Potassium is the most abundant intracellular cation in the body. Approximately 98% of potassium is inside our cells, where it is responsible for a huge number of critical functions:

• Generating electrical impulses in muscles and nerves
• Maintaining smooth muscle tone, including in the intestines
• Facilitating nutrient transport across cell membranes
• Supporting glucose uptake into cells
• Buffering pH and balancing acid-base status
• Supporting enzyme function in energy metabolism pathways
• Regulating heartbeat and cardiac rhythm

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When potassium is low, even within the low end of the reference range, these functions begin to degrade. Unfortunately, conventional lab interpretation doesn’t flag these early dysfunctions.

For example:
A potassium level of 3.5 to 3.9 mmol/L might not raise concern for a conventional provider. But in a child who has muscle weakness, poor stamina, constipation, or speech regression, these numbers are a red flag that cellular energy production and nerve transmission are not being properly supported.

Many children with neurodevelopmental disorders or genetic conditions have biochemical and physiological reasons that make them more susceptible to low or suboptimal potassium levels. For example, low muscle tone and reduced physical activity can impair potassium retention, as skeletal muscle serves as a major reservoir for this electrolyte. Chronic constipation often reflects smooth muscle fatigue or poor peristalsis, both of which rely on adequate intracellular potassium for proper function. Feeding challenges further limit intake of potassium-rich foods, particularly in children with restrictive diets or oral aversions.
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In addition, malabsorption and gut dysbiosis may reduce the body’s ability to absorb and utilize dietary potassium effectively. Mitochondrial dysfunction, which affects energy production in nearly every cell type, further impairs potassium uptake and utilization at the cellular level. Finally, thiamine deficiency, commonly seen in children with Down syndrome and metabolic vulnerability, can disrupt potassium transport into cells, while low potassium in turn can block thiamine uptake, creating a self-perpetuating cycle of fatigue, neurological dysfunction, and impaired motility.

In short, children with special needs are not only more vulnerable to potassium depletion, but often more affected by it, yet the problem is rarely investigated unless there's an acute crisis. 

Signs and Symptoms of Low Potassium

Even mild hypokalemia, when potassium levels are just slightly below optimal, can cause noticeable and impactful symptoms. These often present subtly at first but can significantly affect quality of life, especially in children with neurodevelopmental conditions. In those with Down syndrome, these symptoms are frequently overlooked or dismissed as just part of the diagnosis, when in fact they may reflect an underlying, correctable nutrient deficiency. This same pattern is seen with other nutrients as well, such as iron, zinc, thiamine, or magnesium, where functional symptoms are written off rather than addressed.

Common symptoms of low or suboptimal potassium include:

• Muscle weakness or low tone
• Fatigue or low energy
• Constipation or sluggish bowel movements
• Irritability or mood lability
• Tingling or numbness
• Heart palpitations or irregular rhythm
• Cramping or muscle twitching
• Poor reflexes or difficulty initiating movement

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In functional medicine, we often see that these symptoms are disregarded when lab results are “within normal limits.” Yet correcting a potassium level from 3.5 up to 4.2 mmol/L can lead to remarkable improvements in energy, digestion, and physical coordination. Recognizing that these signs may point to a treatable deficiency, not simply a feature of a genetic condition, can dramatically shift the care approach and outcomes for these children.

​How to Test and What to Look For

​Potassium is most commonly measured in serum, and it’s included as part of a routine comprehensive metabolic panel (CMP), which many children receive during annual physicals or when evaluating fatigue, growth, or gastrointestinal symptoms. However, unless flagged as critically high or low, potassium levels are often overlooked or dismissed, especially if they fall within the lab’s reference range.

In functional and integrative care, we aim for an optimal potassium level between 4.0 and 5.0 mmol/L. Levels below 4.0, even if technically “normal,” can contribute to a wide range of symptoms, including fatigue, muscle weakness, constipation, and neurological slowing. For children with special needs, we pay close attention to any value below this threshold, particularly if clinical signs suggest impaired energy metabolism or poor neuromuscular tone.

If serum potassium is borderline low, and especially if magnesium is also deficient, it may be difficult to replete potassium effectively without correcting other imbalances. The most accurate way to assess magnesium deficiency is by measuring a red blood cell (RBC) magnesium level. Reviewing potassium levels in the context of the broader metabolic picture, including magnesium, thiamine, and mitochondrial function, can offer deeper insight into what the body needs to return to balance.​

Thiamine deficiency in pediatrics can present subtly or with acute symptoms. These include:

• Fatigue, lethargy
• Poor feeding, vomiting
• Constipation, gastroparesis, and reflux
• Muscle weakness, hypotonia
• Developmental delays and irritability
• Tachypnea or labored breathing
• Cardiomegaly, heart failure symptoms

In its more advanced form, infantile beriberi (5), often under-recognized in modern pediatric medicine, can involve:

• Recurrent vomiting
• Aphonia (loss of voice)
• Edema and heart failure
• Lactic acidosis
  
• Esotropia (crossed eyes)
• Gastrointestinal dysmotility
• Sudden cardiovascular collapse

From Restriction to Nourishment
Instead of centering every food conversation around what's off-limits, families can shift the focus to what their child needs more of. This simple change in mindset, from elimination to optimization, opens the door to abundance. A child with Down syndrome may need more antioxidants, more high-quality fats, more protein to build neurotransmitters, or more minerals to support muscle tone and digestion. When we ask, “How can food support this unique body today?” we approach nutrition with compassion instead of comparison.

This approach isn’t about ignoring food sensitivities or pretending dietary boundaries don’t matter. Rather, it’s about creating forward motion. Instead of constantly taking foods away, we ask: Can we add a leafy green to lunch? What healthy fat would pair well with this snack? Can we sneak in a fermented food this week?

Small, consistent additions create momentum and momentum fosters trust, especially with children who have sensory sensitivities or feeding challenges.

Eating Together as a Healing Practice
Food is more than nutrients. It's a medium for connection. Cooking together, gardening, and sharing meals offers children a sense of belonging and safety around food. Mealtimes become an opportunity to ground the nervous system, promote sensory exploration, and enjoy the rhythm of family life. Children are far more likely to engage with new or unfamiliar foods when the environment is calm and when food is framed as connection, not correction.

When mealtime becomes a power struggle, the table turns into a battlefield. It’s a battle parents will inevitably lose, as pressure and control only fuel resistance, anxiety, and long-term aversions to food.

​Children are more likely to eat vegetables when they observe adults enjoying them. A study published in Appetite (Edwards 2021) found that children aged 4 to 6 who watched videos of adults eating raw broccoli with positive facial expressions consumed more than twice as much broccoli compared to those who viewed a non-food-related video. This suggests that parents who consistently model enjoyment of healthy foods, like vegetables, can positively influence their child’s eating habits. Sometimes a simple smile while eating broccoli goes further than any lecture.

A valuable resource that builds on the concept of video modeling to promote healthy eating habits in young children is Copy-Kids, which features real kids joyfully eating fruits and vegetables to inspire peer-driven curiosity and imitation.

Supporting Digestion Through Rhythms and Rituals
The body thrives on rhythm, especially the digestive system. Predictable meal times spaced every three to four hours help regulate blood sugar, appetite signals, and bowel motility. Children with Down syndrome, who often experience low muscle tone or constipation, benefit greatly from this type of digestive consistency.

Food combining also matters. Meals that include protein, fat, and complex carbohydrates are digested more steadily than those heavy in simple carbs. A bowl of crackers or a banana might offer a quick boost, but pairing it with nut butter, eggs, or a slice of avocado slows absorption and promotes stable energy and mood. These small combinations can go a long way toward supporting focus and reducing behavioral fluctuations throughout the day.

Just as important is the environment in which food is eaten. Calm, screen-free meals stimulate the parasympathetic nervous system, the “rest and digest” state that enhances enzyme secretion, stomach acid production, and nutrient uptake. In contrast, rushed or distracted eating inhibits digestion and can increase bloating, reflux, or nutrient malabsorption. Loud noises, visual clutter, or emotional stress can trigger a stress response (sympathetic activation), which shuts down digestion and impairs enzyme secretion. 

Try a fun evening when you play "fancy restaurant" by diming the lights and lighting candles at the table. You may be surprised how eagerly children play along. 

Blood Sugar and Behavioral Regulation
Few factors influence a child’s day-to-day behavior, focus, and emotional regulation more than blood sugar. When children eat foods that cause a spike in glucose - think sugary cereals, processed snacks, or frequent grazing - insulin levels rise sharply. This can lead not only to fat storage and energy crashes, but also to hormonal imbalances and neuroinflammation.

Children with Down syndrome are already navigating complex metabolic pathways. Stabilizing blood sugar with whole foods, quality protein, and fiber-rich vegetables helps support consistent energy, better mood, and clearer focus. It also reduces the stress burden on the adrenal system and prevents reactive hypoglycemia, a common trigger for irritability and meltdowns.

Whole Food Foundations for Health
You don’t need an expensive supplement routine or elaborate protocol to make meaningful nutritional changes. Simple shifts using real, accessible foods can have a powerful impact. Adding colorful vegetables to meals introduces antioxidants and fiber to support gut diversity. Fermented foods like sauerkraut, yogurt, or kefir introduce beneficial microbes and help regulate immune responses.

Healthy fats, like those in avocados, olive oil, and coconut oil, support brain development and reduce inflammation. Nutrient-dense proteins such as eggs, beans, and wild-caught fish provide essential amino acids that support cognition and immune function. And while it’s wise to reduce refined sugar, treats don’t have to be banned, just reimagined. A date-based snack or fruit smoothie can offer sweetness with nourishment.

Fiber-rich foods like lentils, chia seeds, and quinoa help stabilize blood sugar, promote bowel regularity, and support detoxification pathways. Hydration is also crucial when increasing fiber in the diet, but not just with plain water. Adding a pinch of sea salt, a splash of lemon juice, or a trace mineral supplement helps the body absorb and utilize that water more effectively.

Macronutrients and Their Role in Mood, Focus, and Function
Each macronutrient - protein, fat, and carbohydrate - has a distinct and vital role in supporting children with Down syndrome.

Protein is essential for neurotransmitter production, helping regulate mood, attention, and sleep. Many children with Down syndrome have increased needs for certain amino acids, like methionine, taurine and glycine, and benefit from consistent, quality protein intake throughout the day.

Fats, especially omega-3s, are critical for brain structure and function. The brain is made up of over 60% fat by dry weight, and adequate intake of healthy fats helps reduce inflammation and support neural communication. Fats like cod liver oil as a supplement, olive oil, flax oil and coconut oil are the best choices.

Carbohydrates are the body’s preferred energy source, but the type and timing matter. Complex carbs, such as sweet potatoes and oats, provide slow-releasing energy and help prevent sugar crashes that can lead to fatigue or behavioral dysregulation.

The “How” of Eating: Chewing, Posture, and Presence
How a child eats is just as important as what they eat. Chewing thoroughly not only initiates digestion but activates the vagus nerve, which regulates both the digestive and nervous systems. Many children with Down syndrome have low oral tone, which can make chewing difficult and lead to poor digestion or bloating.

Supporting upright posture during meals, with feet flat and stable, helps align the digestive tract and prevents reflux or swallowing issues. For children with hypotonia, a footrest or supportive seating can make a noticeable difference. If your infant needs additional support to maintain an upright posture in their high chair, a simple solution is to use a rolled towel or small blanket around their back and hips for added stability. For more structured support, the Posture Stability Cushion from Talk Tools is a helpful option. It’s also important to ensure that your child’s feet can rest on a stable surface during meals. Choose a high chair with a solid, adjustable footrest, and as your child grows, transition to a toddler chair with foot support or use a foot stool to maintain proper alignment and comfort.

Hydration and Minerals: Subtle But Foundational
Water is vital for every cellular process in the body, but it’s not just about how much your child drinks, it’s also about how well that water is absorbed. Minerals like sodium, potassium, and magnesium regulate fluid balance, support muscle tone, and ensure energy production at the cellular level.

Potassium is especially critical for children with low tone or constipation, as it supports smooth muscle contraction in the gut and also influences sleep quality and adrenal balance. Magnesium helps relax muscles, including those in the digestive tract. Coconut water, bananas, leafy greens, and root vegetables are all high in potassium and great ways to support hydration and mineral status naturally.

Functional Foods That Deserve More Attention
Some of the most powerful foods are also the most overlooked.

• Beets support circulation by increasing nitric oxide production and enhance detoxification pathways by stimulating bile flow and providing betaine, a compound that supports liver function and methylation. They're delicious when peeled, cubed and roasted with olive oil and a pinch of sea salt.
• Cabbage and its cruciferous cousins provide sulfur compounds that aid in gut health and immune modulation.
• Pumpkin seeds are rich in zinc, magnesium, and healthy fats, which are all important for sleep, mood, and healthy immune system function.
• Bone broth offers gut-healing amino acids, like glutamine, glycine, and proline, which help repair the intestinal lining, reduce inflammation, and support overall digestive health.
• Seaweed is an excellent source of iodine and trace minerals.
• Parsley is rich in apigenin, a flavonoid that supports brain health by reducing inflammation and protecting neurons from oxidative stress.
• Cilantro plays a role in detoxification by helping to mobilize and eliminate heavy metals from the body.​
  
  

Creating a Positive Food Environment for Picky Eaters
Feeding challenges are common in children with Down syndrome, often due to sensory sensitivities or oral-motor delays. But pressuring a child to eat usually backfires. The key is to focus on trust and exploration, not control.

Offer meals at consistent times, provide both familiar and new foods, and allow children to decide if and how much they eat. This approach is based on the Division of Responsibility concept, a feeding model developed by Ellyn Satter that reduces mealtime stress and fosters autonomy. In this model, parents are responsible for the what, when, and where of feeding, while children are responsible for whether(if) and how much they eat. You can learn more in her book Secrets of Feeding a Healthy Family: How to Eat, How to Raise Good Eaters, How to Cook. Invite your child into the kitchen. Let them wash, stir, or choose a vegetable at the store. These small experiences help build connection and curiosity over time.
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Food is a full-sensory experience. Children may need multiple exposures, sometimes as much as 10-15+ times, before they’re willing to taste something new. That’s okay. Don't stop offering a food because you're convinced your child will never eat it. Respect their pace, model enjoyment, and celebrate progress, no matter how small. 

Conclusion
In the end, functional nutrition isn’t about perfection, it’s about relationship. It’s about seeing food as a message to your child’s body: a message of stability, energy, safety, and care. When meals are grounded in connection rather than correction, food becomes more than fuel. It becomes a source of healing, bonding, and resilience.

Create simple rituals. Make space for laughter at the table. Let food reflect your family's story, not someone else’s ideal. And trust that even the smallest changes - a pinch of sea salt, a bite of avocado, a shared meal without pressure - can add up to something powerful.

Because every child deserves not just food, but nourishment. And every family deserves the tools to offer it with joy.

This article will explore the role of BH4 in neurotransmitter synthesis, its impact on dopamine, serotonin, and nitric oxide, as well as the influence of methylfolate on the BH4 cycle. Additionally, signs and symptoms of low BH4 levels will be discussed.

BH4 plays a critical role in the synthesis of dopamine, serotonin, and nitric oxide, neurotransmitters essential for healthy neurological function. In the synthesis of dopamine, BH4 acts as a cofactor for the enzyme tyrosine hydroxylase, which converts tyrosine to L-DOPA, a precursor of dopamine. Without adequate BH4 levels, dopamine synthesis is impaired, leading to disruptions in neurological function. Similarly, BH4 is essential for the synthesis of serotonin, as it is a cofactor for tryptophan hydroxylase, the enzyme responsible for converting tryptophan to 5-hydroxytryptophan (5-HTP), a precursor of serotonin. Furthermore, BH4 is involved in the synthesis of nitric oxide (NO) as a cofactor for nitric oxide synthase (NOS). NO is a signaling molecule involved in various physiological processes, including vasodilation and neurotransmission.

Folate plays a crucial roles in the BH4 cycle by influencing the availability of BH4.  Methylfolate, the active form of folate, increases the recycling of BH2 to BH4 by increasing DHFR (dihydrofolate reductase) activity. Therefore, adequate levels of methylfolate are necessary for the proper functioning of the BH4 cycle and the synthesis of neurotransmitters.
Folinic acid can also increase BH4 levels and should be used, especially in the presence of folate receptor antibodies.

The role this process plays in children with Down syndrome is important to note as well. BH4 levels have been found to be low in children with Down syndrome. (Aziz 1982)

​In conclusion, tetrahydrobiopterin (BH4) is a critical cofactor involved in the synthesis of dopamine, serotonin, and nitric oxide, neurotransmitters essential for neurological and physiological function. Methylfolate influences the BH4 cycle and is necessary for BH4 synthesis and regeneration. Low BH4 levels can result in a range of neurological, psychiatric, and cardiovascular symptoms. Understanding the role of BH4 and its associated pathways is crucial for optimizing brain health. Working with a nutritionally trained physician who can recommend the right dose of methylfolate when warranted can improve BH4 production and overall brain health.

If you're interested in reading more about this I highly recommend: Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry

As an Amazon Associate, I earn from qualifying purchases.

​I'll explain the consequences, signs, symptoms and causes of ID as well as the labs used to diagnose it. The answer to ID is not always simply supplementing with iron. As always, the best approach to managing any nutrient deficiency is finding and addressing the root cause.
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FUNCTIONS OF IRON

• Oxygenation - Iron is best known for its role in hemoglobin synthesis. Hemoglobin is the protein within red blood cells that carries oxygen. Without sufficient amounts of iron the body struggles to make hemoglobin which results in a low oxygen carry capacity of red blood cells. Image 1 shows the heme component of hemoglobin that contains iron which is the actual binding site of oxygen within hemoglobin. All tissues of the body require oxygen to function properly, but the brain is especially sensitive to a decrease in supply of oxygen. ​

• Energy Production - Many enzymes within the body rely on iron as a cofactor to function properly including enzymes within the Citric Acid Cycle. This is a process within mitochondria that our body uses to convert food to energy. Iron is also a cofactor for succinate dehydrogenase, an enzyme within the electron transport chain, another essential step of energy production found within the mitochondria. For more information about supporting mitochondrial function you can read Mitochondria - Why They're Important and What They Need to Function
• Immune System - Both the adaptive and the innate immune system are dependent on iron. While the mechanism behind this function of iron isn't totally understood some aspects have been studied and reported. Iron is important for T cell function and development, which is an energy dependent process. (Cronin, et al. 2019). In addition, ID has been shown to significantly impair cell mediated immunity in children. (Das, et al. 2014)
• Cognitive Function​ - The most energy dependent organ of the body is the brain. For that reason alone, ID can contribute to long term, irreversible, cognitive impairment in children. (Lozoff, et al. 2006). In addition to energy production, iron is critical for myelination of neurons. Myelination is the process of creating the fatty sheath surrounding neuronal processes and fibers that increases the efficiency of neve impulse transmission. Impaired myelination results in slower auditory and visual processing within the brain. (Algarín, et al. 2003) Lastly, ID has been shown to ultimately result in lower IQ in children. A study from 2007 showed treatment with iron did increase IQ points by 4.8 in a 30 children, but these points did not bring IQ up to the same level as that of children without ID.(Agoaglu, et al 2007) Lastly, iron plays a role in the metabolism of monoamines, which includes dopamine, norepinephrine and serotonin. The effect of ID on monoamine neurotransmitters appears to impact boys more than girls. (Burhans, 2005) ​

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CONSEQUENCES OF IRON DEFICIENCY

Brain:
ID can have long term cognitive and social-emotional impact on children, especially when experienced in infancy. Due to it's role in oxygenation, energy production, myelination and neurotransmitter function. ID during early brain development can impact white matter formation, monamine metabolism and functioning of the hippocampus. (Beard 2008) The hippocampus plays a major role in learning and memory. The brain changes seen in ID can lead to altered brain function that lasts into adulthood. (Georgieff 2011)
 
Myelination of neurons within the brain begins around the seventh month of gestation. After birth the brain rapidly develops over the following two years. This is also the most common stage of development when ID can occur. For these reasons physicians, midwives and other healthcare practitioners working with pregnant women, newborns and infants must be aware of risk factors that can lead to ID. 

Sleep:
Multiple studies and published review articles exist that link ID to sleep issues in infants and children.(Leung, et al. 2020) Given the importance of sleep to childhood development, growth and overall health one can see that this is yet another means by which ID can greatly impact the health of children. Sleep disturbance in children can be one of the biggest challenges to parenting that can impact the well-being of the entire family.

Sleep spindles are EEG waves seen during NREM (non-rapid eye movement) sleep. They represent brain activity that's necessary for memory formation, development of the cerebral cortex and regulation of motor activity. (Andrillon, et al. 2011) ID in 6 month old infants was shown to result in altered sleep spindle patterns. (Peirano, et al. 2007) Alterations in sleep can be long-lasting despite reversal of ID. A group of researchers in Chile found 4 year old children who experienced ID as infants had persistent alterations to their sleep organization (Peirano, et al. 2013)

Due to the brain changes seen in regulation of motor activity in infants with ID, it's no wonder that restless sleep in children is often a result of ID. (Dosman, et al. 2012) Other causes of restless sleep in children exist, but some sleep specialists recommend supplementing with iron in children with restless sleep who also have a ferritin of <50 ug/L. Researchers in 2013 reported, "The most striking single symptom (of ID) was awakening after 1-3 h of sleep followed by screaming, crying, kicking or hitting the legs." (Tilma, et al. 2013)
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Gross motor skills:
​Researchers at the Center for Human Growth and Development at the University of Michigan in 2006 reported on the effects of ID on gross motor development in children in Costa Rica. Not only are gross motor skills of infants with ID delayed, but "there was no evidence of catch-up in motor development, despite iron therapy in infancy that corrected ID anemia in all cases." (Shafir, et al. 2006) Their findings confirmed that of many others: "Children who have iron-deficiency anemia in infancy are at risk for long-lasting developmental disadvantage as compared with their peers with better iron status." (Lozoff, et al. 1991) These "development disadvantages" extend beyond cognition and include gross motor skills. Shafir, et al later mentioned the dilemma of ID detection without anemia as this is less often detected by practitioners who only use hemoglobin levels to screen for ID. (Shafir, et al. 2008)

Behavior:
​Last, but not least, is the long-term social-emotional issues that can result from ID. Infants and toddlers who experience ID have been found by "virtually every case-controlled study" to be "more wary, hesitant, solemn, unhappy, kept closer to their mothers" (Lozoff, et al. 2006) Once again, these effects were are not necessarily reversible once ID is treated. These effects can be long-term. Parents and teachers had reported more social problems, anxiety/depression and attention problems in children who previously experienced ID.(Lozoff, et al. 2006) Attention problems are also common among children and young adults who were iron deficient as infants. Researchers from Department of Psychology and Social Behavior, University of California, Irvine stated, "Participants with chronic, severe ID in infancy performed less well on frontostriatal-mediated executive functions, including inhibitory control, set-shifting, and planning." (Lukowski, et al. 2010) These and results from other studies show that executive function, impulsivity and decision-making in adolescents and young adults can be impacted by previous ID in infancy. Experts from Division of Child Development and Community Health at the Universty of California in San Diego went so far as to say, "Youth with a known history of IDA would benefit from monitoring for emotional volatility and inattention, both during childhood and at adolescence, as they become more independent and have the potential to engage in serious risk behaviors." (East, et al. 2018)
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SYMPTOMS OF IRON DEFICIENCY

​The most common symptom of ID in children is fatigue. However, fatigue can manifest very differently in children than it does in adults. Children who are tired can actually present as hyperactive as they continuously move in order to avoid falling asleep during the day. It's commonly referred to as "tired-wired". Fatigue can also present as behavioral issues that include lack of focus, irritability and even aggression. Fatigue from ID is due not only to the low oxygen carrying capacity of red blood cells but also to low activity of the enzymes mentioned above needed for energy production within mitochondria.

DIAGNOSIS OF IRON DEFICIENCY

For these reasons, assessing iron status in children is very important. This is done through a blood draw that includes a serum iron, TIBC, % saturation and ferritin. The ferritin level is the most accurate means of assessing overall iron status in the absence of infection and inflammation. (WHO, 2011) Ferritin is an intracellular protein that stores iron and releases it as needed. It helps maintain a stable amount of iron in the body by storing it when there's too much and releasing it when there's too little. Because it can be elevated in the presence of infection or inflammation it shouldn't be the only means used to assess iron status.(Kell and Pretorius 2014) Many doctors will only assess iron status based on hemoglobin (Hb) levels. This is a poor means of assessing iron status as Hb levels will be low in those with long-standing ID and will miss early onset ID.
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CAUSES OF IRON DEFICIENCY

Malabsorption is a major cause of ID. There are multiple factors within the gut that can contribute to malabsorption. 

Gut factors that impact iron absorption:

• stomach acidity (pH)
• microbiome
• infections
• inflammation
• biofilm

Iron can be found within the body in two states: Fe2+ and Fe3+. The form that's absorbable by the body is Fe2+. Iron takes this form in a low pH (acidic) environment. This low pH is created by gastric acid production within the stomach. Without gastric acid or when gastric acid production is blocked by an acid blocker like Omeprazole (Prilosec) or Ranitadine (Zantac) iron absorption will also be blocked. Taking supplemental iron may be helpful but if the pH environment within the GI tract is not remedied then the supplemental iron will not be absorbed. Iron that is not absorbed causes GI irritation, upset tummies and constipation. 

Iron is absorbed from the duodenum which is in the uppermost part of the small intestines. ​Abnormally high levels of bacteria or yeast here will result in malabsorption of iron and other micronutrients.

Iron is an essential element for nearly all living organisms including bacteria within the gut. These bacteria fundamentally get served iron first and we get the leftovers. In this way elevated levels of bacteria in the small intestine reduces the amount of iron available for absorption. Our bodies essentially play iron tug-of-war with bacteria in the gut. Taking iron as a supplement also nourishes this elevated level of bacteria in the gut, potentially making the root cause of ID worse. 

A fascinating way that bacteria scavenge iron is through iron chelating compounds called siderophores. These siderophores are some of the strongest iron binding agents known. They possess a higher affinity for iron than host transport proteins do. Bacteria secrete siderophores that bind to iron then harvest the siderophores as a means to collect iron from their environment. (Miethke and Marahiel 2007) The tug-of-war continues as the host cells secrete, a protein that binds siderophores. (Wilson, et al, 2016) This battle for iron underscores it's importance not only to human health but to the health of all organisms including bacteria.

One pathogenic bacteria that's worth noting for its dependence on iron is Klebsiella pneumoniae. The presence of this bacteria in the gastrointestinal tract has been implicated as "most likely triggering factor involved in the initiation and development of" two autoimmune conditions Ankylosing Spondylitis and Crohn's Disease. (Rashid, et al. 2013)

Pathogenic (disease causing) as well as commensal (healthy, symbiotic) bacteria within the gut create biofilm. They will pull positively charged ions (cations) from their environment in order to strengthen their biofilm. These cations are often in the form of magnesium, calcium and iron. Dr. Rodney Donlan from the CDC has written, "...divalent cations such as calcium and magnesium, which have been shown to cross-link with the polymer strands and provide greater binding force in a developed biofilm." (Donlan 2002) "Metal cations, such as calcium, magnesium, and iron have been implicated in maintaining matrix integrity." (Kostakioti, 2013) Using these minerals as supplements can actually worsen a biofilm situation in the presence of a pathogenic bacteria. Some examples of pathogenic bacteria that do this are Pseudomonas aeruginosa, Campylobacter jejuni and Klebsiella pneumoniae. (Kang and Kirienko, 2018; Oh, et al, 2018; Chen, etal 2020)  Researchers in India showed that limiting iron availability through the use of an iron antagonizing agent helped to reduce biofilm formation by K. pneumoniae. (Chhibber, et al. 2013) They also reminded us that "Free iron is critical for the growth of biofilm associated bacteria."

Hepcidin is the key regulator of systemic iron homeostasis that is released by the liver in response to inflammation and iron overload. It works by blocking iron absorption in the duodenum. Inflammation, autoimmune disease, critical illness, some cancers and chronic kidney disease all result in elevated hepcidin which will reduce iron absorption. (Ruchala and Nemeth 2015) While testing hepcidin levels would be ideal in determining the cause of ID, it's currently not readily available through routine laboratories.(Girelli, et al. 2016) However, knowing the mechanisms that control hepcidin can help clinicians understand the means by which these physiologic states can interfere with iron absorption.

Malabsorption of iron can also occur in the presence of a riboflavin deficiency (Agte, et al. 1998, Powers, et al. 1998),  which can be seen as an elevated glutaric acid on an organic acid test as well as through signs and symptoms:

Signs and symptoms of a riboflavin deficiency include:

• glossitis (red, swollen tongue)
• angular cheilitis (rash or cracks in the corners of the mouth)
• cracked, dry lips
• irritated mucosal membrane of the mouth
• sore throat
• moist, scaly skin inflammation
• hearing loss
• choking, swallowing, feeding issues
• tongue and/or facial weakness
• sensory gait ataxia (clumsy, staggering walk)
• dysphonia – inability to produce sound due to laryngeal weakness

For more information about riboflavin deficiency I recommend reading Riboflavin (vitamin B-2) and health.

Aside from the above mentioned gut issues, the most common cause of ID in children is lack of iron in the diet.  Iron from meat (heme iron) is more easily absorbed than non-heme (plant-based) iron. Ensuring foods rich in iron, both heme and non-heme, are part of the diet of pregnant women and children can go a long way to prevent issues associated with ID.

Lastly, it should not go unmentioned that certain phenolic compounds are strong inhibitors of iron absorption. (Merceles and Hunstein 2011, Lesjak, et al. 2014)  Polyphenols that are given as supplements such as EGCG, curcumin, resveratrol and quercetin can all result in decreased absorption of non-heme iron. Heme iron is found only in meat, poultry, and seafood. Non-heme iron is found in plants like whole grains, nuts, seeds, legumes, leafy greens and most iron supplements. While phenolic compounds have multiple healing properties including neuroprotection, anti-cancer, anti-inflammatory and anti-histamine their potential side effects, especially when used at higher pharmaceutical doses, should be monitored. Checking serum iron and ferritin levels regularly in those who use these substances is an ideal way to monitor this potential side effect.
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TREATMENT OF IRON DEFICIENCY

You can now see that treating ID can be a little more complicated than just supplementing with iron given all of the above information, especially the role that bacteria in the gut can play in iron absorption. While giving children with ID an iron supplement seems like the quickest, easiest solution, in some situations it can make the root cause of the problem worse. We sometimes don't recommend iron supplementation in patients who have obvious gastrointestinal issues and stool testing can be done immediately. It's imperative that clinicians working with children with ID have an understanding of all factors involved in iron absorption in order to optimize the health of these children as safely and efficiently as possible.

It's important to assess for gastrointestinal issues when other causes of ID are not readily evident. This is best done through a comprehensive stool analysis that can be ordered and interpreted by a trained functional medical or Naturopathic physician. These stool tests are able to detect pathogenic and commensal bacteria in the gut that can impact iron absorption. You can read more about stool analysis options on this page of our website: Stool Test Options.

Choosing the right form of iron to give as a supplement is important as well. Iron that is not absorbed causes GI irritation and constipation. Dark or black stools that are seen after the start of iron supplementation is a sign of poor iron absorption. Non-heme iron supplements are the standard for iron supplementation, but come in many forms. Many standard iron supplements come as iron sulfate which is not easily absorbed and subsequently is more likely to cause gastrointestinal side effects. Iron bisglycinate is a form of iron that is bound to glycine which makes it more absorbable and less likely to cause gastrointestinal issues. The taste  of both of these forms of iron can be a problem for most children who cannot swallow capsules.

Micronised microencapsulated iron pyrophosphate is a form of liquid iron that solves both issues of absorption and taste. Micronisation is the process of reducing particles to a smaller size often with the goal of increasing absorption. Microencapsulation is the process of coating small particles with a substance that will either protect it from being broken down in digestion or increase its absorption. Using a phospholipid bilayer or liposome as the protective layer increases absorption of iron pyrophosphate and blocks the iron from coming into contact with taste buds in the mouth, masking the iron flavor. "Micronised microencapsulated ferric pyrophosphate (MMFP) is a recently developed formulation characterised by a higher intestinal bioavailability due to the small particle size distribution at nanometer level. " (Pappalardo, et al. 2019)

Lactoferrin is a natural glycoprotein that is one of the main proteins found in human breast milk. It's an iron binding protein that is involved in regulation of iron absorption in the bowel as well as inflammation within the body, having both pro- and anti-inflammatory properties. It also has anti-bacterial properties and helps breakdown biofilm as it sequesters iron away from bacteria.(Giansanti, et al. 2016) "Its ability to limit iron availability to microbes is one of its crucial amicrobial properties" (Kell, et al. 2020) 

Bovine lactoferrin can be taken as a supplement and has been shown to increase total serum iron, red blood cell count, hemoglobin, and hematocrit of pregnant women experiencing ID anemia. (Rosa, et al. 2017) They were given 100 mg of lactoferrin twice a day. Taking lactoferrin also decreased their IL-6 level, which is a cytokine involved in inflammation. Infants who received bovine lactoferrin added to their formula were shown to have accelerated neurodevelopment by one year old and improved language by 18 months old. (Li, et al. 2019)

Vitamin C (ascorbic acid) is a powerful enhancer or non-heme iron absorption. Taking an iron supplement together with a vitamin C supplement can greatly improve iron absorption. "Ascorbic acid forms a chelate with ferric (Fe3+) iron in the low pH of the stomach which persists and remains soluble in the alkaline environment of the duodenum." (Ems, et al. 2020) 
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CONCLUSION

It is critical that ID be detected as early as possible and prevented in infancy to prevent irreversible long term effects. Managing ID safely and effectively can be a complex process. In some children it can be solved as simply as taking an iron supplement. For other children, it can involve looking deeper for the source of the problem in order to treat it safely and effectively. Taking the right steps, using the right supplements and running the right tests can go a long way to prevent the long term effects that ID can have on a child's health and development.