive diffusion, independent of intrinsic factor
- *Never give folate before replacing B12 - precipitates or worsens subacute combined degeneration*
- Watch for hypokalaemia as brisk haematopoiesis resumes
Folate deficiency - treatment
Folate deficiency
- Folic acid 5 mg daily for 1-4 months
- Preconception 400-500 microgram/day, from 1 month before conception to 12 weeks - 5 mg/day if previous NTD, diabetes, obesity, antiepileptics, or methotrexate exposure
Iron overload
- Venesection to ferritin ~50-100 microgram/L, then maintenance
- Iron chelation (deferasirox, deferoxamine, deferiprone) where venesection is impossible - transfusion-dependent anaemia
- Avoid vitamin C supplements and uncooked shellfish (Vibrio vulnificus, Yersinia thrive in iron excess)
Associations
- Pernicious anaemia with other organ-specific autoimmunity: autoimmune thyroid disease, T1DM, vitiligo, Addison
- Coeliac disease - malabsorbs iron, folate and (if extensive) B12
- Atrophic gastritis / PPI / metformin - impaired B12
- Terminal ileal disease: Crohn, ileal resection, tropical sprue, *fish tapeworm (Diphyllobothrium latum)*, bacterial overgrowth
- Nitrous oxide - oxidises cobalt in cobalamin, inactivates methionine synthase -> acute functional B12 deficiency with SACD
- Hereditary haemochromatosis - cirrhosis, diabetes, cardiomyopathy, arthropathy (2nd/3rd MCP), hypogonadism, bronze skin
- Ineffective erythropoiesis (thalassaemia, MDS, congenital dyserythropoietic anaemia) - non-transfusional iron loading
- Anaemia of chronic disease - hepcidin-mediated
Consequences of delay
- B12 neurology can be irreversible if replacement is delayed >6-12 months - the blood count always recovers, the cord may not
- Neurological disease can occur with a normal haemoglobin and MCV
- Iron deficiency without anaemia still causes fatigue, restless legs, pica, impaired exercise tolerance and cognition
- Pernicious anaemia: ~2-3x risk of gastric adenocarcinoma and gastric carcinoid (hypergastrinaemia -> ECL hyperplasia)
- Haemochromatosis: cirrhosis -> HCC risk persists even after iron depletion; venesection reverses fibrosis, cardiomyopathy and skin change, but not arthropathy, cirrhosis or hypogonadism
- Untreated folate deficiency in pregnancy -> neural tube defects
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