Abstract
Reduced levels of iron, folate, vitamin B12, vitamin D, zinc, and magnesium are common in untreated celiac disease (CD) patients probably due to loss of brush border proteins and enzymes needed for the absorption of these nutrients. In the majority of patients, removal of gluten from the diet leads to histological recovery and normalization of iron, vitamin, and mineral levels. Iron deficiency anemia is the most common extra-intestinal sign of CD and usually resolves with adherence to a gluten-free diet. However, deficiencies of both folate and vitamin B12 may persist in some patients on a gluten-free diet, thus requiring vitamin supplementation to improve subjective health status. Similarly, exclusion of gluten from the diet does not always normalize bone mineral density; in these cases, supplementation of vitamin D and calcium is recommended. Resolution of mucosal inflammation may not be sufficient to abrogate magnesium deficiency. Since gluten-free cereal products have a lower magnesium content as compared with gluten-containing counterparts, a magnesium-enriched diet should be encouraged in CD patients. In this article we discuss the frequency and clinical relevance of nutrient deficiency in CD and whether and when nutrient supplementation is needed.
Key messages
Reduced levels of iron, folate, vitamin B12, vitamin D, zinc, and magnesium are common in untreated celiac disease, and some of these deficiencies can persist even after removal of gluten from the diet.
Nutrient deficiencies may be responsible for extra-intestinal signs/symptoms of celiac disease.
Assessment of nutrient status may help identify celiac disease patients who need supplementation for preventing and/or treating clinical manifestations of the disease.
Introduction
Celiac disease (CD) is a chronic enteropathy, which affects approximately 1% of the general population (Citation1,Citation2). In genetically susceptible individuals ingestion of gluten triggers a dual innate and adaptive immune response leading to the destruction of intestinal epithelial cells. Histologically, CD is characterized by various grades of villous atrophy, crypt cell hyperplasia, and marked infiltration of T lymphocytes in both epithelial and lamina propria compartments (Citation3). The clinical spectrum of CD is wide, ranging from asymptomatic presentations, discovered through serological screenings, to symptomatic cases with either classical intestinal (e.g. abdominal pain, chronic diarrhea, weight loss) or non-classical extra-intestinal (e.g. anemia, osteoporosis, neurological disturbances) features. CD patients have also an enhanced risk of developing additional immune-mediated diseases (Citation4). Treatment of CD is based on a strict and lifelong gluten-free diet (GFD), which leads to disappearance of the signs/symptoms (Citation4,Citation5). However, some patients on a GFD may exhibit clinical features possibly related to nutrient deficiencies (i.e. vitamins B and D and calcium). In such subsets of treated patients, nutrient supplementation is useful to attenuate signs/symptoms and improve subjective health status. The aim of this study was to determine the impact of CD on iron, folate, vitamin B12, vitamin D, zinc, and magnesium statuses. To this end, we performed a PubMed-related search in July 2013 using the following terms: ‘celiac disease’, ‘nutritional deficiencies’, ‘nutritional status’, ‘iron deficiency’, ‘folate deficiency’, ‘vitamin B12 deficiency’, ‘vitamin D deficiency’, ‘zinc deficiency’, ‘magnesium deficiency’, ‘guidelines’, and ‘dietary guidelines’.
Iron absorption
Under physiological conditions iron enters the human body across the placenta during fetal life and across the wall of the small intestines in postnatal life. Absorption of iron occurs in the duodenum and upper part of the jejunum (Citation6) and depends on several factors (e.g. chemical nature and amount of iron in the diet, characteristics of ingested food, and effects of gastrointestinal resection) (Citation7). Dietary iron compounds are typically classified as either heme or non-heme. In humans, the former is absorbed more efficiently than the latter. Heme enters enterocytes through the brush border membrane, likely by receptor-mediated endocytosis. Within these cells iron is released by the action of the microsomal enzyme, heme oxygenase (Citation6,Citation8). Non-heme iron is transported into enterocytes in its ferrous form, Fe2+, mainly by the carrier divalent metal transporter (DMT)-1 (Citation9). The reduction of dietary ferric iron Fe3+ to the ferrous form is facilitated by ferric reductases, such as duodenal cytochrome B (DcytB) or Steap2 (Citation10). Within the enterocyte, iron can either be stored or exported into the circulation depending on iron requirements. Transport across the basolateral membrane is regulated by the transmembrane protein, ferroportin (FPN1); once in the blood stream iron binds to plasma transferrin (Tf) (Citation11). The absorption of iron is also regulated by the 25 amino acid peptide hormone hepcidin (Citation12). Hepcidin binds FPN1 on the enterocyte basolateral membrane, thus promoting internalization and degradation of FPN1 and leading to reduced release of iron into the circulation (Citation13). Other factors, which do not participate directly in the absorptive process but regulate efficiency, include the membrane proteins transferrin receptor 2 (TfR2) and the hemochromatosis protein (HFE), which are involved in sensing Tf saturation (Citation14).
Iron levels in celiac disease
Iron deficiency anemia (IDA) is the most common extra-intestinal manifestation of CD (Citation1,Citation15–18). It can be seen in 7%–81% of patients at time of diagnosis and is more frequent in adults and in women () (Citation15,Citation19–24). On the other hand, the prevalence of biopsy-proven CD ranges between 2.3% and 4.7% in patients examined for IDA (Citation25,Citation26). IDA in CD results mainly from malabsorption, even though it can be, at least in part, secondary to intestinal blood loss or colonic diseases (Citation27–30). By using sensitive and specific radiochromium tests, Mant and colleagues documented gastrointestinal bleeding in 4 out of 30 (13%) of CD patients (Citation31), even though previous studies reported higher prevalences (25%–54%) (Citation32,Citation33). IDA could also rely on persistent systemic inflammation (Citation22,Citation34). Indeed, it has been reported that that 13% of anemic CD patients presented ferritin levels higher than controls, and these patients were considered as suffering from anemia of chronic disease (Citation22). IDA usually resolves with adherence to a GFD () (Citation35,Citation36), although repletion of iron stores may require a significant amount of time (e.g. 6–12 months) after healing of the small intestinal mucosa. Therefore, some patients may exhibit iron deficiency without anemia (Citation37).
Table I. Estimation of vitamin deficiency in untreated celiac disease patients.
Table II. Estimation of vitamin deficiency in treated patients with celiac disease.
When iron supplements are indicated, supplementation should be initiated after intestinal healing has been achieved. The primary method of iron rehabilitation is to prescribe oral supplements until the values of hemoglobin and iron deposits have been normalized. However, in particular situations (such as poor tolerance, inadequate compliance, ineffectiveness, or clinical emergency), the use of parenteral iron is justified (Citation38). In this context, since gluten-free products contain low amounts of iron (Citation39), foods rich in iron, such as fruits, vegetables, and red meat, should be recommended to CD patients.
Folate absorption and metabolism
Folate, a water-soluble vitamin (vitamin B9), is not synthesized by humans (Citation40). Folate is present in various foods in a polyglutamyl form and is absorbed in the proximal small intestine (mostly duodenum and upper jejunum), where it is converted to monoglutamates by the action of intestinal folylpoly-γ-glutamate carboxypeptidase. The uptake of folate monoglutamates occurs via a specific pH-dependent, Na+-independent carrier-mediated mechanism (Citation41). Reduced folate carrier (RFC) (the product of the SLC19A1 gene) and PCFT/HCP1 mediate intestinal absorption of folate (Citation42,Citation43). Both proteins are expressed at the apical membrane domain of intestinal epithelial cells. RFC functions at a neutral pH, while transport of negatively charged folates by the PCFT system works in an acidic-pH-dependent (proton coupled) and electrogenic manner (Citation42,Citation44). Therefore, the contribution of each of these proteins in total folate absorption in vivo depends not only on their level of expression but also on the prevailing pH at the site of absorption (Citation41). In enterocytes, folate is reduced and methylated forming 5-methyltetrahydrofolate. Following intestinal absorption, folate is transported to the liver and subsequently into systemic circulation (Citation45).
5-Methyltetrahydrofolate donates a methyl group to vitamin B12, which subsequently transfers it to homocysteine, with the downstream effect of preventing accumulation of homocysteine in the cells. Thus it is not surprising that folate deficiency may be associated with increased levels of plasma homocysteine (Citation45).
Folate levels in celiac disease
Since villous atrophy is a hallmark of CD (Citation3), patients can have folate deficiency. This defect has been documented in 8%–85% of adult CD patients and 10%–40% of children with CD () (Citation26,Citation46–55). Haapalahti and co-workers assessed the nutritional status in 26 adolescent CD patients and demonstrated that one-third of screen-detected adolescent CD patients had low folate levels at time of diagnosis (Citation56). In a prospective study Saibeni and colleagues analyzed homocysteine, folate, and vitamin B12 levels in 40 patients with gluten-sensitive enteropathy (GSE) (32 patients with untreated CD and 8 patients with dermatitis herpetiformis) (Citation57). Folate deficiency was more frequent in patients with GSE (17/40, 42.5%) than in control subjects (10/120, 8.3%). Concordantly, more GSE patients had hyperhomocysteinemia (8/40, 20.0%) compared to controls (7/120, 5.8%). In contrast, there was no significant difference between patients and controls in terms of vitamin B12 deficiency (7/40, 17.5% versus 11/120, 9.2%) (Citation57). Folate deficiency was significantly more frequent in patients with hyperhomocysteinemia (6 of 8, 75.0%) than in normohomocysteinemic patients (11/32, 34.4%). In untreated CD patients, increased severity of villous atrophy correlated with lower folate and higher homocysteine levels (Citation57). These results were confirmed by data published by Kemppainen and co-workers who showed that erythrocyte folate concentrations were decreased in CD patients with total villous atrophy as compared to other groups (Citation58). Consistently, Vilppula and co-workers demonstrated that 13 out of 35 untreated CD patients (37%) had erythrocyte folic acid concentration below reference values (Citation35). Dickey and colleagues confirmed that homocysteine concentrations were significantly higher and red cell and serum folate significantly lower in untreated CD patients compared with controls (Citation59). Notably all these studies showed that a GFD normalized folate status and decreased plasma homocysteine levels () (Citation35,Citation57,Citation59). Consistently, McFarlane and colleagues showed that 55 adult CD patients (45 women and 10 men), who were on an established GFD, displayed red cell folate concentrations in the normal range (Citation60). A somewhat contrasting scenario emerges, however, from the study published by Hallert and colleagues. In this study the authors analyzed folate levels in CD patients on a GFD for at least 10 years with neither evidence of histological damage nor positive serological markers (Citation61). Of the patients in this population, 20% had low folate levels which correlated negatively with total plasma homocysteine levels (Citation61). Results from this study raise an intriguing question: why should folate deficiency persist in treated CD patients? Altered folate status may reflect the pitfalls of the GFD, which has been proven to be deficient in various nutrients (Citation61). Indeed, a lower daily folate intake has been described in treated CD patients compared to controls (Citation61–63). This observation fits with the demonstration that gluten-free cereal products, including breads and pastas, contain lower amounts of folate compared to their gluten-containing counterparts (Citation39). Genetic changes altering the expression of proteins involved in absorption and metabolism (e.g. RFC, PCFT) can also contribute to decreased folate levels, even though no study has yet addressed this issue.
While future studies are needed to ascertain the real frequency of folate deficiency in treated CD patients, Hallert and colleagues suggest that routine folate measurements and supplementation should be recommended to those who have folate deficiency (Citation61). In this context, it is noteworthy that results from Hallert's study show that folic acid and vitamin B12 supplements for 6 months significantly improved anxiety and depressed mood in patients with long-standing treated CD (Citation64). Although further investigations will be needed to confirm these results, this study supports the hypothesis that patients on a GFD and those with untreated CD may need folate and B vitamin supplementation in order to attenuate psychiatric symptoms (Citation64).
Neurologic complications (i.e. epilepsy, cerebellar ataxia, peripheral neuropathy, neuromyotonia, myelopathy, and dementia) can occur in up to 10% of both symptomatic and asymptomatic adult CD patients and have been ascribed to vitamin deficiencies (e.g. vitamin B12, folic acid, pyridoxine) (Citation65–67). However, Kieslich and co-workers assessed the spectrum, incidence, and risk factors of neurological complications in a cohort of 75 pediatric treated CD patients, showing that patients with neurological symptoms or anamnestic seizures (10/75, 13%) did not exhibit folate deficiency (Citation67).
CD patients have an increased risk of venous thromboembolism (VTE) and vascular diseases (Citation68,Citation69), but the mechanisms responsible for such extra-intestinal complications are not known. However, folate deficiency and hyperhomocysteinemia may be involved, as previous studies have implicated aberrant homocysteine and folic acid as risk factors for these pathologies (Citation70). The effect of folic acid supplementation on these complications, however, remains unknown.
Vitamin B12 absorption and metabolism
Vitamin B12, also known as cobalamin, can exist in several isoforms including cyano-, methyl-, 5-deoxyadenosyl-, and hydroxy-cobalamin (Citation71). The cyano form, which is used in supplements due to its biological stability, can be found in foods. Other forms of cobalamin can be converted to methyl- or 5-deoxyadenosyl derivatives, which act as co-factors for methionine synthase and L-methyl-malonyl-CoA mutase (Citation72). Methionine synthase catalyzes the transfer of a methyl group from methyltetrahydrofolate to homocysteine which is needed to synthetize methionine and tetrahydrofolate (Citation73). Interruption of this reaction by a vitamin B12 and/or folate deficiency can lead to the development of megaloblastic anemia (Citation74). Methylmalonyl CoA mutase converts methylmalonyl CoA to succinyl CoA by using 5-deoxyadenosyl-cobalamin as a co-factor. A deficiency of this co-factor promotes the accumulation of methylmalonyl CoA, which is responsible for the neurological symptoms documentable in vitamin B12-deficient patients (Citation74).
Following shedding from food proteins by gastric hydrochloric acid, vitamin B12 reaches the duodenum and binds intrinsic factor (IF); the IF-cobalamin complex is then absorbed in the terminal ileum (Citation74). Serum vitamin B12 is bound to proteins known as transcobalamins (TC); 80% of vitamin B12 is transported by TCI (also known as haptocorrin), whereas the remaining 20% is bound to TCII, which delivers vitamin B12 to the cells (Citation75).
Vitamin B12 status can be evaluated through the measurement of its plasma concentration or the plasma levels of methylmalonic acid and homocysteine (Citation76,Citation77). As noted above, homocysteine catabolism involves both folate and vitamin B12, whereas methylmalonic acid catabolism requires solely vitamin B12. Therefore, hyperhomocysteinemia is a product of both folate and vitamin B12 deficiencies, whereas increased levels of methylmalonic acid reflect a selective deficit in vitamin B12 (Citation77). Another indicator of vitamin B12 status is the level of TCII-bound cobalamin, namely holoTC, although the overall predictive value of this test does not offer any major advantages over the plasma vitamin B12 measurement (Citation77). Uptake of vitamin B12 in the ileum can be evaluated through the Schilling test, which measures the absorption of radiolabeled vitamin B12, with or without IF administration (Citation73).
Since vitamin B12 is mainly concentrated in animal tissues, meat and dairy products represent the only dietary source of vitamin B12 in humans (Citation71,Citation73). The bioavailability of vitamin B12 is strictly dependent on the individual's absorption capacity, which can be influenced by the quantity and type of protein consumed (Citation78). It is assumed that 50% of dietary vitamin B12 is absorbed. Total body stores of vitamin B12 range from 2000 to 5000 μg, with approximately one-half of that stored in the liver. The recommended dietary intakes are 2.4 mg for adults, 0.4–1.8 for children, 2.6 for pregnant women, and 2.8 for lactating women (Citation71,Citation79). Causes of vitamin B12 deficiency include: inadequate IF production due to atrophic gastritis, reduced ileal absorption due to disease or resection, and interference by bacterial overgrowth and drug interactions (Citation75). Pernicious anemia is the most frequent result of vitamin B12 deficiency (Citation71). Subclinical vitamin B12 deficiency can be due to malabsorption or dietary inadequacy, and is more frequent in developing countries, in the elderly, and in vegetarians (Citation73). While the symptoms of subclinical deficiency are mild, this condition can increase the risk of various severe diseases, such as neural tube defects, cardiovascular diseases, and age-related macular degeneration (Citation73).
Vitamin B12 levels in celiac disease
Vitamin B12 deficiency should be infrequent in CD, given that absorption occurs mainly in the terminal ileum, which is relatively spared in CD (Citation80). However, assessment of vitamin B12 status in CD has revealed that the circulating levels of this vitamin are inadequate in 5% to 41% of untreated patients () (Citation22,Citation46,Citation52,Citation59,Citation81). Vitamin B12 levels seem to be independent of clinical presentation of CD (Citation46,Citation47), degree of villous atrophy (Citation47,Citation58), and gender of patients (Citation47). The deficit is frequently mild, restricted to patients with advanced disease involving the ileum (Citation80), and corrected by a GFD (Citation35,Citation56) unless it is caused by co-existing diseases (e.g. pernicious anemia, pancreatic insufficiency) (Citation82). Folate depletion causing a CD-related vitamin B12 deficit is unlikely. A prospective study, in which the levels of vitamin B12 and folate were evaluated in a cohort of 39 untreated CD patients, showed that while 16 out of 39 (41%) patients had vitamin B12 deficiency, a concomitant folate deficiency was registered in only 5 out of the 16 (31%) vitamin B12-deficient patients (Citation46). Vitamin B12 levels were normalized in all 16 patients either through GFD (11 out of 16) or parenteral supplementation (the remaining 5) (Citation46).
Hallert et al. found that, unlike folate and pyridoxal 5’-phosphate, the concentration of vitamin B12 was normal in 30 well-managed CD patients on a long-term GFD (Citation61). The same group performed a double blind, placebo-controlled multicenter study, to assess the clinical effects of vitamin B supplementations in adults with long-standing CD (Citation64). Sixty-five CD patients on a GFD were given a daily dose of 0.8 mg folic acid, 0.5 mg cyanocobalamin, and 3 mg pyridoxine, or placebo, for 6 months. The treatment normalized plasmatic homocysteine levels and improved psychological well-being; in particular, an improvement of anxiety and depressed mood was observed following 6-month supplementation (Citation64). These observations indicate that for some subsets of CD patients with psychiatric symptoms both folate and vitamin B12 supplementation is beneficial even when on a GFD. Future studies will be necessary to clarify the role that each vitamin plays in the amelioration of psychiatric symptoms. It may also be prudent to establish an appropriate route of administration of vitamin B12, as oral supplementation has been proven as an effective treatment route in other diseases (Citation83).
Vitamin D absorption and metabolism
Vitamin D is produced mainly in the skin, where it is converted from 7-dehydrocholesterol to pre-vitamin D3 by ultraviolet sunlight (Citation84). Pre-vitamin D3 is then transformed into active vitamin D3, also known as cholecalciferol, by a thermally induced isomerization (Citation84,Citation85). Cholecalciferol then preferentially binds vitamin D-binding protein and enters the circulation (Citation85). Vitamin D can also derive from the diet: it is ingested as a pro-hormone, absorbed in the terminal ileum, and released in the liver. Once in the liver CYP2R1, one of the four hepatic cytochrome P-450 enzymes, converts vitamin D to 25-hydroxyvitamin D (also termed calcidiol) (Citation71,Citation86). 25-Hydroxyvitamin D is then transformed into 1-alpha-25 di-hydroxyvitamin D, calcitriol, by CYP27B1 in the kidney (Citation86); this active form of vitamin D regulates the serum levels of calcium by increasing intestinal calcium absorption and bone calcium resorption (Citation71,Citation87).
Since serum 25-hydroxyvitamin D is the major circulating form of vitamin D, measurement of this metabolite provides the best estimation of vitamin D stores. Clinical values of 25-hydroxyvitamin D should range from 30 to 50 ng/dL (Citation88). Despite the physiological production of vitamin D in the skin, a dietary intake of 600–800 IU of vitamin D is recommended to meet the needs of healthy individuals (Citation89).
Vitamin D and calcium levels in celiac disease
Circulating levels of vitamin D and calcium are reduced in many untreated CD patients (). These deficiencies may be a product of nutrient malabsorption secondary to intestinal epithelial damage and/or the elimination of milk products from the diet due to lactose intolerance (Citation90). Deficiency may also be related to the reduced expression of calcium-binding protein, a vitamin D-regulated protein that controls intestinal uptake of calcium (Citation91). This is not surprising as osteopenia and osteoporosis have been described in nearly half of untreated CD patients (Citation60,Citation92,Citation93) and associated with enhanced risk of fractures. Since osteoporosis in healthy individuals can be related to polymorphisms of vitamin-D-receptor (VDR) gene, it has been hypothesized that osteopenia/osteoporosis in CD could be secondary to such genetic changes. However, studies by Vogelsang and colleagues found that the frequency of the VDR gene polymorphisms did not differ between CD patients and healthy controls (Citation94). Additionally, Colston and colleagues showed that the expression of VDR on enterocytes was not negatively regulated in CD, even in the presence of villous atrophy (Citation95). Other studies have, however, reported a surprisingly low prevalence of reduced bone mineral density (BMD) and no significant increase of fracture rates in CD (Citation96). The reason for this discrepancy has not yet been elucidated, although it could be related to potential confounding variables (e.g. age, body mass index, postmenopausal status, concomitant endocrine pathologies).
Vitamin D and calcium levels normalize and BMD significantly improves following 1–2 years of a strict GFD () (Citation97–102). However, some CD patients on a GFD, particularly postmenopausal women, exhibit persistently low BMD. In these subsets of patients, long-term vitamin D and calcium supplementation prevents further bone loss and improves BMD (Citation60,Citation103–109). However, Mautalen and co-workers showed that calcium and vitamin D supplementation for a 12-month period did not provide additional benefit to that obtained by a GFD alone on BMD normalization (Citation110).
Severe vitamin D deficiency in adults may cause osteomalacia (Citation111), and this can be the presenting sign of CD. There is also evidence that a combination of a GFD and vitamin D supplementation is effective in improving osteomalacia-related symptoms and normalizing calcium levels (Citation112–117).
Zinc and magnesium absorption
Zinc is an essential trace element involved in numerous enzymatic reactions, biochemical functions, and immune responses (Citation118). Zinc is an integral constituent of many enzymes, such as DNA polymerase, reverse transcriptase, and RNA polymerase, and is therefore required for cellular growth and function (Citation119,Citation120). Consistently, zinc deficiency can affect protein synthesis and leads to growth arrest (Citation120,Citation121). Zinc is widely distributed in foods and many tissues, such as bone, blood, and liver, where it is tightly bound to proteins (Citation119,Citation120). It is primarily absorbed in the duodenum and jejunum, and its intestinal uptake exhibits both unsaturable and saturable kinetics, the latter involving a carrier-mediated process (Citation122,Citation123). Following intestinal absorption, zinc binds albumin or alpha-2 macroglobulin, which facilitates transport to the blood stream and liver (Citation124). Binding of zinc to metallothionein prevents entry into circulation (Citation124). Zinc is excreted mainly in the feces and in small amounts in the urine. Endogenous zinc pools are mobilized in the fasting state and can fluctuate in response to stress and infections, thus raising doubts on the utility of serum zinc concentrations to assess deficiency (Citation125,Citation126). Plasma zinc levels range from 80 to 120 μg/L (or 12–18 μmol/L), and zinc requirements in adults are 8–11 mg/day. Infants require zinc for growth; thus, daily requirements are about 300–500 μg/kg per day during the first 3 weeks of postnatal life (Citation120,Citation127). In older children, 50 μg/kg per day is needed to maintain normal serum zinc levels, while 100 μg/kg per day is required for growth (Citation128).
Magnesium is the main divalent intracellular cation essential for several enzymatic functions (e.g. DNA transcription and replication, mRNA translation, ionic pumps, and calcium channel function) (Citation129). Magnesium plays also a key role in the metabolism of proteins, nucleic acids, glucose, fats, and transmembrane transportation (Citation130). Magnesium balance is maintained within a narrow range by the small intestine and kidney, which can increase magnesium absorption under deficient conditions (Citation131). The normal magnesium body pool is roughly 22.6 g, with up to 60% located in bone (Citation129). If magnesium levels become depleted, bone stores maintain appropriate serum concentrations through exchange with the extra-cellular fluid (Citation132). The recommended magnesium dietary amount for adults is approximately 420 mg/day in men and 320 mg/day in women. Under physiologic conditions, 30%–50% of magnesium intake is absorbed by the small intestine, and this process is, in part, influenced by vitamin D (Citation133,Citation134). In the kidney, approximately 80% of magnesium is ultrafiltrated across the glomerular membrane and then reabsorbed in consecutive segments of the nephron (Citation131,Citation134). Plasma magnesium levels are in the range of 1.7–2.2 mg/dL (or 0.75–0.95 mmol/L or 1.5–1.9 mEq/L) at any age. Nearly 20% of magnesium is bound to albumin in the blood stream, which is relevant as evidence suggests some CD patients may present with low albumin (Citation135). The most reliable method for assessing magnesium content is the magnesium tolerance test (Citation136), while tissue magnesium deficiency can be evaluated by the intravenous magnesium loading test (Citation130).
Zinc and magnesium levels in celiac disease
It has been reported that more than 50% of untreated CD patients have zinc deficiencies () (Citation58,Citation81,Citation97,Citation137–142). This may be due to villous atrophy-dependent impaired absorption. Other factors (e.g. chelation of zinc by fatty acids, excessive loss due to protein-losing enteropathy, or excessive utilization due to enhanced enterocyte turnover) can contribute to zinc deficiency in CD (Citation140,Citation143). Zinc deficiency can contribute to growth retardation, impairment of sexual maturation and of wound healing, and hypogeusia (Citation144–146). So, it is conceivable that some of CD-associated symptoms/signs (e.g. reduced growth rate and anorexia) may be related, in part, to zinc deficiency. Notably, zinc deficiency resolves usually after 1 year of a strict GFD () (Citation58,Citation61,Citation97,Citation138,Citation140,Citation147,Citation148), and long-term supplementation is not needed.
Magnesium deficiency has been reported in nearly 20% of untreated CD patients () (Citation49,Citation81,Citation130), even if normal levels of serum magnesium have been documented in untreated CD patients (Citation58). Moreover, Rujner and co-workers documented a similar frequency of magnesium deficiency in untreated patients with subclinical CD or in treated CD patients and in controls (Citation130). Persistence of magnesium deficiency in treated CD patients () (Citation130) is probably reflective of the low magnesium content of gluten-free cereal products (Citation62,Citation130,Citation149,Citation150). Therefore, patients on a GFD should be encouraged to take magnesium-enriched foods.
Conclusions
Reduced levels of iron, folate, vitamin B12, vitamin D, zinc, and magnesium have been documented in CD patients (Citation46,Citation56–60, Citation81,Citation92,Citation93,Citation130,Citation137–142,Citation151–154) and are probably reflective of a loss of brush border proteins and enzymes needed for absorption. In the majority of patients, the intestine heals with removal of gluten from the diet, thus promoting normalization of biochemical alterations and amelioration of symptoms. However, nutrient deficiencies, such as low levels of folate, vitamin B12, and vitamin D, can persist in some subsets of treated CD patients, thus contributing to extra-intestinal clinical manifestations, such as neurologic complications (i.e. epilepsy, cerebellar ataxia, peripheral neuropathy, neuromyotonia, myelopathy, and dementia), psychiatric symptoms (i.e. parasthesia, anxiety, depression), or bone alterations (i.e. osteopenia, osteoporosis) (Citation64–67,Citation103–109). A clear and evidence-based approach to the timing of vitamin and mineral testing in treated patients is not yet available; international guidelines suggest testing deficient patients on a GFD annually (Citation155). Since laboratory tests for assessing nutritional deficiencies are expensive (Citation155), it would be useful to monitor only treated CD patients who have clinical manifestations which are potentially dependent on nutrient deficiencies. However, recent clinical guidelines suggest testing and treating newly diagnosed CD patients for nutrient deficiencies. Moreover, annual monitoring of treated CD patients should include verification of normalization of laboratory tests (such as ferritin, iron, vitamin D, vitamin B12, folate, and zinc), which are impaired at baseline (Citation156). Additionally, we feel it is fair to encourage treated CD patients to consume foods containing folate (e.g. beans, leafy green vegetables, asparagus, lentils, orange juice, and citrus fruits), vitamin B12 (e.g. liver, beef, lamb, chicken, eggs, and dairy foods), magnesium (e.g. leafy green vegetables, legumes, meat, and seafood), zinc, and vitamin D, as gluten-free products may provide inadequate amounts of these nutrients (Citation39,Citation62).
Acknowledgements
We wish to thank Daniel DiGiacomo (Tulane University School of Medicine, New Orleans, LA, USA) for the English editing of the manuscript. This work received support from the Fondazione Umberto di Mario Onlus, FC Fondazione Celiachia Onlus, and Giuliani Spa, Milan, Italy.
Fondazione Umberto di Mario Onlus, FC Fondazione Celiachia Onlus, and Giuliani Spa had no role in the design, analysis, or writing of this article.
Declaration of interest: There are no conflicts of interest to disclose for all the authors.
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