1. Iron Deficiency Anemia
My name is Heather Escoto, and I am a Pediatric Hematologist/Oncologist at the Children’s Center for Cancer and Blood Diseases at St. Vincent.
My topic today is listed as anemia, but it is actually going to be much more focused on the topic of Iron deficiency anemia. I plan to provide a brief review of the definition and classification of anemia, and then turn attention to iron deficiency and iron deficiency anemia, which is likely the most common hematologic issue that is seen in primary care pediatrics, and it is also a common referral that we see in hematology clinic.
Heather Escoto, MD
Pediatric Hematology/Oncology
Children’s Center for Cancer and Blood Diseases at St. Vincent

2. Disclosures
Nothing to disclose I

3. Objectives Review of the following:
The definitions and classifications of anemia and factors affecting hemoglobin levels
The function, mechanisms of absorption, transport, and storage of iron
The incidence, risk factors, and etiology of iron deficiency
Physical exam findings, laboratory values, staging, and differential diagnosis of iron deficiency and iron deficiency anemia
AAP Screening recommendations, prevention, and treatment of iron deficiency
Effects of iron deficiency and iron deficiency anemia
The objectives of this lecture are two fold, first to review the definition and classificiation of anemia, and then to discuss iron deficiency anemia, including incidence, risk factors, laboratory values, staging, and differential diagnosis.
Then, we will discuss AAP screening recommendations, prevention, and treatment of iron deficiency
Finally, we will discuss long tern effects of iron deficiency

4. Definition Classification
“Anemia 101”
Definition Classification
Here we see a nice picture of RBCs.
There are two main ways to define anemia.
Skip to next slide. .

5. Definitions of Anemia
Physiologic definition: -Hemoglobin too low to meet oxygenation demands Laboratory definition: -Hemoglobin at least 2 standard deviations below mean value based on age, gender, and race **Laboratory definition of anemia does not always agree with physiologic definition of anemia!
The first way to define anemia is by the laboratory definition, or hemoglobin at least 2 Standard deviations below the mean value as determined by age, gender, and race.
However, it is also important to determine if the patient is physicologically anemic, or having a hemoglobin level that is unable to meet oxygenation demands.
For example, a 2 month old growing preterm infant may have a hemoglobin of 8.9, meeting the laboratory definition for anemia, but not considered phyisiologically anemic, as he is thriving and obviously meeting oxygenation needs.
On the other hand, there may be a 2 year old patient with cyanotic congenital heart disease who has a hemoglobin of 12, not anemic by laboratory criteria, but likely not high enough to meet physiologic demands given his underlying cyanotic condition.
So, it is important to consider both of these definitions when classifiying a patient as anemic.

6. Factors that affect hemoglobin levels
Age
Sex
Race
Puberty
Altitude
Heredity
Hemoglobin levels depend on many factors, including age, sex, race, puberty, altitude, and heredity.
I do not have a separate slide for altitude, but know that at higher elevations, the lower the oxygen concentration in the atmosphere, the higher your baseline hemoglobin.
This does not affect us in Indiana, but for pediatricians working in Denver or other higher elevations, their patients will have a higher baseline hemoglobin. .

7. Hemoglobin levels in infants- the physiologic nadir
Term infant -nadir- 12 weeks of age -hemoglobin 9.5 gm/dL at nadir Premature infant - nadir- 6-8 weeks of age -hemoglobin 7.0 gm/dL at nadir -nadir earlier and lower!!!
Newborns initially are born with a high hemoglobin, and then the levels tend to drop until about 8-12 weeks of age. This physiologic nadir occurs due to multiple mechanisms. As neonates transition from fetal to extrauterine life with the changes in oxygenation, red cell production falls, red cell mass decreases, and red cell survival is shortened.
The differences between term and pretem physiologic anemia are illustrated above, and it is important to know that preterm infants will have a much earlier and lower hemoglobin nadir compared to term infants. .

8. Age specific Hemoglobin levels
Age Hgb (g/dL)
26-30 week (11)
28 week
32 week
Term (cord) (13.5)
1-3 day (14.5)
2 week (13.4)
1 month (10.7)
2 month (9.4)
6 month (11.1)
6 mo-2 year (10.5)
2 year-6 year (11.5)
The next two slides contain age specific hemoglobin levels. This information is taken from the Harriet Lane Handbook, which is referenced from a variety of hematologic reference manuals.
The first number listed is the average hemoglobin level, and the number in parentheses is 2 SD below that number, or the low end of normal.
Notice that hemoglobin levels are lowest at 2 months of age, and then at 6 months-2 years of age as well. From that point the hemoglobin increases until adulthood.
Data from Table 14.1, the Harriet Lane Handbook: A manual for pediatric house officers/ the Harriet Lane Service, Children’s Medical and Surgical Center of the Johns Hopkins Hospital; editors, Jason Custer, Rachel Rau-18th edition.

9. Age specific Hemoglobin levels (cont.)
Age Hgb (g/dL) 2 year- 6 year 12.5 (11.5) 6 year-12 year 13.5 (11.5) year (male) 14.5 (13) year (female) 14.0 (12)
Data from Table 14.1, the Harriet Lane Handbook: A manual for pediatric house officers/ the Harriet Lane Service, Children’s Medical and Surgical Center of the Johns Hopkins Hospital; editors, Jason Custer, Rachel Rau-18th edition.

10. Age and Hemoglobin levels
This is a graphical representation from an article in Journal of Pediatrics in 1979 which classifies hemoglobin levels and MCV levels by age and sex. Remember, MCV is mean corpuscular volume, or the size of RBCs.
The left graph shows data from girls, and the right graph shows data from boys. One observation is that the hemoglobin levels are similar in boys and girls until pubertal age, and then boys have a much sharper increase in hemoglobin, and ultimately higher hemoglobin levels in later adolescence and adulthood.
MCV slowly and linearly increases as age increases in both boys and girls.
Hemoglobin and mean conpuscular volume (MCV) percentile curves for girls and boys. (Redrawn from Dallman PR, Siimes MA: Percentile curves for hemoglobin and red cell volume in infancy and childhood. J Pediatr 1979; 94:28.)

11. Hemoglobin differences between African-American and Caucasian children
Mean Hgb g/dL
This is a graphical representation of data from a paper looking at differences in hemoglobin between African American and Caucausian children. I have to point out two errors in the printed slides, the 2nd and 4th bar should read age 10-14, not 14-18, and all of these age groups have statistically significant differences.
The results of this paper, as well as other large surveys, show that African American children between 5 and 14 generally have a statistically significant hemoglobin about 0.5g/dL lower than Caucasian children of the same age. The largest difference is seen in males age 10-14, and the smallest difference is seen in males age 5-9.
Reasons for why there are racial differences in hemoglobin between the two groups may be explained by an higher prevalence of thalassemia trait in African Americans, or other hemoglobin variants, although no conclusive explanation has been proposed.
Males
Females
Data from: Dallman et al. Hemoglobin concentration in white, black and Oriental children: is there a need for separate criteria in screening for anemia? Am. J. Clin. Nutr.:1978; 31:

12. Sexual Maturity and Hematocrit
The next two graphs look at Tanner Stage and Hematocrit levels. This information was published in an article from Pediatrics. The graph on this page shows the relationship between hematocrit and Tanner Staging in males, notice that there is a smooth linear increase in hematocrit with advancing Tanner staging.
This same paper also graphs the relationship between age and hematocrit in adolescents age 12-18, and the relationship is not as linear.
The authors conclude that hematocrit values increase in males in relation to chronologic age only when sexual maturation is taking place. They also hypothesize that testosterone and body mass increases during puberty cause the increase in hematocrit.
Also notice the difference between Caucasians and African Americans, which agrees with data seen from previous slides.
Daniel et al. Hematocrit: maturity relationship in adolescence.
Pediatrics 1973;52:388–394.

13. Sexual Maturity and Hematocrit
This graph is taken from the same paper, and shows the relationship between hematocrit and Tanner staging for females. There is not a linear increase in hematocrit as seen with males, and this is hypothesized to be due to females generally having a lower testosterone level and smaller muscle mass
Daniel et al. Hematocrit: maturity relationship in adolescence.
Pediatrics 1973;52:388–394.

14. Heredity and Hemoglobin
This graph represents data from a paper that studied 5-year-old children and their parents in 80 families and observed an association between the hemoglobin concentrations of the children and their parents. It was concluded that inheritance may exert a significant influence on hemoglobin levels.
Siimes et al, J Pediatr 1994 Jan;124(1): Effect of Hereditary on Hemoglobin Concentration.

15. Basic Laboratory Evaluation of Anemia
Complete blood count
Red blood cell indices- MCV, MCHC, RDW
Reticulocyte count
Peripheral smear-red cell morphology
5. Other labs as clinically indicated- iron studies, electrophoresis, hemolytic workup, Coombs
This slide is not in your handouts, but it lists a basic laboratory workup of anemia.
Once you determine that your patient is anemic, these addition labs will help determine the underlying etiology of the anemia.
Red cell indices are important- such as MCV- the size of the red blood cell, RDW- the red cell distribution width- describes the variation in red cell size. In conditions where there is a lot of variability in red cell size- iron deficiency being one of them- the RDW will be elevated.
Reticulocyte count will be discussed on the next slide
Peripheral smear is important to determine any abnormal red cell morphology- such as fragments, inclusions, abnormal shape, etc.
Other workup can be performed as clinically indicated
Quote or statistic could go here. Either the same one throughout, or change from page to page.

16. Reticulocyte count and anemia
This is a peripheral blood smear with reticulin staining that is showing two reticulocytes. Reticulocytes are young red blood cells that still contain precipitated RNA, caused reticulin, thus their name. The staining allows them to be more visible, without the staining they look light purple.
Mature red blood cells as you may remember, have lost their nucleus and do not contain any RNA/DNA.
The reticulocyte count is a nice, non invasive measure of bone marrow production/function, and is essential in the evaluation of anemia.

17. Reticulocyte count-absolute and percentage
Reticulocyte count (percentage)- - % of absolute concentration of RBCs containing precipitated RNA (reticulin) -non-invasive measure of new red cell production by bone marrow -dependent on RBC count -overestimated with severe anemia Absolute reticulocyte count % Reticulocytes X RBC count/100 Hgb % X 2,080,000 /100=ARC 62,400 Hgb % X 3,470,000 /100= ARC 104,100
There are two ways to evaluate reticulocytosis. One calculation is based on a percentage of RBCs containing reticulin and the second calculation is an absolute reticulocyte count.
Both of these numbers are important to use when calculating reticulocytisis. However, the reticulocyte count percentage can be overestimated in cases of severe anemia, so it is important to calculate the absolute reticulocyte count to determine whether the response is appropriate or not.
Look at the example with the hemoglobin of 6.4, and reticulocyte count of 3%, this is actually a lower reticulocyte response than if you had a hemoglobin of 11.2 with a 3% reticulocyte count. .

18. Physiologic response to anemia
Increased heart rate Increased stroke volume Vasodilation Decreased oxygen affinity (right shift in oxygen-hemoglobin dissociation curve)
This slide briefly shows the physiologic compensation mechanisms for amemia, including increasing circulation of hemoglobin, and increasing the oxygen transport to tissues.

19. Classification of Anemia
Mechanism- -Decreased production -Hemolysis -Blood loss RBC size- -Microcytic -Macrocytic -Normocytic
There are three main causes of anemia. Either red cell production is too low, the red blood cells are being destroyed, or they are being lost. That is it. Very simple.
On the other hand, the morphologic characteristics of the red blood cells are important in classification and understanding the etiology of the underlying anemia as well.
We are going to discuss the main mechanisms of anemia and discuss the laboratory findings seen. .

20. Classification of anemia
Mechanism-
Decreased production
-Marrow infiltration-malignancy
-Marrow injury- infections, toxins
-Nutritional deficiency
-Ineffective erythropoesis (thalassemias)
-Erythropoietin deficiency
-Labs: Low reticulocyte count, variable MCV
Decreased production of red blood cells can be caused by marrow injury or infiltration, or by a deficiency in some of the necessary ingredients to make the components of hemoglobin.
Decreased production can also be caused by low erythropoietin levels, commonly seen in chronic renal disease and other conditions
Common laboratory findings include a low reticulocyte count and variable MCV

21. Classification of anemia
Blood loss- -Reticulocyte count usually elevated- bone marrow trying to compensate -MCV usually normal to slightly elevated Hemolysis- -Acquired -autoimmune process, vessel injury, -Inherited RBC defect -Reticulocyte count usually elevated -MCV normal to slightly elevated
With blood loss, the reticulocyte count is usually elevated because the bone marrow is trying to compensate
MCV is usually normal to slightly elevated
Hemolysis can be caused by aquired or inherited conditions listed here. Usually the reticulocyte count is elevated and MCV is normal to slightly elevated.

22. Classification of anemia- morphology
Microcytic Normocytic
-Iron deficiency -Chronic disease
-Thalassemia -Malignancy
-Chronic disease -Renal failure
-Copper deficiency -Blood loss
Macrocytic -Hemolytic disorders
-Folate deficiency -Hemoglobinopathies
-Vitamin B12 deficiency
-Inherited bone marrow failure
-Hypothyroidism
-Drug induced
-Active hemolysis
Classifying anemia by morphology can also be very helpful in determining the underlying cause. This slide is not in your handouts, but I wanted to review this with you.
Microcytic anemia is mainly seen when you are deficient in the ingredients to make hemoglobin, whether it be iron, or copper, or there is diminished production of the hemoglobin chains seen with thalassemias. Microcytosis can also be seen with anemia of chronic disease, but this can be variable. We will discuss anemia of chronic disease a little later.
Macrocytosis can be caused by an inability of the red blood cells to mature as seen in folate deficiency. Macrocytosis is also seen with bone marrow failure syndromes when there is an underlying issue with red blood cell production and development. Macrocytosis can also be present when there is active reticulocytosis seen in cases of acute hemolysis. Remember reticulocytes are younger and are larger than mature RBCs.
Normocytic anemia can be seen with chronic disease, renal failure, blood loss and hemolytic disorders with chronic low level hemolysis, including hemoglobinopathies.
Quote or statistic could go here. Either the same one throughout, or change from page to page.

23. Iron Deficiency Anemia
On to iron deficiency anemia.
This is a peripheral blood smear showing signs of iron deficiency anemia.
The red blood cells are small, microcytic. This can be determined by comparing the size of the red blood cells the size of the lymphocyte. Normally red blood cells are similar in size to lymphocytes, and some of these red blood cells are not.
In addition, these red blood cells have increased central pallor, called hypochromia. Usually central pallor is 1/3rd the diameter of the red blood cell.
There are also many platelets present on this slide, and thrombocytosis can be a common finding with iron deficiency anemia. .

24. Why is iron deficiency important?
Remains most common nutrient deficiency in developing countries
Over 1 billion people affected, nearly half of the world’s young children
Decline in prevalence in industrialized countries- but still common
In US, most common in lower income infants and toddlers months of age and teenage girls
Over 700,000 toddlers affected in the US, 1/3 with anemia, over 7.8 million adolescent females/women
Long term effects on neurodevelopment, behavior, neurotransmitter myelination, energy metabolism
Increased susceptibility to lead toxicity

25. Why is Iron important?
-Essential component of hemoglobin and myoglobin -Component of certain proteins important for respiration and energy metabolism -Component of enzymes involved in the synthesis of collagen and some neurotransmitters -Essential for normal immune function
Iron is essential, not only for the hematologic system, but it is an important component of proteins and enzymes involved in respiration, energy metabolism, synthesis of collagen and neurotransmitters.
It is also essential for normal immune function

26. Iron: too much is bad Generates free radicals
Causes oxidative damage to cells
Protective mechanisms
Intracellular and intravascular iron bound to carrier proteins- transferrin, ferritin, hemoglobin, etc.
Iron absorption tightly regulated
Iron overload- most commonly from chronic transfusions: 1ml PRBCs has 1 mg iron
Iron is good, but too much is toxic.
Iron generates free radicals and causes oxidative damage to cells
There are many protective mechanisms in place to prevent this form occurring, including tight regulation of iron absorption and intracellular binding of iron to carrier proteins.
However, excretion of iron is fairly constant and limited to about 1 mg iron excreted/day.
Iron overload is most commonly caused by chronic transfusions, as 1 ml PRBC contains 1 mg iron. .

27. Iron: How much do we need?
Preterm infants: 2-4 mg/kg/day Full term infants: 1 mg/kg day Children 1-3 years old: 7 mg/day Children 4-8 years old: 10 mg/day Children 9-13 years old: 8 mg/day Males 14-18: 11 mg/day Females 14-18: 15 mg/day
Iron requirements are age dependent. The highest iron requirements occur at times of most rapid growth as seen in preterm and term infants. Female adolescents also require a significant amount of iron due to increased growth as well as menses.
Food and Nutrition Board of the Institute of Medicine. Iron in: Dietary reference intakes for Vitamin A, Vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academy Press, Washington DC, 2000; p. 339.

28. Iron distribution in the body
Once iron is absorbed, the majority is taken up and used in the production of hemoglobin. The remainder is stored as ferritin, used in myoglobin, or used by various enzyme systems.

29. Hemoglobin 4 globin chains (2 alpha and 2 beta globin chains)
4 heme molecules with iron in the center
This is a picture illustrating how iron is incorporated in the heme molecule, and then how the heme is incorporated into the hemoglobin molecule. Remember there are 4 heme molecules with 4 iron molecules in each hemoglobin structure made.
Heme molecule
Hemoglobin

30. Ferritin
Intracellular protein that stores and releases iron in a controlled fashion
Aggregates of ferritin form hemosiderin
Ferritin is also an acute phase reactant- acts to protect iron from being used by an infective agent
Fe3+
Ferritin
Fe 2+
apoferritin
The remainder of iron is stored as ferritin, in myoglobin, or incorporated into various enzymes.
1ng ferritin can contain 10 mg iron. To be considered iron replete, ferritin levels should be greater than 10-12, corresponding to mg iron.
To make ferritin, the ferric form of iron is combined with apoferritin to make ferritin.
Ferritin can form aggregates called hemosiderin, which can be seen in iron overload
Ferritin is stored in the liver, macrophages, bone marrow, spleen, and reticuloendothelial system
Serum ferritin is an acute phase reactant. It is increased during periods of inflammation and infection, and acts to sequester iron to prevent its uptake and use by bacteria or other infectious agents.

31. Iron containing enzymes
-Important in oxidative metabolism and DNA synthesis
Heme proteins:
-Cytochromes
-Catalase
-Peroxidase
-Cytochrome oxidase
Flavoproteins:
-Cytochrome C reductase
-Succinic dehydrogenase
-NADH oxidase
-Xanthine oxidase
A small amount of iron is found in a variety of enzymes necessary for basic cellular functioning. .

32. Iron Balance Intake= 10 mg/day Absorption= 1 mg/day- variable
Loss- 1 mg/day- mainly by sloughing of enterocytes (and menstruation in females)
Iron stored in macrophages and hepatocytes
On average, oral iron intake is usually about 10 mg/day, slightly less for younger children. However, on average, only about 10% of the consumed iron is actually absorbed, but this can be regulated to some degee.
There is no mechanism for regulation of iron excretion. Iron is generally excreted in sweat, shed skin cells, and sloghing of enterocytes. In females, iron is also excreted through menstruation.
Iron loss is generally about 1mg/day. Women generally have an extra menstrual loss of 1-2 mg of iron/day.
Iron is also released from daily breakdown of senescent red blood cells in macrophages, and can also be mobilized from iron stored as ferritin in the liver

33. Iron absorption 10% of dietary iron is absorbed Absorption depends on:
-dietary iron content
- bioavailability (heme vs. non- heme)
- mucosal cell receptor number
Main absorption occurs in duodenum
How much iron is absorbed depends on how much is taken in and what form of iron is taken in. Heme iron, generally found in meat sources, is much more bioavailable than non-heme iron.
Iron absorption is increased when iron stores are reduced or absent and when there increased erythropoesis.
Main iron absorption occurs in the duodenem. .

34. Iron absorption -Heme (meat) >> non-heme iron sources
-(30%-50% vs. <10%)
-Ferrous sulfate >> ferric sulfate
-Enhanced by red meat, ascorbic acid, breast milk
-Diminished by vegetable fiber, cow milk, egg yolk, tea, phytates, phosphates (soda)
As was said previously, heme sources of iron are absorbed to a much higher degree compared to non-heme sources. Generally, about 30-50% of heme iron is absorbed compared to 10% or less of non-heme iron.
Ferrous sulfate forms of iron are absorbed much better than ferric sulfate
Absorption is enhanced by intake of red meat, ascorbic acid, and breast milk
Absorption is diminished by intake of vegetable fiber, cow milk, egg yolk, tea, and phosphates, which are components of soda

35. Iron absorption Iron is converted from Fe3+ to Fe2+ by ferrireductase
Fe2+ transported across mucosal surface of enterocyte by DMT1, stored as ferritin
Ferritin releases Fe2+ which is transported across basolateral surface of enterocyte with help of ferroportin *****
Fe2+ converted back to Fe3+ by Hephaestin
Fe3+ binds to transferrin in plasma
I am going to skip this slide and go on to the illustration that describes iron absorption, but you can follow along with the text.

36. Iron absorption
First, the ferric (Fe3+) form of iron is converted on the outside of the enterocyte to the ferrous (fe2+) form of iron, and is then transported into the enterocyte. Ferrous forms of iron (meats) are directly absorbed without needing conversion.
Iron is then either stored as ferritin or transported into circulation by ferroportin.
As the ferrous form of iron is released into circulation, it is converted into the ferric form of iron by ferroxidase. It is then bound to transferrin for transport in circulation.
Ferroportin and hepcidin are important in the regulation of iron transport. .

37. Ferroportin and Hepcidin
Hepcidin -Blocks ferroportin -Prevents absorption of iron from enterocytes -Prevents iron exportation from macrophages -Increased in inflammation -Leads to reduced serum iron, microcytic anemia, and incomplete response to iron therapy Ferroportin -Transporter protein in enterocytes and macrophages -Blocked by hepcidin
Ferroportin functions as a major exporter of iron, transporting iron from enterocytes into circulation and transferring iron from damaged red blood cells found in macrophages back into circulation. It is regulated by the amount of available iron, and is blocked by the action of hepcidin.
Hepcidin is an acute phase reactant, increased in inflammation and infection. It inhibits ferroportin, blocking the absorption of iron from enterocytes and macrophages. It is down regulated in hypoxia, anemia, and iron deficiency
In cases of anemia of chronic disease, hepcidin is elevated, leading to a low serum iron, microcytic anemia, and decreased absorption of iron, leading to an incomplete response to oral iron.

38. Iron uptake by the erythroblast
Fe3+ bound to transferrin attaches to transferrin receptor on erythroblast
Transferrin and Fe3+ separate, Fe3+ combines with heme to make hemoglobin
Extra Fe stored as ferritin
Apotransferrin exported out of erythoblast
Skip this slide

39. Iron uptake by the erythroblast
Fe3+
Binding of iron-transferrin to its receptor
Release of apotransferrin
TfR
Incorporation into iron-protein
Release of iron to storage
to storage
Once iron is bound to transferrin in the plasma, it is taken into the red blood cell, and iron is incorporated into heme to make hemoglobin. Extra iron is stored as ferritin in the red blood cell.
Ferritin
Hemosiderin
Katz JH. Iron and protein kinetics studied by means of doubly labeled human crystalline transferrin. J Clin Invest 1961;40:

40. Iron deficiency- definitions
Iron deficiency (ID)- deficient in iron, no anemia
Iron deficiency anemia (IDA)- deficient in iron leading to anemia
Anemia- 2 SD below defined “normal” mean based on age and gender
Now that we have discussed the mechanisms of iron absorption and storage, let’s talk about iron deficiency. We will use the terms iron deficiency without anemia and iron deficiency anemia in further slides, so be aware of this difference.

41. Incidence of ID and IDA in US
Infants
-no national statistics on incidence of ID and IDA in infants before 1 year of age
-Norwegian cohort showed 4% incidence at 6 months increasing to 12% incidence at 12 months
Toddlers (1-3 years)
Iron deficiency- 9%-15%
Iron deficiency anemia- 3-5%
Children
Iron deficiency- 4% incidence
In infants less than 1 year, there are no national US statistics on the incidence of iron deficiency and iron deficiency anemia . There was a norwegian cohort of infants from a published report in 1994 that showed a 4% incidence of ID at 6 months increasing to 12% incidence at 12 months, but this is difficult to correlate.
In toddlers, the incidence of iron deficiency is 9-15%, and iron deficiency anemia is 3-5%
In children, the incidence of iron deficiency is 4%. The risk of iron deficiency anemia is very low in this population, except in certain risk groups to be discussed shortly.
Looker AC, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):
Hay et al. Iron status in a group of Norwegian Children aged 6-24 months. Acta Paediatr. 2004;93(5):

42. Incidence of ID and IDA in US adolescents
Adolescent females Iron deficiency- 9-11% Iron deficiency anemia- 2-5% Adolescent males Iron deficiency < 1%
Adolescent females have an increased incidence of iron deficiency and iron deficiency anemia
Adolescent males have a very low risk of iron deficiency.
Looker AC, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):

43. Prevalence of iron deficiency in US children 1-3 years old
Hispanic- 12% English speaking- 7% African American- 6% Non-English speaking- 14% Caucasian- 6% Overweight-20% Daycare- 5% Normal weight-7% No daycare- 10% Bottle fed <12 months -3.8% Bottle fed >24 months- 12.4%
In the toddler population, there are specific subgroups of patients which have a higher incidence of iron deficiency, including hispanic patients, non-English speaking patients, overweight toddlers, toddlers who bottle feed longer that 2 years, and interestingly, children who are not in daycare.
Brotanek et al. Iron Deficiency in Early Childhood in the United States: Risk Factors and Racial/Ethnic Disparities. Pediatrics 2007;120;568. Arch Pediatr Adolesc Med 2005; 159: .

44. Risk factors for Iron Deficiency in Infants and Children
-Prematurity or low birthweight
-Exclusively breastfeeding beyond 4-5 months without iron supplementation
-Cows milk before 1 year
-Excessive milk intake
-Obesity
-Poverty/Low socioeconomic status
-Malnutrition
-Chronic illness or special health needs
Other risk factors for iron deficiency include prematurity, low birthweight, exclusive breastfeeding beyond 4-5 months without iron supplementation, drinking cows milk too early or too much, obesity, poverty, malnutrition, or chronic illness
Brotanek et al. Iron Deficiency in Early Childhood in the United States: Risk Factors and Racial/Ethnic Disparities. Pediatrics 2007;120;568
Pizzaro et al. Iron status with different infant feeding regimens: relevance to screening and prevention of iron deficiency. J Pediatr May;118(5):687-92

45. Risk Factors for iron deficiency in Adolescents
Growth spurts
Heavy menses
Chronic illness
H pylori infection
Endurance training
Vegetarian diets
Obesity
Poverty
Pregnancy
In adolescents, the risk factors for iron deficiency include increased growth, heavy menses, chronic illness, endurance training, and vegetarian diet.
As seen in toddlers and children, poverty and obesity are also risk factor.s
H.Pylori has been shown to be associated with iron deficiency anemia in adolescents, likely due to chronic microscopic blood loss and inflammation.
And we can’t forget pregnancy.

46. Etiology of Iron Deficiency
Low birth stores
Dietary- not enough intake to meet requirements
Blood loss- majority of iron stored in RBCS
Poor absorption
There are 4 main causes for the development of iron deficiency, and they are as follows: Either you are not born with enough, you are not taking in enough, you are losing too much, or you are not absorbing enough.

47. Newborn Iron Stores Endowed with 75 mg/kg of iron at birth
Dependent on hemoglobin concentration at birth (majority of iron in circulating RBCs)
Minimally dependent on maternal iron status
Depleted by 3 months in low birth weight infants without supplementation
Depleted by age 5-6 months in term infants
Delayed cord clamping (by 2 minutes) leads to higher ferritin and iron stores at 6 months of age
Neonates are born with 75mg/kg of iron at birth. This is dependent on hemoglobin concentration at birth- remember that about 70% of iron is found in circulating RBCs. It has been shown that delayed cord clamping by 2 minutes does lead to a higher ferritin at 6 months of age. Iron stores are only minimally dependent on maternal iron status.
Iron stores tend to be depleted by 3 months in low birth weight infants without extra supplementation. Their needs are too great at that time to be fulfilled by dietary intake alone, and pharmacologic iron is necessary.
Iron stores are depleted by 5-6 months in term infants. At this time, extra dietary or pharmacologic iron is required.

48. Dietary iron content Milk mg Fe/Liter Breast milk 0.5-1 **
Whole cow
Skim
Formula (low iron) 2- 4
Formula (high iron)
Foods mg/serving
Infant cereal 6
Baby foods
**more bioavailable
This slide shows the concentration of iron in different sources of milk. Although breast milk has the same concentration of iron as cows milk, it is much more bioavaliable than cows milk.
You can also see the difference between low iron and high iron formula, fortunately, low iron formula is not easily accessible anymore.
Also note the amount of iron in infant cereal, this is a very good source of iron in infants 6 months and greater. I think a lot of parents may forget about infant cereal once they start baby food, but it provides an excellent source of dietary iron.

49. Iron content of Common Toddler foods/drinks
Foods % daily value/serving
Fruit snacks 0 mg
Chicken nuggets 8%
Macaroni and cheese 10%
Chips 5%
Graham crackers 17%
Cheerios 25%
Goldfish 2%
Drinks % daily value
Apple juice 5%
Pediasure %
Soda %
I have also included a slide looking at iron content in some common toddler foods/drinks. The iron content is listed as % daily value/serving instead of milligrams.
Cereals and grain products tend to be iron fortified as you can see with the cheerios and graham crackers. Unfortunately fruit snacks and goldfish, common toddler staples, are not good sources of iron. Also for the toddler who comes to clinic drinking soda out of a milk bottle- I know we have all seen them- also not a good source of iron.
If only we could supplement fruit snacks or chips…

50. Cows milk and iron deficiency
Poor source of iron
Poor absorption (5-10%)
Reduces consumption of other foods, especially with overconsumption
Can cause microscopic GI bleeding
Cows milk is a poor source of iron, it is poorly absorbed, it reduces consumption of other foods, and it can cause microscopic GI bleeding. .

51. Iron rich foods
Heme iron (better bioavailability) Meat (beef and turkey best) Shellfish Non-heme iron (less bioavailability) Breakfast cereal (iron fortified) Pasta (iron fortified) Beans and lentils Baked potato with skin Foods that increase iron absorption Fruits, vegetables, meat, fish, poultry, white wine
This is an abbreviated list of iron rich foods. Basically the different categories include meats (turkey and beef best), shellfish if age appropriate. I didn’t include liver, although it contains the most iron, because it usually isn’t a childhood favorite. Other iron rich foods include breakfast cereal, pasta, beans, and baked potatoes with the skin (also not a childhood favorite).
Fruits and vegetables are generally not high in iron content, but can increase the iron absorption of other foods. .

52. Causes of Iron deficiency: Blood Loss
GI blood loss:
-cow’s milk, IBD, esophageal varices, ulcers, anatomic lesions, parasitic infections
Menorrhagia
Epistaxis
Other rare causes:
pulmonary, renal, intravascular
We have discussed two causes of iron deficiency- decreased newborn stores and inadequate dietary intake, now we will discuss the third cause of iron deficiency: blood loss.
Blood loss most commonly occurs in the GI tract, due to multiple etiologies listed here. Other causes of blood loss include menorrhagia, epistaxis, and rare causes such as pulmonary blood loss, renal loss, and intravascular loss.
It is also important to consider frequent phlebotomy as a cause of blood loss and iron deficiency in frequently hospitalized patients.

53. Iron Deficiency: Malabsorption
Short gut
Celiac disease
Medications (GERD)
Chronic Giardiasis
IRIDA (Iron Refractory Iron deficiency anemia)
Dx: Iron absorption test
The 4th cause of iron deficiency is malabsorption, either from anatomic deficiencies, chronic inflammatory/infectious GI disease, and medications.
There is also a syndrome called iron refractory iron deficiency anemia, which is an autosomal recessive disorder characterized by iron deficiency anemia unresponsive to oral iron and partially responsive to parenteral iron.
IRIDA leads to abnormal regulation and increased levels of hepcidin, leading to decreased absorption of intestinal iron and inability to recirculate iron from macrophages

54. Diagnosis: History and Physical
blood loss?
dietary history
GI symptoms?
Heavy menses?
Irritability?
Weakness?
PICA?
Physical exam-
pallor, tachycardia, irritability
On taking a history from a patient with suspected iron deficiency anemia, it is important to determine if there are any symptoms of ongoing blood loss, GI symptoms, dietary history, symptoms of PICA, signs of irritability or weakness.
Physical exam findings are usually non specific but include pallor, tachycardia, and irritabliity .

55. So what is PICA? PICA is a very interesting phenomenon where patients with iron deficiency crave non-nutritive substances, here we see a nice plate of dirt.

56. PICA
Patients can also crave rocks.

57. PICA
Cardboard is common ingested by patients with PICA– especially the the hard cardboard books for young children.

58. PICA and iron deficiency
Compulsive ingestion of usually a single non-nutritive substance
Behavior cured with therapeutic iron therapy
Typical ingested substances
Rocks Carpet
Dirt Hair
Paint chips Clothing
Cardboard Insects
Clay Ice chips
Another interesting fact about PICA is that it improves with iron therapy.
Other ingested substances include paint chips, clay, carpet, insects, and ice chips

59. Lead and iron deficiency
Iron deficiency PICA
PICA lead ingestion
Iron deficiency increases lead absorption from intestine
Lead toxicity does not cause microcytic anemia
There can be a lot of confusion about the relationship between iron deficiency and lead toxicity. Basically, iron deficiency can cause PICA, which can cause lead ingestion. Also, iron deficiency increases lead absorption from the intestine.
Lead toxicity by itself does not cause a microcytic anemia, this is due to an underlying iron deficiency anemia.

60. Diagnosis of Iron Deficiency: Staging
Depletion of iron stores
Iron deficient erythropoiesis
Iron deficiency anemia
There are three main stages of iron deficiency. The first stage involves depletion of the iron stores. As this progresses, erythropoesis if affected, leading to the second stage. Finally, as erythropoesis continues to be affected, this leads to iron deficiency anemia.

61. 3 stages of Iron Deficiency
This graph details the stages of iron deficiency and the associated laboratory findings. Typically, serum ferritin is the first abnormal finding to be seen with iron depletion, then transferrin saturation decreases and the RBC protoporphyrin level increases. Finally, with iron deficiency anemia, the hemoglobin decreases to below normal.
Generally, serum ferritin is actually apoferritin (without bound iron). We have also discussed transferrin briefly. RBC protoporphyrin levels are sometimes used to measure iron deficiency, but are pretty non-specific. Basically, protoporphyrin is a precursor to heme formation, so with iron deficiency, there is diminished heme synthesis and increased protoporphyrin levels.
>11
>11
>11
<11
FIG Measurements of Iron Status in Relationship to Body Iron Stores (mg). J.D. Cook and C.A. Finch, "Assessing Iron Status of a Population," A J. Clin Nutr, 32: 2115 (1979) Graph in Methods for the Evaluation of the Impact of Food and Nutrition Programmes (UNU, 1984, 287 pages).

62. Diagnosis of Iron Deficiency: Laboratory Workup
Laboratory Value Ferritin <12 µg/dL Serum iron <40 µg/dL Serum transferrin (TIBC) >400 µg/dL Transferrin saturation ratio (Fe/TIBC) <10% Hemoglobin <11 g/dL MCV <70 fl RDW >16% Reticulocyte count <1%
There are common laboratory values that are used to diagnose iron deficiency and iron deficiency anemia. I think we have discussed a majority of these. The RDW, is the red cell distribution width, and is elevated when there is increase variablilty in red cell size. With iron deficiency, this is usually elevated.

63. Diagnosis of Iron Deficiency: Laboratory Workup
Other supporting labs:
-Platelet count elevated
-Serum transferrin receptor >35
-Reticulocyte hemoglobin content ** <26
-Hemoglobin A reduced
-Free erythrocyte protoporphyrin >100
Hepcidin reduced
C reactive protein
**first laboratory test abnormal
Other supporting laboratory findings include thrombocytosis. It it is also important to evaluate a marker of inflammation such as CRP, to ensure that the ferritin is not falsely elevated due to inflammation.
Other newer , less available testing includes the reticulocyte hemoglobin content which has been show to be the earliest laboratory marker for iron deficiency.
Hemoglobin A2 is decreased with iron deficiency, so evaluation for B thalassemia may be inconclusive in the face of iron deficiency

64. Diagnosis: peripheral smear
This is another peripheral blood smear which shows some of the morphologic findings seen with iron deficiency. In the middle you see a normal lymphocyte, and you may notice that the RBCS are signficantly smaller,, they are microcytic. In addition, they have increased central pallor, called hypochromia. You also can see a lot of platelets as well.
Hypochromia
Microcytosis
Thrombocytosis l

65. Differential diagnosis of microcytic/hypochromic anemia
Iron deficiency Thalassemia Inflammation Hemoglobin C or Hemoglobin E disease Hereditary hyropoikilocytosis Copper deficiency Sideroblastic anemia Congenital atransferrinemia
We discussed this a little bit earlier, but the differential diagnosis of a microcytic/hypochromic anemia most commonly includes iron deficiency, thalassemia, and inflammation.

66. Laboratory parameters in thalassemia trait and iron deficiency
α thal trait
Β thal trait
IDA
Hemoglobin (g/dL)
12.6
11.3
10.2
Red cell count (X10^6/µL
5.6
4.7
4.67
MCV (fl)
60.8 67
MCHC
23.2
20.3
21.8
HgB A2
Normal or decreased
Elevated
Mentzer index
(MCV/RBC
<13
>13
This table compares the common laboratory findings with thalassemia trait and iron deficiency anemia, and you can see that there is really not a lot of difference in most of the values.
There is a value at the bottom called the Mentzer index, which is a measure of MCV/RBC. In iron deficiency anemia this has been shown to generally be greater than 13, where in thalassemias, it has been shown to be less than 13. And this number can be calculated with both types of thalassemias.
However, this data should be correlated with iron studies to be most helpful.
Nathan and Oski’s Hematology of Infancy and Children, 7th ed. p.1054 table 20.7

67. Differential Diagnosis of Microcytic Hypochromic Anemia
Anemia of inflammation
Iron restricted erythropoesis:
- Secondary to inflammation, chronic kidney disease, aging, chemotherapy, IRIDA
Due to sequestration of iron in macrophages
Increased hepcidin
Low serum iron
Low transferrin saturation
Normal or increased iron stores
Anemia of inflammation can also present with microcytic hypochromic anemia
This type of anemia is also referred to as iron restricted erythropoesis, which better describes the underlying cause. Mainly this anemia is due to elevated hepcidin, an acute phase reactant, which decreases absorption of iron and prevents the release of iron from macrophages. So the iron stores are there but they can’t be used.
Common laboratory findings include normal to increased ferritin, low transferrin saturation, low serum iron.
Goodenough et al, Blood 2010; 116:

68. *increased hepcidin blocks release of iron from macrophages
This picture describes the blockage of iron release from macrophages, seen with any condition that elevates hepcidin
*increased hepcidin blocks
release of iron from macrophages

69. Differential Diagnosis of Low Serum Iron
-Iron deficiency -Infection -Inflammation -Malignancy -Postoperative -Stress
Causes of low serum iron alone are seen here, mainly these are two groups, iron deficiency and conditions causing iron restricted hematopoiesis- anemia or chronic disease. .

70. Screening for iron deficiency
AAP recommendations: Determination of hemoglobin concentration -Term infants - 12 months of age -Preterm infants - 9 months of age Assessment of risk factors for ID/IDA: -Inadequate iron intake, poor nutrition, feeding problems, poor growth Additional screening at months of age?
Current AAP recommendations for screening for iron deficiency are to determine hemoglobin concentration at the following age:
In term infants, 12 months of age
In preterm infants, 9 months of age
It is also recommended to perform routine assessments of risk factors for ID/IDA, including inadequate iron intake, poor nutrition, feeding problems, poor growth
While not a current recommendation, it has been advocated to perform additional screening at months of age., due to the increased incidence of iron deficiency at this time.
Pediatrics 2010; 126:

71. Screening for Iron Deficiency Anemia in Adolescents
AAP recommendations: -Menstruating girls be screened annually by measuring hemoglobin concentration -Adolescent boys- screened once during peak growth period -Consider risk factors for anemia and screen appropriate patients at any time
In adolescents, it is recommended to screen menstruating females annually by measuring hemoglobin concentration
Adolescent boys should be screened once during the peak growth period
It is also important to routinely evaluate for risk factors for iron deficiency anemia and perform screening if determined necessary
Committee on Nutrition, American Academy of Pediatrics. Screening for Iron Deficiency, in: Pediatric Nutrition Handbook, 6th ed, Kleinman, RE (ED). American Academy of Pediatrics, Elk Grove Village, IL p. 419

72. Prevention of Iron Deficiency Anemia in Infants and Toddlers
Breastfeeding for the first 6 months of life
Iron fortified formula
Iron fortified infant cereal beginning at 6 months of age
Iron supplementation for preterm infants
Iron supplementation for breastfeeding infants at 4 months of age
Avoid cows milk before 1 year of age
Limit cows milk intake to oz/day after 12 months of age
There are many ways to prevent iron deficiency in infants and toddlers, including breastfeeding for the first 6 months of life or using iron fortified formula.
Giving iron fortified cereal beginning at 6 months of age
Giving iron supplementation for preterm infants
Giving iron supplementation for breastfeeding infants at 4 months of age
Avoiding cows milk before 1 year of age
Limiting cows milk intake

73. Iron Deficiency-Treatment
Oral iron therapy
Mild iron deficiency- 3 mg/kg/d elemental iron in daily dose
Moderate to severe- 6 mg/kg/d elemental iron divided twice daily
Severe- consider PRBC transfusion (Hgb <4 gm/dl) AND oral iron
In patients with iron deficiency with or without anemia, oral iron therapy should be initiated.
Iron supplementation should contain 3-6 mg/kg/day of elemental iron depending on the severity of the iron deficiency
In patients with severe anemia, usually a hemoglobin < 4, consider PRBC transfusion and oral iron .

74. Types of Oral iron Ferrous sulfate Carbonyl iron
- 20 % elemental iron -100% elemental iron
- well absorbed** mg tab
- 325 mg tab- 65 mg elemental -15 mg/1.25 ml
-75mg/0.8 ml – 15 mg elemental -less absorption
-15mg/ml- 15mg elemental
Ferrous gluconate Iron polysaccharide
-12% elemental iron % elemental iron
-300 mg tab- 36 mg elemental mg/5 ml, 150 mg tab
-well absorbed
Ferrous fumarate
-33% elemental iron
-200 mg tab- 66 mg elemental
-chewable tab 33 mg
-extended release tabs- poorer absorption
-Iron sprinkles (developing countries)
This table is mainly to illustrate that there are many different types of iron with different elemental ratios, different absorption, and different dosing
This can be challenging when counseling families on the correct dosing.
Most commonly, ferrous sulfate is used- good absorption, inexpensive
Unfortunately, concentrated fer-in-sol is not easy to find, now usually 15 mg/ml
Iron polysaccharide- Niferex- contains Vitamin C to enhance absorption. It is difficult to find liquid Niferex, but tablets can be used, tends to be more expensive .

75. Oral iron therapy- side effects
-BAD TASTE! -GI intolerance -Dark stools -Staining of teeth
The major issue with oral iron therapy is that it tastes bad. It is really hard to hide the metal taste. It should not be taken with milk or dairy products either, and for kids that only want to drink milk, this can be a challenge.
It can also cause constipation, dark stools, and staining of teeth

76. Response to Oral Iron therapy
Monitoring: 1-2 weeks- (for moderate to severe anemia) -increase in reticulocyte count - increase in hemoglobin (1-2 gm/dl) 4-6 weeks- -correction of hemoglobin Continue iron therapy for at least 3-4 months, possibly longer
After beginning iron therapy, it is important to monitor laboratory parameters to assess for response and compliance.
In some cases of severe anemia, you may want to recheck in 1-2 weeks, and at this point, you can see an increase in reticulocytosis, and an increase in hemoglobin by 1-2 gm/dl)
After 4-6 weeks, you should see correction of the hemoglobin
Iron therapy should be continued for at least 3-4 months, possibly longer

77. Causes for poor response to oral iron
-Non-compliance ***
-Incorrect administration***
-Incorrect diagnosis
-Incorrect dosing
-Ongoing blood loss
-Malabsorption
-IRIDA
There can be many causes for poor response to oral iron including non-compliance, non-compliance, and non-compliance.
There can also be issues with incorrect administration, incorrect diagnosis, incorrect dosing, ongoing blood loss, and malabsorption issues.

78. Indications for IV iron therapy
Iron deficiency not responding to oral iron therapy
-Poor compliance
-Adverse effects
-Malabsorption*
-Ongoing hemorrhage*
Anemia of chronic disease (iron restricted erythropoiesis)
-Renal failure, inflammatory disorders
For some patients, IV iron therapy may be considered, mainly in patients with absorption issues, chronic disease, and ongoing hemorrhage. .

79. IV iron therapy Preparations: Iron dextran (HMW and LMW)
Ferric gluconate
Iron sucrose
Side effects:
Anaphylaxis (2-3% with iron dextran)
Chills, back pain, body aches
There are three main preparations of IV iron therapy. Iron dextran is the older from of IV iron, and is associated with a 2-3% risk of anaphylaxis
Iron sucrose is a newer form of IV iron, and has been found to be safer.
Newer forms of iron, including iron sucrose have been shown to have an improved safety profile, and are well tolerated and have been shown to be efficacious. Dosing in IV iron is based on calculating the total iron deficit and giving increments of this dose every 3-7 days. Some practices will give one large dose of IV iron sucrose only. .

80. Neurodevelopmental effects of ID and IDA
Psychomotor development and cognitive function
-MULTIPLE studies
-conflicting studies for ID
-moderate to severe IDA- long term decreased cognitive function-may not recover with correction of iron status
Learning:
NHANES III- lower math scores with iron deficiency, no effect seen with reading, verbal, and performance scores
Attention, concentration and cognitive function:
Meta-analysis of randomized trials in older children and adults showed some improvement in attention, concentration, and cognitive function with improvement in ID
To conclude this presentation, I want to spend a few minutes discussing the data regarding neurodevelopmental effects of iron deficiency and IDA.
There have been MULTIPLE studies looking at effects of iron deficiency and iron deficiency anemia on development and cognitive function. Although the data is conflicting for ID, there is reported long term decreased cognitive function with IDA, which may or may not be reversible.
In addition, there have been studies that show lower math scores with iron deficiency
Adolescents and adults report improvement in attention, concentration, and cognitive function with improvement of iron deficiency
Lozoff, et al. J Pediatr 1996; Halterman et al. Pediatrics 2001; 107: Lozoff et al. Arch Pediatr Adolesc Med 2006; 160:1108. Falkinham et al. Nutr J 2010; 9:4.

81. Other Effects of ID and IDA
Changes in transmission through auditory and visual systems in young infants
Mild to moderate defects in leukocyte and lymphocyte function
Increased risk of cerebral vein thrombosis
Breath holding spells
Decreased exercise capacity
PICA
? Febrile seizures
Impaired myelination
Neurotransmitter metabolism
Other effects seen with ID and IDA inclued changes in transmission through auditory and visual systems in young adults, mild to moderate defects in leukocyte and lymphocyte function
-There has been reported increased risk of cerebral vein thrombosis with ID and IDA, breath holding spells, decreased exercise capacity, PICA, ?febrile seizures (conflicting data) and impaired myelination and neurotransmitter metabolism.
So, iron deficiency anemia causes much more than just anemia.
.Algarin et al. BMJ 1996;313:343. Hartfield et al. Clin Pediatr (Phil) 2009; 48:420. Zehetner et al. Cochrane Database Syst Rev 2010; :CD Ekiz et al. Hematol J 2005; 5:579. Benedict et al. J Chld Neurol 2004; 19;526.