IRON DEFICIENCY ANEMIA

Iron is the most important micronutrient in child­ren, distributed in RBCs (60%), bone marrow, reticuloendothelial system (RES) and various iron- containing enzymes. Iron deficiency anemia (IDA) is the commonest cause of nutritional anemia, present in gt;50% of preschool and adolescent children.

Physiology: Fetus receives preferential delivery of iron transplacentally to build up body stores and maternal Hb status does not affect iron stores in baby unless she is severely anemic. However, as most of the transplacental transfer occurs in last trimester, preterms are more likely to have poor iron stores. Iron stores at birth are further enhanced by increased breakdown of RBCs in early postnatal life, and are sufficient for first 3-6 months of life.

Dietary requirements: While daily iron requirement is ~1 mg elemental iron/day, RDA varies from 6-12 mg/ day in different age groups, as only lt;20% of ingested iron is actually absorbed.

Sources: Breast milk is the main source of iron in early infancy. Though iron content of human and animal milk is nearly same, absorption is 2-3 times more efficient from human milk and breast-fed babies are less likely to develop IDA than top-fed infants.

For older children, dietary iron is widely present as heme form in animal sources, e.g. meat, fish and poultry, or as non-heme form in green vegetables, pulses and jaggery.

Normal metabolism: Most of the dietary iron is in ferric form. Important steps in iron metabolism are as follows:

• Gastric digestion, i.e. conversion of ingested ferric salts to ferrous form in presence of gastric acids, which is better absorbed than ferric form. Presence of iron-binders, e.g. phosphates, phytates, oxalates in diet inhibits iron absorption, while lactose, vitamin C and certain amino acids enhance it.

• Intestinal absorption of iron at duodenum and upper jejunum by two energy-dependent processes: (a) mucosal uptake, and (b) transfer from mucosal cells to plasma.

• Plasma transport: Absorbed iron in plasma is transported to bone marrow as bound form with transferrina plasma protein, synthesized by liver. Transferrin receptors, present mainly on erythroid and hepatic cells, accept the iron from circulating iron­transferrin complex for further utilization. Percentage saturation of transferrin (total iron binding capacity or TIBC) is an important guide of iron state in body.

• Storage: Excess iron is stored in bone marrow and other reticuloendothelial (RES) tissues as ferritin, for future mobilization. In IDA, these stores are exhausted before the clinical appearance of anemia.

• Recycling: A part of the body iron is also produced by constant breakdown of hemoglobin in RES and stored in similar manner.

In brief, iron metabolism is regulated by: (a) intrinsic factors, i.e. body requirements, depending upon the rate of erythropoiesis and state of body stores, and (b) extrinsic factors, i.e. quality of consumed iron (ferrous vs. ferric form, presence of iron-binders or absorption-enhancers in diet, and state of intestinal mucosa.

In IDA, the iron deficiency is compensated by: (a) increased gut absorption, (b) enhanced bone marrow uptake from plasma, and (c) mobilization from stores. Etiology: Common causes of IDA include:

• Decreased iron stores

± Preterms/twin births

± Delayed clamping of cord

± Fetofetal or fetomaternal transfusion

• Reduced dietary intake

± Top feeding

± Delayed weaning

± Improper dietary habits

• Impaired absorption

± High phytate content in veg. diet

± Achlorhydria/malabsorption syndrome

± Malabsorption syndromes

• Excessive blood loss

± Occult: Hookworms, Meckel's diverticulum

± External: Trauma, surgery, bleeding diathesis

• Higher requirements

± Preterms, adolescents and pregnancy

± Recovery from malnutrition

• Error in iron metabolism

± Idiopathic pulmonary hemosiderosis

± Congenital transferrin deficiency

± Sideroblastic anemia

Pathophysiology: Earliest event in IDA is excessive consumption of iron stores, which may be detected as reduced hemosiderin pigment in bone marrow many months before the actual fall in Hb levels.

Clinical manifestations: IDA is most common in late infancy (6 months-2 years) and adolescence. Clinical spectrum varies according to the severity of deficiency, as follows:

• Mild or early IDA is characterized by mental changes, e.g. lack of attention span and irritability, due to impaired activity of iron-containing enzymes, e.g. monoamino oxide (MAO), cytochrome oxidase, etc. Pica-a behavioral problem, is frequently associated with IDA, though the cause-effect relationship is unclear.

• Moderate IDA presents with visible pallor of variable severity and features of chronic hypoxia, e.g. easy fatigability, anorexia, growth failure, etc. Mild spleno­megaly and platynychia/koilonychia is common on examination.

• Severe IDA may be associated with hemodynamic decompensation, e.g. tachycardia, cardiomegaly, functional murmurs and even CCF.

Plummer-Vinson syndrome is a rare presentation of IDA with esophageal dysphagia (webs), koilonychia and splenomegaly.

Laboratory investigations in IDA include:

• Basic hematological work-up showing:

± Microcytic, hypochromic anemia on PS

± Low MCV, MCH, MCHC with high RDW (gt;14%) ± Normal/slightly high reticulocyte count.

TABLE 19.7: Sequence of events in IDA

• Depletion of iron stores

• #934; Serum ferritin levels

• #8593; Total iron binding capacity (TIBC)

• #934; Hemoglobin levels

• #934; Iron-containing enzymes activity

• Clinical pallor

• Biochemical investigations revealing:

- Serum ferritin levels (lt;10 ng/ml)

- Serum iron levels (lt;75 #956;g#8725;dl)

- TIBC (gt;470 #956;g#8725;dl) with % saturation lt;16%

- Free erythrocyte protoporphyrin (heme precursor) levels (gt;2.8 #956;g#8725;g)

Serum ferritin levels correlate well with total iron body stores, but may be falsely elevated or normal in acute inflammatory disorders despite low iron stores.

• Bone marrow exam, though not routinely indicated, reveals hypercellularity with erythroid hyperplasia and absence of hemosiderin on Prussian blue staining.

• Ancillary investigations, e.g. stool exam for occult blood#8725;parasites, to search for primary cause.

D/D of IDA includes other causes of microcytic hypo­chromic anemia, i.e. (a) chronic lead poisoning (basophilic stippling of RBCs), (b) thalassemia trait (normal RDW and raised HbA₂), (c) sideroblastic anemias, and (d) rare causes, e.g. congenital atransferrinemia.

Management includes correction of anemia and treat^­ment of primary cause, e.g. worm infestations. Modalities to correct the anemia depend on its severity and include:

• Oral iron therapy is the treatment of choice in most cases, given as ferrous salts (PO 3-6 mg/kg/d q8-12hr on empty stomach) for 2-3 months or at least 8 weeks after Hb returns to normal. Many oral preparations are available containing heme or different ferrous salts, each with variable content of elemental iron. Anhydrous ferrous sulfate is the richest source of elemental iron (37%), followed by fumarate (33%), succinate (23%) and gluconate salts (20%).

Iron absorption may be enhanced by—(i) avoiding concomitant intake of meals/milk, and (ii) additional vitamin C supplementation (50 mg/kg).

Common side-effects of iron therapy include GIT upsets, e.g. diarrhea/constipation (which can managed by change of iron salt) and blackish staining of teeth.

Response to therapy may be monitored by assess­ing the sequence of recovery events (Table 19.8).

Therapeutic failure to oral iron therapy indicates: (a) continued blood loss, (b) improper preparation/ dose/compliance, (c) high phosphate diet, (d) associated megaloblastic (Dimorphic) or/hemolytic anemia, and (e) presence of chronic illnesses/ infection, and (f) congenital causes, e.g. sideroblastic anemia.

*due to replacement of enzymatic iron

• Parenteral (intravenous) iron therapy is rarely requi­red in children with: (a) intolerance to oral therapy, (b) severe malabsorption states, e.g.

- Dose of parenteral iron can be calculated by Ganzoni formula, as:

Iron (mg) = Wt in kg x Hb deficit x 2.4 + (15 x Wt in kg) where Hb deficit is (Target Hb - actual Hb in mg/dl), 2.4 is the constant derived by multiplying blood volume (0.7 L/kg) with 3.4 (iron content/gm Hb) and 15 mg/kg is the iron required to replace stores.

Total calculated dose must be given over 3-7 days, diluted with equal volume of normal saline and infused slowly as 100 mg/30 minutes. Total daily dose should not exceed 7 mg/kg/day (max 300 mg) to minimize side effects, test dose is not necessary in children above 1 month of age.

- Formulations: Many parenteral formulations as iron­carbohydrate complex are available with variable elemental iron concentrations and immunogenic potential. Preferred option is ferric carboxymaltose (50 mg iron/ml), which can be safely administered as 15 mg/kg (Max 1000 mg) over 15-20 minutes with minimal risk of hypersensitivity reactions. Iron­sucrose maltose is frequently used in children with advanced renal disease, given as 1 mg/kg per session of dialysis followed by 1-2 mg/kg/week, diluted in 150 ml of normal saline and infused slowly over 30-90 minutes.

- Side effects of parental iron include infusion-related reactions such as flushing, headache, muscle/joint pain, nausea, rashes, fever, chills and very rarely, anaphylaxis.

- Contraindications include hypersensitivity to previous parenteral dose, when even the alternative formulation must be used cautiously.

• Blood transfusion is recommended only in very severe anemia (lt;5 gm/dl), given as packed cells (10 ml/kg) with monitoring for fluid overload, which may be prevented by pre-/post-transfusion furosemide. In very severe anemia with CCF, transfusion should be given very slowly, not exceeding 5 ml/kg/sitting, or preferably as exchange transfusion.

Prevention for IDA include: (a) promotion of breast­feeding, (b) increased consumption of iron-rich foods, e.g. beans, green leafy vegetables, jaggery, ragi, etc.,

(c) routine iron supplements in early infancy and adolescence, and (d) early diagnosis and treatment of cause, e.g. hookworms.

National Iron Plus Initiative (NIPI) Programme

National Iron Plus Initiative 2013 is the current version of previous National Nutritional Anemia Prophylaxis Programme (1970) and National Nutritional Anemia Control Programme (1995), presently administered as a component of Reproductive Maternal, Newborn, Child and Adolescent (RMNCH+A) strategy under National Health Mission.

Major interventions under NIPI, with reference to children include:

• Prevention of anemia in non-anemic children with prophylactic IFA supplements, as follows:

- 6-59 mo : 20 mg + 100 #956;g biweekly

- 5-10 yrs : 45 mg + 400 #956;g weekly

- 10-19 yrs : 100 mg + 500 #956;g weekly

• Treatment of mild to moderate anemia in anemic children with iron therapy as follows:

- 6-59 mo (Hb lt;10.9 gm/dl ): 3 mg/kg/d for 2 mo

- 5-10 yrs (Hb lt;11.5 gm/dl) : 3 mg/kg/d for 2 mo

- 10-19 yrs (Hb lt;11.9 gm/dl) : 60 mg/d for 3 mo

• Referral of children with severe anemia, i.e. Hb lt;7 gm/ dl below 5 years of age and lt;8 mg in older children, to nearest district hospital or first referral unit.

NIPI also provides IFA supplements (100 mg+500 #956;g) to pregnant women for 100 days after first trimester, to lactating mothers for 100 days in postpartum period and to all reproductive age (15-45 years) women once a week throughout the year. It also has provisions and guidelines for treatment of anemia in pregnant and lactating women.

Anemia Mukt Bharat

“Anemia Mukt Bharatquot; is a component of Poshan Abhiyaan, launched in 2018 to provide holistic nourishment. It aims to reduce the prevalence of anemia by 3% points per year in children, adolescents and reproductive age women, using a 6x6x6 strategy, i.e. 6 beneficiaries, 6 interventions and 6 institutional mechanisms.

• Six beneficiaries include: (1) children 6-59 months; (2) children 5-9 years, (3) Adolescents 10-19 years, (4) reproductive age women (20-24 years), (5) pregnant women and (6) lactating mothers.

• Six interventions include: (1) prophylactic IFA supple­mentation as in NIPI, (2) periodic 6-monthly deworm­ing with oral albendazole for children 1-19 years, (3) behavioral change campaign including to promote delayed cord clamping, (4) digital testing of anemia and point-of-care treatment, (5) iron fortified foods in public health programs, and (6) linkage with endemic diseases, e.g. malaria, hemoglobinopathies, etc.

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