NUTRITION REVIEWS IN GASTROENTEROLOGY

Micronutrient Considerations for Celiac Disease

October 2023 • Volume XLVII, Issue 10
Jessica Lebovits,Anne R. Lee

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While the benefit of a gluten-free diet to promote healing in individuals with celiac disease is clear, it is critical for providers to consider the micronutrient fluctuations that are associated with this conditionand its dietary treatment. Nutritional deficiencies of micronutrients are frequently found in untreated or newly diagnosed celiac disease often as a byproduct of malabsorption. Deficiencies may persist even after strict adherence to a gluten-free diet related to lower nutrient profiles of gluten-free grains and gluten-free products and possibly concurrent dietary restrictions. Micronutrients of concern that may or may not require supplementation include vitamin D, calcium, vitamin B12, folate, and iron. A team approach, including a dietitian specializing in celiac disease, is necessary to ensure micronutrient needs are met on an ongoing basis. This review will summarize considerations for monitoring and supplementation of micronutrients of concern for those adherent to a gluten-free diet.

 INTRODUCTION 

Celiac disease (CeD) is a genetically-mediated autoimmune disease in which gluten causes damage to the small intestine, resulting in interference of nutrient absorption.1 At this time, the only treatment for CeD is strict avoidance of gluten, a protein found in wheat, barley, and rye.2 Gluten triggers a reversible inflammatory process in the small bowel mucosa, which may induce diarrhea, steatorrhea, constipation, bloating, nausea, vomiting, and/or weight loss in individuals with CeD.1 Once a gluten-free diet (GFD) is initiated, the bowel begins to heal, and most individuals report resolution of symptoms. Despite symptom improvement, a strict GFD must be maintained for life to prevent ongoing damage.3 A strict GFD can restore the histology of the small bowel in 95% of children within two years, whereas 34% and 66% of adults experience mucosal recovery after two and five years, respectively.1 

Nutritional deficiencies of micronutrients are frequently found in untreated or newly diagnosed CeD.2 Long-term consequences of mucosal damage and inflammation include malabsorption of nutrients such as calcium, vitamin D, iron, vitamin B12, folic acid, and zinc, which increases the risk for osteoporosis, anemia, and stunted growth.1 The degree of malabsorption depends on the length of time before the CeD diagnosis and the degree of intestinal mucosal injury.2 Moreover, development and/or persistence of symptoms, such as diarrhea and vomiting, may result in decreased total intake and may impact the quality of the diet, further increasing this risk. Parallel restrictions of lactose avoidance and vegan/vegetarian diets may exacerbate the risk for deficiencies and subsequent comorbidities. In a cross-sectional age and gender matched study of Spanish adults, the individuals with CeD on a GFD for >1 year had a deficient intake of folate, vitamin E, vitamin D, iodine, and calcium.4 Women with CeD also had lower iron intake than the women in the control group.4 Additionally, a cross-sectional study of 20 individuals with CeD and 39 healthy controls showed significant differences in serum and dietary folate levels.5 Specifically, the folate, B6, and B12 values were lower in the diet of the individuals on a GFD compared to the healthy controls.5 

Gluten free (GF) products tend to also have lower iron and B vitamins as well as other nutrients, such as calcium, zinc, and magnesium. As the FDA enriches wheat products back to the natural nutrient value of the wheat grain,6 a wheat-based diet is inherently rich in iron, fiber, and B complex vitamins. Food products such as GF breads, pastas, and cereals are not required to be enriched by the FDA.6 Lee and colleagues found that by adding only GF whole grains to a typical GFD, the overall nutrient value improved, specifically with increases in thiamin, iron, calcium, and folate.7 

While the benefit of adhering to a GFD to promote healing in individuals with CeD is clear, it is critical for clinicians to consider the micronutrient fluctuations that are associated with this condition and its medically required dietary pattern. This review will summarize considerations for monitoring and supplementation of micronutrients of concern for those adherent to a GFD. 

Nutrient-Specific Recommendations 

Through discussions with our specialist providers at the Celiac Disease Center at Columbia University, we developed guidelines based on current evidence along with our clinical experience and judgment. Typically ordered nutrient labs include iron studies, folate, vitamin B12, and vitamin D. There is no consensus on the optimal timing for a dual x-ray absorptiometry (DEXA) scan to evaluate bone mineral density (BMD) in CeD, whether at diagnosis or during follow up.2 

For a newly diagnosed CeD patient who just started a GFD: 

Pediatric: we recommend ordering the typical nutrient labs after 4-6 months on a GFD. 

Adult: we recommend ordering the typical nutrient labs at the CeD diagnosis and annually for monitoring. However, if nutrient labs are low at diagnosis, we generally recommend rechecking labs in 3-6 months. 

If usual food intake shows nutritional inadequacies that cannot be alleviated through improved eating habits to meet the Recommended Dietary Allowances (RDA), the dietitian should recommend a GF multivitamin/mineral (MVM).8 If nutrient deficiencies are found through lab work, clinicians should consider recommending a MVM or nutrient-specific supplementation (Table 1, Table 2). A prenatal MVM is recommended for all pregnant or lactating individuals.9 

Vitamin D 

Vitamin D plays an important role in promoting bone health, both through hormonal regulation of bone remodeling and calcium absorption.2 Vitamin D deficiency is common in CeD, which may be due to villous atrophy, fat malabsorption, and possibly reduced dairy intake secondary to lactose intolerance.2 In addition, much of the bone loss in CeD is related to secondary hyperparathyroidism, which is likely caused by vitamin D deficiency and can only be partially reversed with a GFD.2 Verma studied 60 newly diagnosed pediatric patients and found a significant increase in vitamin D levels as well as BMD and bone mass content after 6 months on a GFD.10 

Vitamin D can be obtained through sunlight, supplements, and food.11 The skin makes vitamin D when it is exposed to sunlight; amounts vary based on the time of day, season, geographical 

latitude, skin pigmentation, and other factors.12 Food sources include fatty fish, such as salmon, mackerel, and tuna.11,12 Vitamin D is added to milk and other dairy products, orange juice, and fortified cereals.11,12 However, GF cereals may not be fortified. Cheese and egg yolks naturally contain small amounts of vitamin D.11,12 Many of these sources are animal-based and therefore, individuals following vegan or vegetarian dietary plans must be counseled on strategies to incorporate plant-based vitamin D sources, such as fortified dairy alternatives.11,12 

There are two types of vitamin D supplements: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol).13 The primary source of vitamin D2 is plants, and D2 can be manufactured 

synthetically, whereas vitamin D3 is synthesized in the skin after exposure to the sun.13 Both forms are well-absorbed in the small bowel.11 Vitamin D supplements should ideally be taken with a meal and the full amount can be taken at one time.12 Many calcium supplements also contain vitamin D. Although the body needs vitamin D to absorb calcium, a vitamin D supplement does not need to be taken at the same time as a calcium supplement.12 Note that individuals may not need supplementation over the summer months if increased exposure to sunlight is expected. 

Calcium 

Calcium is an essential mineral for development and maintenance of bone integrity.12 Calcium is  also part of teeth constitution and enables blood to clot, muscles to contract, and the heart to beat.12 The body cannot produce its own calcium, so sufficient dietary intake is critical.12 If calcium intake is insufficient, calcium is taken from the bones.12 Additionally, mucosal damage in CeD impairs calcium absorption, which can lead to impaired bone health. Initially, lactose intolerance may occur related to impaired release of lactase enzyme from the damaged mucosa, which may further limit dairy intake. However, this lactose intolerance is likely to resolve with mucosal healing. Pediatric patients with untreated CeD are at risk of short stature and constitutional delay of puberty.1 Nonetheless, a 2022 meta-analysis concluded that the GFD was associated with higher bone mineral content and BMD in children and adolescents with CeD.14 Calcium-rich foods include dairy (milk, yogurt, cheese), fortified milk substitutes (soy, nut, pea), kale, and salmon.15 

It is important to note that absorption from calcium is highest with doses of 500 mg or less.15 Therefore, calcium intake, from food or supplements, should be spread out throughout the day for maximum absorption. The bioavailability of calcium from dairy products and fortified foods is 30%.15 The presence of oxalic acid and phytic acid in plants reduces calcium absorption.15 Foods such as milk, broccoli, kale, and cabbage have an absorption rate of 27% while spinach, collard greens, sweet potatoes, and beans have an absorption rate of 5%.15 Nevertheless, when individuals consume a variety of foods, the interactions with oxalic or phytic acid likely have minimal or negligible nutritional consequences.15 Absorption of dietary calcium is also reduced to a small extent by intakes of caffeine and phosphorus and to a greater extent by insufficient vitamin D status.15 

Dietitians are necessary to assess dietary intake because serum calcium is an unreliable marker for calcium status.15 Calcium supplementation may be recommended if dietary calcium is inadequate or if malabsorption is suspected. If supplementation is recommended, calcium citrate is often the supplement of choice. Calcium citrate can be taken with or without food, is more easily absorbed, and causes fewer symptoms of gas, bloating, and constipation than calcium carbonate.15 Calcium citrate is also recommended for individuals who are taking acid suppressants as the calcium citrate is better absorbed even in a lower acid environment than calcium carbonate.15 However, calcium citrate supplements only contain approximately 20% calcium.15 Therefore, in order to reach daily requirements, individuals may need to take more of the calcium citrate supplement. 

Vitamin B12 

Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis.16 Vitamin B12 is absorbed primarily in the ileum.2 Possible reasons for deficiency in CeD, although not well-established, include terminal ileal involvement, pancreatic insufficiency, and competition for vitamin B12 by undesirable bacteria in SIBO.2 

Vitamin B12 is naturally found in animal products, including fish, meat, poultry, eggs, milk, and milk products.16 Therefore, individuals following vegan diet plans must be counseled on strategies to incorporate plant-based vitamin B12 sources, such as fortified nutritional yeast and dairy alternatives.16 

Absorption of vitamin B12 is dose dependent.16 The estimated bioavailability from food varies because absorption decreases drastically when the availability of intrinsic factor is at capacity (at 1–2 mcg of vitamin B12).16 Bioavailability also varies by the type of food source; it appears to be about three times higher in dairy products compared to meat, fish, and poultry.16 The bioavailability from dietary supplements is about 50% higher than that from food sources.16 Gastric acid inhibitors (proton pump inhibitors and histamine 2-receptor antagonists) used to treat gastroesophageal reflux disease and peptic ulcer disease may interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach.16 

Vitamin B12 administered parenterally as a prescription medication through intramuscular injections may be considered for severe deficiency, neurologic features, or ongoing malabsorption.2 Clinicians should assess for intake of supplements, herbals, and energy drinks, which may be sources of vitamin B12.

Folate 

Folate is a B vitamin that is naturally present in some foods whereas folic acid is the form of vitamin B9 that is used in fortified foods and most dietary supplements.17 Folate deficiency is common in CeD likely related to malabsorption, lower folate content of GF grains, and the lack of fortification/ enrichment of GF products.7 Folate is found in a wide variety of foods, including vegetables, especially dark green leafy vegetables, fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy products, meat, poultry, and grains.17 Spinach, liver, asparagus, and Brussels sprouts are among the foods with the highest folate levels.17 Dietitians should assess for a lack of variety and inadequate intake of GF whole grains in the diet as studies have shown improvement in folate levels with the inclusion of GF whole grains.7 

At least 85% of folic acid is estimated to be bioavailable when taken with food, whereas only about 50% of folate naturally present in food is bioavailable.17 When consumed without food, nearly 100% of supplemental folic acid is bioavailable.17 Given the risk of neural tube defects related to low folate levels, a prenatal MVM with folic acid is recommended for all females of child-bearing age through pregnancy and lactation.17 

Iron 

Iron is an essential mineral for carrying oxygen in the hemoglobin of red blood cells.18 Iron also supports the body’s metabolism, growth, development, cellular functioning and synthesis of some hormones and connective tissue.18 Iron deficiency is common in newly diagnosed CeD due to malabsorption, but iron deficiency discovered further along into the GFD warrants additional investigation to determine the etiology. 

Dietary iron is in the form of heme or non-heme iron.18 Heme iron comes from animal sources, such as meat, fish, and poultry and is most readily absorbed by the body.18 Non-heme iron is found in plant-based foods, such as fruits, vegetables, beans and nuts and has a lower bioavailability.18 Strategies to increase absorption of iron include cooking with a cast iron skillet and consuming heme iron sources or vitamin C along with non-heme iron sources to enhance the absorption of the non-heme iron.18 

Fortified foods are recommended for children between ages 1-2 to ensure iron stores are repleted as prenatal iron stores are exhausted by 6 months.18 Pediatric diets commonly fall short of adequate iron intake and most GF pediatric chewable supplements do not contain iron. Special attention should be paid to toddlers who drink milk in excess of 24 oz per day due to possible interference with iron absorption. 

Frequently used forms of iron in supplements include ferrous and ferric iron salts, such as ferrous sulfate, ferrous gluconate, ferric citrate, and ferric sulfate.18 Ferrous iron in dietary supplements is more bioavailable than ferric iron.18 It is important to note that supplements containing 25 mg iron or more can reduce zinc absorption and plasma zinc concentrations so these levels should be monitored.18 Calcium might interfere with the absorption of iron, although this effect has not been definitively established and the effect is expected to be mitigated by a typical mixed western diet.18 Nevertheless, some experts suggest taking individual calcium and iron supplements at different times of the day to maximize absorption.18 

Although high doses of supplemental iron (45 mg/day or more) are often used to replete iron stores in iron deficiency, it is important to consider that they may cause gastrointestinal side effects, such as nausea and constipation.18 Other forms of supplemental iron, such as heme iron polypeptides, carbonyl iron, iron amino-acid chelates, and polysaccharide-iron complexes, might have fewer gastrointestinal side effects than ferrous or ferric salts.18 Iron infusion is recommended if there is failure or intolerance of oral iron in the setting of persistent iron deficiency anemia. Because proton pump inhibitors reduce production of gastric acid, they can reduce iron absorption as well. Therefore, consider that individuals with iron deficiency on proton pump inhibitors can have suboptimal responses to iron supplementation.18 

CONCLUSION 

A GFD prescription should include standard nutritional guidance emphasizing naturally GF whole foods such as fruits, vegetables, dairy, meat, seafood, nuts, seeds, and legumes for a sound nutritional base.2 The addition of naturally GF 

whole grains or pseudocereals, such as amaranth and quinoa, provides the fiber, B vitamins, and minerals (calcium, iron, magnesium) missing when gluten is removed.2 

Research has indicated that micronutrient deficiencies are common at the time of diagnosis and even after initiation and adherence to a GFD. Deficiencies may be attributed to malabsorption from villous atrophy, lower nutrient profiles of GF grains and GF products, as well as additional dietary restrictions. Routine monitoring of at-risk vitamin and mineral levels should be part of comprehensive follow-up for patients with CeD. A patient-centered team approach including consultation and regular follow up with a specialist dietitian will ensure optimal outcomes. 

Acknowledgements 

We are grateful for the contributions of Cecilia Chen and our colleagues at the Celiac Disease Center, including Dr. Jacqueline Jossen, Dr. Amy DeFelice, Dr. Peter Green, Dr. Benjamin Lebwohl, Dr. Suzanne Lewis, Dr. Suneeta Krishnareddy, Dr. Randi Wolf, and Dr. Marcella Walker. 

References 

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