Episode Transcript
Hi and Welcome to Clerkship Ready - Pediatrics - A podcast aimed at helping you excel during your clinical clerkship in Pediatrics.
I am Riley Calicchia, and I am a 4th year medical student at the University of Virginia.
Today, we will be reviewing what you need to know before you first see a patient with possible iron deficiency. We will discuss why iron is so important, when and why iron deficiency occurs, screening, diagnosis, and treatment for iron deficiency.
Iron deficiency is the most common nutritional deficiency that occurs in children in the United States. Due to high iron demand, depletion of iron stores, and changes in diet, children are at a high risk for iron deficiency and iron deficiency anemia at different stages of life. The first is from 9-24 months of age. Because of this high risk, current guidelines advise screening children at 12 months of age for iron deficiency anemia. This screening is typically done with a history, physical, and a serum hemoglobin. We screen because iron deficiency in infancy can lead to significant impairment in development. Adolescents are also at high risk for iron deficiency, and we’ll talk about both of these groups in more detail in a few minutes.
Let’s first talk about why iron is so important. Iron is important in cellular function, hemoglobin synthesis, nervous system development, and immune function. Let’s talk about each in a little more detail.
First, iron plays a crucial role in cellular function, specifically metabolism- so it’s important in all organ systems. It’s involved in oxygen and electron transport. It is also a cofactor of ribonucleotide reductase, which converts ribonucleotides to deoxyribonucleotides- the building blocks for DNA replication and repair.
Second, iron is extremely important in the synthesis of hemoglobin. The production of hemoglobin is dependent upon, and regulated by, iron. This why iron deficiency can lead to anemia. As you may recall from your basic science classes, the formation of heme molecules involves the incorporation of iron into protoporphyrin IX by ferrochelatase in the last step of the pathway. Along with its direct role in heme synthesis, iron also serves as a regulator of the entire hemoglobin synthesis pathway by affecting the translation of the enzymes needed to make hemoglobin- such as ferrochelatase and aminolevulinic acid synthase. The anemia that occurs due to this block in the hemoglobin synthesis pathway can cause children to become pale and weak, eat less, and tire easily. Long term, anemia leads to poor weight gain and growth.
Third, iron is extremely important for neural development, which occurs from mid to late gestation and continues through the first 3 years of life. Iron deficiency negatively affects the development of the hippocampus, cerebellum, spinal cord, basal ganglia, and the dopaminergic pathways in the brain. It is involved in oligodendrocyte metabolism and myelination. A lack of iron leads to deficient myelination, with the most prominent effects seen in the spinal cord and in the cerebellum. If you recall the functions of these areas of the nervous system, you can recognize that this likely contributes to the motor deficits that may be seen in children with iron deficiency. Children with iron deficiency may walk later, and have delayed development of fine motor skills and coordination as well. So they may have delayed or poor body control, body transport, and object control. Put more simply, children with iron deficiency are less likely to be able to stand independently, walk, and have coordinated hand movements than age-matched children without IDA.
Iron is also required for neurotransmitter synthesis and metabolism. Specifically, iron plays a crucial role in dopamine and gamma aminobutyric acid or GABA , synthesis and metabolism. Poor development of dopamine and GABA pathways may result in changes in mood, attention, and behavior that can be seen in children with iron deficiency.
The last core role of iron that we’re going to discuss is its role in the immune system. Iron supports innate t-cell mediated immunity and the adaptive antibody response. When iron is low, there’s a shift from the pro-inflammatory TH 1 cytokine regulated response to a TH2 cell mediated, anti-inflammatory response. This means that those with iron deficiency may have an increased risk of extra cellular infections, as they cannot mount a normal immune response.
Since iron is essential for so many processes, the body stores iron for future use in the form of ferritin. Ferritin is stored in tissues and is used when the body isn’t getting enough dietary iron intake to keep up with needs. When there is low iron, the following changes occur sequentially:
- The body will first responds by mobilizing ferritin stores. Tissue stores of ferritin are the first thing to run out when the body is using up more iron than it’s taking in. So the first detectable laboratory test to change in iron deficiency is the serum ferritin.
- If iron deficiency continues, as the body continues to scavenge for iron, serum iron levels drop, transferrin saturation decreases, and transferrin binding capacity increases.
- Next, red blood cells become microcytic – or small. So, your MCV (mean corpuscular volume, or the mean size of red cells) will decrease. There will also be a population of older, normal size cells and newer, small cells, and your RDW, or red cell distribution width – or the size difference between the largest and smallest cells – increases.
- Hemoglobin is the last lab value to become abnormal- so Iron deficiency won’t affect hemoglobin levels until pretty far in the course. This is very important to keep in mind clinically: By the time you have anemia – or a decrease in the hemoglobin, iron deficiency has already been present for awhile.
As I mentioned before, iron’s role in DNA synthesis and other metabolic processes means that there is high demand for iron during periods where there is a lot of growth. There is also at the same times in children frequently insufficient dietary intake of iron. Both rapid growth and insufficient dietary intake occurs in childhood during two periods- the first few years of life and adolescence.
Let’s talk about infancy and early childhood first. Children experience rapid growth from birth to about 3 years of age- this increases the demand for iron. This period is also when neurodevelopment occurs, further increasing iron demand. Brain development is ongoing from mid to late gestation through the first three years of life as I stated earlier. Because of this high demand, there is often a period of relative physiologic iron deficiency.
When babies are born, they usually have sufficient iron stores. This is because throughout pregnancy, iron is transferred from the parent to the fetus in high quantities- both to help the fetus grow and to establish iron stores in the fetus. Accretion of iron occurs mostly in the third trimester of pregnancy. The stores that are built up while in utero last until the child is about 6 to 9 months old. At that point, the child has used up all the iron stores they had from the prenatal period. However, they still have a high demand for iron as they continue to grow quickly. Since their stores are now relatively depleted, infants need increased iron intake to keep up with their growth.
Although it is rare, it is possible for an infant to have low iron stores or even be iron deficient at birth. Neonates born to individuals with iron deficiency anemia during pregnancy generally have serum iron levels and hematocrits in the same range as neonates born to iron-replete individuals. However, serum ferritin has been found to be lower in these infants- indicating decreased iron stores. Decreased stores are also seen in babies born to a diabetic parent and those babies that are born early or small for gestational age.
Dietary iron takes over as the main source of iron once a baby is born. Infants get iron through breastmilk or formula early in life. So, for the first 6-9 months of life, between the iron stored from gestation and the iron gained through the diet, most children have sufficient levels. However, after 6-9 months neither breast milk nor formula have enough iron content to satisfy needs. Therefore, at this 6-9 month mark children start to need iron-rich foods in their diet. - this is a big reason why we suggest introduction of solids at six months. A perfect example of an iron-rich food to introduce is baby cereals, because they are fortified with iron. Pureed or finely chopped meats are also an appropriate iron-rich food. Additionally, remember that at 12 months, babies often begin drinking cow’s milk. Cow’s milk is a poor source of dietary iron, and also can lead to a child consuming fewer solid foods containing iron due to filling up on milk. Additionally, while cow’s milk has high concentrations of calcium, which is important for bone growth, calcium – and high concentrations of casein –are potent inhibitors of iron absorption, so the iron is less bioavailable.
All children from 9 months-24 months are at higher risk of iron deficiency due to the physiologic factors we just went over. For some patients, this is also compounded by other risk factors. Some of the significant risk factors for iron deficiency in children include increased losses of iron, preterm birth, and diet restriction. Let’s talk a little about each of these.
Increased loss of iron can occur due to blood loss or malabsorption. This would include menstruating individuals, children with hematologic disorders that lead to bleeding, and children with GI disorders, such as inflammatory bowel disease or celiac disease.
Preterm infants have a relative lack of iron stores when they are born as we discussed. 80% of iron is acquired by the fetus during the last trimester of pregnancy. Therefore, when these children are born early, they have not gotten that last bolus of iron from their parent and thus do not have the same amount of iron stored as the term infant. This is compounded by rapid catch-up growth and often blood losses from frequent blood draws and procedures.
Now let’s talk about adolescence. Puberty is characterized by rapid growth and weight gain, and so demand for iron can again outpace the supply. This risk can be compounded in biological females by menses. We don’t routinely screen adolescents for iron deficiency anemia though, because the important iron dependent processes like neural development have already finished and in the absence of other risk factors, most adolescents have sufficient dietary iron intake. But, considering they are at higher risk due to rapid growth, it is important to do a comprehensive history and physical to monitor for iron deficiency anemia in this population. Although much of neural development is completed by adolescence, studies have shown that there may be some cognitive deficit seen in children with iron deficiency. Evidence shows that adolescents that are iron deficient have lower math scores compared to those children with no history of iron deficiency. This is correctable with iron supplementation, which we will discuss further when we talk about treatment.
The most common reasons for iron deficiency in adolescents are restrictive diets and heavy menstrual bleeding. Vegetarian diets can be very healthy and allow for intake of all necessary nutrients- but it can be difficult for children to obtain all the micronutrients they need if they are not as familiar with non-meat iron-rich foods. Risk factors like blood loss, restrictive diets, and some of those other medical conditions we discussed, in combination with findings concerning for iron deficiency , which we will discuss later, can prompt testing with hemoglobin and iron studies.
By now, I have referenced “screening” multiple times. When it comes to deciding what conditions should be screened for, there are a few criteria that we look at. Remember that the best screening tests are ones that screen for conditions that present asymptomatically, have severe consequences, and can benefit from treatment.
Iron deficiency meets these criteria: Although it can leads to long-term disruptions in cognitive, social, and behavioral development many patients with iron deficiency are asymptomatic or present only with vague symptoms. Finally, treatment with iron is easy and can mitigate or eliminate some of these long-term effects.
So, how do we screen?
As with evaluating any other disease process, the first thing is to take a comprehensive history and physical. This is particularly important at ages when we do not routinely check a hemoglobin. It is important to pay special attention to those risk factors we talked about earlier. Asking about prematurity, exclusive breast-feeding beyond six months of age, weaning to whole milk without addition of iron rich foods, feeding problems, and any past medical conditions-especially previous anemia, family history of anemia, and any history of bleeding disorders or GI conditions. You should also ask about symptoms that may be associated with iron deficiency anemia – fatigue is one that is well known in patients of all ages, but there are 2 that are specific to children: breath holding spells, and pica.
Breath holding spells can occur in healthy children, but it also seen in association with iron deficiency anemia. Breath holding spells are just what they sound like - involuntary, reflexive, holding of breath. We most commonly see this in toddlers, usually when they are very angry, frustrated, upset, or in pain. It can results in a brief period of loss of consciousness, and some children can exhibit jerky movements during the spells, which may look like seizures. . It is unclear why there is an association between iron deficiency anemia and breath holding spells. However, if you treat the patient with iron, the breath holding spells usually decrease or resolve.
Pica is the compulsive consumption of non-food items. Often this can mean a compulsion to eat ice, but other examples include geophagia (compulsion to eat clay), xylophagia (compulsion to eat paper), and ryzophagia (the compulsion to eat uncooked rice). Again, we don’t really know the exact pathophysiology of pica in association with iron deficiency, but generally if you treat the iron deficiency the pica improves or resolves.
Let’s now move on to physical exam. Children may exhibit pallor which can be notable as paleness in mucous membranes – it’s usually easiest to see in the conjunctivae and lips. However, just to be clear, anemia cannot be diagnosed by clinical presentation alone.
Now let’s talk about lab testing. The AAP currently recommends screening for iron deficiency anemia with serum hemoglobin level. However, there is growing evidence that this could be improved upon. Remember that the hemoglobin is the last parameter to change when there is iron deficiency. So, hemoglobin is a poor measure of iron deficiency, since it does not provide a measure of iron deficiency in the absence of anemia. Considering this, many practitioners are now electing to initially screen with serum ferritin in addition to serum hemoglobin, as it has a significantly higher sensitivity and specificity and is the first clue of iron deficiency! Other practitioners will get a full CBC, because in addition to the hemoglobin, you can see what the MCV and RDW are as well. You may be asking: Why do we usually screen at 12 months? Why not earlier or later? This is a good question, considering that children may have iron deficiency beginning at 6-9 months. The timing of screening in this case is driven by the screening tool- that is to say, hemoglobin is the last clue to present in iron deficiency. So, a drop in hemoglobin due to depletion of iron stores starting at 9 months is much more likely to be caught on lab tests at 12 months.
Anemia screening is also timed for 12 months because we can then also do screening for lead poisoning at that time, so it’s just 1 blood draw for the 2 tests. Incidence of lead toxicity peaks at 9-12 months- as children become significantly more mobile and are at higher risk of exposure to lead. Children with lead toxicity are most often asymptomatic, but labs will reveal a hypochromic microcytic anemia similar to iron deficiency anemia. Interestingly, iron deficiency is actually a risk factor for lead toxicity, because it increases intestinal lead absorption- making infants with iron deficiency more likely to develop lead toxicity. Lead screening will be covered in a different podcast episode.
Now we will briefly cover treatment of iron deficiency anemia. Anemia is defined as a hemoglobin level two standard deviations below normal for age and sex. This places the threshold for anemia for children aged 6 months to 2 years at a hemoglobin level of 11.0 g/dL or below. In adolescents, the threshold for anemia is a little bit higher, generally a hemoglobin of 11.5-13 g/dL. As we mentioned, different practices will use different screening practices – some will just use the hemoglobin; others will use the full CBC or ferritin. Different practices may also use different thresholds for treatment, so check with your resident or attending.
Also remember that hemoglobin is a poor measure of anemia and an even poorer measure of iron deficiency. You may want to treat a child with a hemoglobin above this threshold if there are certain elements in the clinical history – like a history of poor dietary intake - or other lab studies, like a high RDW or low MCV. Some practices will treat children empirically for iron deficiency if there is a low hemoglobin or microcytosis without iron studies, since iron deficiency is by far and away the most common cause of anemia. They will then follow up after iron therapy to see if there is a positive response in the hemoglobin, MCV, or ferritin. Others will obtain iron studies before giving iron.
When we treat iron deficiency, we start with oral iron- it has an excellent efficacy, safety, and cost profile. Typically, a daily dose of 3 to 6 mg per kilogram of elemental iron, divided into 1 – 3 doses daily, is adequate. For some families, only having to give the iron once a day is easier; for others, dividing it into smaller daily doses is easier. Iron has a distinct taste, and often children don’t like it. It is therefore very important to let parents know this, and to reinforce why it is important to give it even when the child doesn’t like it. We need to treat for a minimum of three months- this allows for re-establishment of iron stores. We often tell families to give iron supplements with a juice or food that has a lot of ascorbic acid or vitamin C, because this increases iron absorption! Juices that are high in ascorbic acid include orange and apple juice. In addition to iron supplementation, the other aspect of treatment is encouraging dietary intake of iron rich foods. Foods to suggest include meat and fish, cereals, legumes, vegetables such as spinach, sweet potato, and broccoli, soy, and eggs.
After treatment is completed, it is very important to follow up with a reassessment- this should include a history and physical, and lab studies, which could include hemoglobin, CBC, reticulocyte count, and/or serum ferritin. Depending on the severity of the anemia, hemoglobin increases by about 0.1 to 0.4 units per day with iron supplementation. By the four-week mark, hemoglobin has usually risen by at least 1 to 2 points. So, response to treatment is often monitored by checking a hemoglobin about 4 weeks after starting treatment. However, if the child’s hemoglobin is extremely low, for instance <5, you may want to know that the child is responding appropriately sooner than 4 weeks. If that’s the case, then you could check a reticulocyte count. You should see a rise within 1 week of beginning treatment.
Iron treatment can help to decrease those cognitive and motor deficits, although depending on the extent and duration of the iron deficiency, there may not be total recovery. Particularly in older children and adolescents, iron supplementation can lead to improvement in attention, memory, perception, and visual motor coordination.
That concludes our talk on iron deficiency anemia! Remember to screen at 12 months. If treatment is needed, you will prescribe oral iron supplements and dietary changes. Iron supplements should be given with a juice high in ascorbic acid, like apple or orange juice to helps with absorption. Lastly, always remember to follow up to evaluate the response to treatment.
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