Haematinics

Haematinics are the nutrients and cofactors needed for red cell production: iron, folate (vitamin B9) and vitamin B12 (cobalamin). Each corrects a specific deficiency anaemia, and giving the wrong one, or giving one without a diagnosis, delays recognition of the cause and can cause harm. Treatment follows a confirmed deficiency, a search for the underlying cause and a measured response.

Mechanism. Iron is incorporated into haem and haemoglobin in erythroid precursors. Folate and vitamin B12 are cofactors in thymidylate and DNA synthesis; deficiency causes ineffective erythropoiesis and megaloblastic change. Vitamin B12 is also needed for myelin maintenance, so deficiency causes neurological damage that folate does not prevent.

Diagnostic thresholds. Anaemia is haemoglobin under 130 g/L in men, under 120 g/L in non-pregnant women and under 110 g/L in pregnancy and young children.

Iron and B12 thresholds. Iron deficiency is ferritin under 30 micrograms/L, or under 100 micrograms/L with inflammation, chronic kidney disease or heart failure (transferrin saturation under 20%). Vitamin B12 deficiency is a serum level under 200 nanograms/L (148 picomol/L); methylmalonic acid confirms borderline results. Low red cell folate confirms folate deficiency.

Pharmacokinetics. Iron is absorbed in the duodenum and is limited by hepcidin. Vitamin B12 needs gastric intrinsic factor and ileal uptake. Folate is absorbed in the jejunum.

Other agents. Pyridoxine (vitamin B6) 50 to 200 mg daily for some sideroblastic anaemias; vitamin C improves iron absorption; copper deficiency (after bariatric surgery or excess zinc) mimics B12 deficiency and needs copper replacement.

• First-line. Oral iron for uncomplicated iron deficiency; hydroxocobalamin or oral high-dose cyanocobalamin for B12 deficiency; folic acid for folate deficiency, haemolytic states and periconceptional prevention.
• Alternative. Parenteral iron when oral iron fails, is not tolerated or cannot be absorbed, or when rapid repletion is needed (late pregnancy, heart failure, chronic kidney disease, bleeding).
• Specialist. Combined deficiency, pernicious anaemia with neurological disease, and refractory anaemia.
• Emergency. Red cell transfusion for haemodynamic compromise or heart failure; avoid transfusion in stable chronic anaemia.

Principles.

• Define the type of anaemia before treating, and treat the cause (bleeding, helminths, malabsorption, diet, drugs).
• Never give folic acid alone to a patient with untreated B12 deficiency, because haematological improvement can hide progressing neurological damage.
• In severe megaloblastic anaemia give B12 and folate together until the cause is clear.
• Recheck haemoglobin at 2 to 4 weeks; failure to respond means wrong diagnosis, continued loss, nonadherence, malabsorption, inflammation or mixed deficiency.

Contraindications. Iron: haemochromatosis, iron overload, anaemia not caused by iron deficiency, and parenteral iron in active infection. Folate: untreated B12 deficiency. B12: Leber hereditary optic neuropathy (cyanocobalamin); hypersensitivity.

Serious adverse effects. Oral iron: gastrointestinal upset, constipation, dark stools; acute iron poisoning in children. Parenteral iron: hypersensitivity, hypophosphataemia (ferric carboxymaltose). B12: hypokalaemia in the first days of treating severe megaloblastic anaemia; rarely anaphylaxis. Folic acid: rarely hypersensitivity.

Major interactions. Iron reduces absorption of levothyroxine, quinolones, tetracyclines, bisphosphonates, levodopa and mycophenolate; proton pump inhibitors, calcium, tea and antacids reduce iron absorption. Phenytoin and methotrexate lower folate; metformin, proton pump inhibitors and nitrous oxide lower B12.

Common prescribing errors.

• Iron prescribed without ferritin or a source of loss.
• Folic acid given alone in B12 deficiency.
• Premature stopping before stores are replete.
• Multiple daily iron doses, which raise hepcidin and reduce absorption.
• No search for gastrointestinal malignancy in men and postmenopausal women with iron deficiency.

Special groups.

• Pregnancy: iron 30 to 60 mg elemental daily for prevention and 100 to 200 mg for treatment; folic acid 400 micrograms daily before conception to 12 weeks, 5 mg in high-risk women.
• Breastfeeding: all compatible.
• Children: weight-based iron (3 mg/kg elemental daily); screen for lead and helminths.
• Older adults: B12 deficiency is common; check before attributing cognitive change to other causes.
• Kidney: parenteral iron and erythropoiesis-stimulating agents often needed.
• Liver: iron overload risk in chronic liver disease.
• East Africa: treat hookworm and schistosomiasis (albendazole 400 mg single dose, praziquantel 40 mg/kg), exclude and treat malaria, and consider sickle cell disease and HIV; iron supplementation in malaria-endemic areas should accompany malaria diagnosis and treatment.

Monitoring. Haemoglobin and reticulocytes at 2 to 4 weeks; ferritin and transferrin saturation after 3 months; potassium in the first week of severe B12 treatment; B12 and folate levels when stopping.

Referral and escalation. No response by 4 weeks; haemoglobin under 70 g/L or symptomatic heart failure; neurological signs of B12 deficiency; unexplained iron deficiency in men and postmenopausal women (endoscopy); pancytopenia.

Comparison with alternative classes. Haematinics correct deficiency cheaply and safely. Erythropoiesis-stimulating agents are for anaemia of chronic disease with adequate iron, not a substitute; transfusion gives immediate benefit but no cure.