Celiac Disease and Non-Celiac Gluten Sensitivity
Iron-deficiency anemia is one of the most common extraintestinal signs of celiac disease (Horowitz 2011; Caruso 2013); iron deficiency without anemia may also occur. Although iron deficiency is usually corrected by a gluten-free diet, restoration of iron levels can require 6–12 months after the lining of the small intestine has healed (Caruso 2013). Blood tests for iron deficiency, including a complete blood count and ferritin level, are important in diagnosis (Ferri 2015) and iron supplementation is considered part of necessary care for celiac patients, in part due to the nutritional insufficiency possible with a gluten-free diet (Thompson 2000; Kupper 2005; Lidums 2015; Kelly 2014).
In celiac disease, damage to the intestinal lining often leads to calcium malabsorption and decreased serum levels of calcium (Rastogi 2012; Pantaleoni 2014; Babar 2011; Szymczak 2012), which then lead to bone loss, osteopenia, osteoporosis, and increased fracture risk (AGA 2001; Pantaleoni 2014). Calcium levels and bone mineral density improve on a gluten-free diet, but only after one to two years (Caruso 2013; Molteni 1995). However, a gluten-free diet can be low in calcium, and can lead to calcium deficiency (Kupper 2005; UCMC 2013; Blazina 2010) and subsequent low bone mineral density (Blazina 2010). Thus, supplementation with calcium is important for patients with celiac disease (Rastogi 2012; Mancini 2011; Szymczak 2012; Blazina 2010; Lucendo 2013; Caruso 2013; Bianchi 2008).
Vitamin D deficiency is a common problem in celiac disease and is associated with a range of musculoskeletal disorders including bone pain, muscle disorders (myopathy), loss of bone mineral density, osteopenia, and osteoporosis (Mulder 2011; Rastogi 2012; Rabelink 2011; Karaahmet 2014; Caruso 2013). One study found low vitamin D levels in 64% of men and 71% of women with celiac disease (Kemppainen 1999). Importantly, however, this study defined vitamin D “deficiency” as below 10 ng/mL 25-hydroxyvitamin D, which is far below levels considered optimal. Also, evidence suggests serum vitamin D levels decrease with age in individuals with celiac disease, and low levels occur even in sunny climates (Lerner 2012). A case report described a celiac patient with myopathy and a vitamin D level below 4 ng/dL. The patient was started on a gluten-free diet and initiated vitamin D supplementation at a dose of 300 000 IU once every two weeks, while under physician supervision. The patient’s symptoms resolved within a week (Karaahmet 2014).
Supplementation with vitamin D and calcium, along with a gluten-free diet, has been shown to markedly improve bone status in celiac patients (Duerksen 2012; Bianchi 2008; Rastogi 2012), and supplementation with vitamin D and calcium is widely recommended for celiac patients (Szymczak 2012; Lucendo 2013; Rastogi 2012). Vitamin D has many additional functions beyond its role in the musculoskeletal system, particularly modulation of the immune system and anti-inflammatory effects. Data from laboratory studies provide evidence for vitamin D’s potential to decrease systemic inflammation and prevent autoimmune disease in humans (Richards 2007; Kriegel 2011; Agmon-Levin 2013; Antico 2012). Specifically, vitamin D inhibits secretion of pro-inflammatory cytokines such as interferon-gamma and TNF-α, while promoting the production of anti-inflammatory cytokines including IL-4, IL-5, and IL-10 (Prietl 2013).
Blood tests for 25-hydroxyvitamin D can determine baseline levels and monitor changes in levels resulting from vitamin D supplementation and a gluten-free diet.
Deficiencies of folate and vitamins B12 and B6 are common in celiac disease (Dickey 2002; Haapalahti 2005; Tikkakoski 2007; Dahele 2001; Reinken 1978; Caruso 2013), and supplementation with these B vitamins, and also niacin (vitamin B3) and riboflavin (vitamin B2), is considered an important part of conventional care for celiac patients (Hadithi 2009; Caruso 2013; Wierdsma 2013; Halfdanarson 2007; Lidums 2015). In one study, folate and pyridoxal 5’-phosphate, the active form of vitamin B6, were deficient in 37% and 20% of adult celiac patients, respectively, who had been on a gluten-free diet for 10 years and who exhibited biopsy-proven recovery. Among the participants in this study, mean daily folate and vitamin B12 intake were significantly lower in those with celiac than in controls (Hallert 2002).
Homocysteine is an amino acid derivative that can damage the lining of blood vessels and promote atherosclerotic disease (Eren 2014; Pushpakumar 2014). Elevated homocysteine is often attributable to a lack of vitamins B12, B6, and folate, which are necessary for the metabolism of homocysteine (Higdon 2014a; Higdon 2014b). Several studies have demonstrated elevated blood levels of homocysteine in celiac patients (Hallert 2002; Dickey 2008; Saibeni 2005). One study showed celiac patients who took vitamin supplements had higher blood levels of folate and vitamins B6 and B12, and lower levels of homocysteine, compared with those who did not use supplements (Hadithi 2009). Deficiency in folate and vitamin B12 can cause B-deficiency anemia, which is common in celiac disease, occurring in up to 34% of untreated patients (Wierdsma 2013; Halfdanarson 2007).
Magnesium is an essential mineral involved in hundreds of enzymatic reactions in the body (Higdon 2013a). Magnesium is also required for proper metabolism of vitamin D and calcium, and thus for bone health (Zofkova 1995; Hardwick 1991).
The importance of magnesium deficiency in celiac disease was first recognized over fifty years ago, when a detailed case report showed a dramatic improvement in magnesium absorption and status in a young adult celiac patient after she commenced a gluten-free diet (Goldman 1962). Another study investigated magnesium status in children and adolescents with celiac disease. While all of the patients with classical celiac disease (with malabsorption) were magnesium deficient, only 1 in 5 patients on a gluten-free diet (no malabsorption) and 1 in 5 patients with silent celiac disease (no malabsorption) were low in magnesium (Rujner 2001). A later study examined magnesium in 41 children and adolescents with celiac disease or normal intestinal villi who had been on a gluten-free diet for an average of 11 years; 28 patients with untreated atypical celiac disease and eight controls were also included in the study. The researchers found magnesium deficiency, as assessed by red blood cell magnesium levels, in 14.6% of those on the gluten-free diet and 25% of untreated patients (Rujner 2004).
An earlier study in 23 adult celiac patients found that all of them had depleted intracellular magnesium levels despite being asymptomatic (no malabsorption) and on a gluten-free diet. Magnesium therapy in these individuals resulted in increases in both red blood cell magnesium and bone mineral density, suggesting magnesium deficiency may play a role in the development of osteoporosis in people with celiac disease (Rude 1996). Screening for magnesium status and deficiency, and magnesium supplementation and dietary enrichment, are considered essential aspects of care for celiac patients (Ferri 2015; Lidums 2015; Caruso 2013).
Zinc is an essential nutrient mineral that acts as a catalytic agent for over 300 separate enzymatic reactions in the body (Higdon 2013b). Zinc deficiency is common in untreated celiac disease, and this deficiency is not always corrected by a gluten-free diet; zinc supplementation is considered a necessary part of celiac treatment by some sources (Caruso 2013; Lidums 2015; Kupper 2005). Zinc deficiency may be a culprit in poor growth, immune function, and wound healing, and skin problems in celiac disease.
A review of studies of both untreated and treated celiac patients found a remarkable prevalence of zinc deficiency, as measured by either plasma or serum zinc. Eleven separate studies of untreated adults and children with celiac disease found zinc deficiency in up to 100% of patients. Three of nine studies of celiac patients on a gluten-free diet for as little as three months to as long as 10 years found zinc deficiency persisted in 20–40% of patients. On a gluten-free diet alone, zinc deficiency usually takes a full year to resolve, and monitoring of serum zinc levels in celiac patients has been suggested (Caruso 2013; Wierdsma 2013; Guevara Pacheco 2014).
Vitamin E is an important fat-soluble vitamin and free radical scavenger that plays a major role in protecting cell membranes from oxidative damage (Higdon 2008). Several studies have reported low levels of vitamin E in individuals with celiac disease (Odetti 1998; Guevara Pacheco 2014; Henri-Bhargava 2008). Vitamin E deficiency has also been implicated in the development of neurological symptoms in celiac disease (Kleopa 2005; Mauro 1991; Battisti 1996; Henri-Bhargava 2008). Vitamin E supplementation, together with a gluten-free diet, has been shown to improve neurological impairment caused by vitamin E deficiency in celiac disease (Kleopa 2005; Henri-Bhargava 2008; Mauro 1991).
Vitamin A is a fat-soluble nutrient that can become deficient in celiac disease patients as a result of malabsorption. Vitamin A is important for normal immune function, vision, and gene expression (Higdon 2007a). The treatment for vitamin A deficiency in celiac disease is both a gluten-free diet and supplementation (Lidums 2015). One study of newly diagnosed celiac patients found that 7.5% of them were deficient in vitamin A versus none in a healthy control group (Wierdsma 2013). A case study reaffirmed the importance of vitamin A, even in controlled celiac cases. A 64-year-old man, with biopsy-proven celiac disease controlled on a gluten-free diet, presented with recent onset of diarrhea as well as redness and blurring in one eye. During three weeks of treatment of his eye symptoms with medication, his condition deteriorated. Testing of vitamin A revealed a stark deficiency. The patient received an intramuscular injection containing 100 000 IU vitamin A, and dramatic improvement in vision and the condition of his eye was noted within a week. This patient’s follow-up included regular vitamin A treatment (Alwitry 2000).
Vitamin K is another fat soluble vitamin that can become deficient in celiac disease as a result of malabsorption (Lidums 2015; Mager 2012; Kelly 2014; Lidums 2015). Vitamin K deficiency can contribute to easy bruising, an atypical sign of celiac disease; vitamin K deficiency has also been shown to increase risk of blood clots and bleeding events in individuals with celiac disease (Berthoux 2011; Chen 2007; Vaynshtein 2004; Lerner 2014; Lerner 2014; Chen 2007; Vaynshtein 2004). In a 2012 study in children and adolescents with celiac disease, dietary intake of vitamin K was assessed. At diagnosis, 41% of patients had intakes less than half of the recommended amount, while intake remained deficient in 31% of patients after one year on a gluten-free diet (Mager 2012).
Children with both symptomatic and asymptomatic celiac disease have been found to have reduced bone mass at diagnosis (Mager 2012; Turner 2009; Rajani 2010). Vitamin K enhances calcium metabolism and therefore plays an important role in bone health (Zittermann 2001; Booth 2009). Because dietary intake of calcium and vitamins K and D is often inadequate, including for patients on a gluten-free diet, routine supplementation with vitamin K at the time of diagnosis of celiac disease has been suggested (Mager 2012).
Selenium is an integral part of the enzyme glutathione peroxidase, which plays a major role in cellular antioxidant defense (Higdon 2007b). In a study of 30 children with celiac disease, 80% had serum selenium levels below the normal range (Yuce 2004). Selenium is essential for thyroid hormone regulation, and selenium deficiency in celiac disease has been linked to an increased risk of autoimmune thyroid disease (Stazi 2008; Stazi 2010).
Probiotics are beneficial microorganisms that colonize the intestine and play an important role in intestinal health; the balance of these organisms appears to be deranged in patients with celiac disease (Pozo-Rubio 2012; Round 2009). In a three-week randomized controlled trial, supplementation with Bifidobacterium infantis NLS super strainin untreated celiac disease patients resulted in improvements in indigestion, constipation, and acid reflux (Smecuol 2013).
Various strains of probiotics are being developed to specifically target mechanisms of immune and intestinal damage in celiac disease. The probiotic strain Bifidobacterium lactis has been shown to protect cultured gut epithelial cells from damage induced by gluten, possibly by blocking gluten-induced increases in intestinal permeability (Lindfors 2008). Also, in a lab experiment, a blend of eight different strains of probiotic bacteria, including several Lactobacillus and Bifidobacterium species, was demonstrated to extensively pre-digest gluten proteins in wheat flour. When intestinal biopsy samples from celiac patients were exposed to these pre-digested gluten proteins, recruitment of immune cells was reduced. Researchers concluded that the probiotic formulation reduced or eliminated the toxicity of wheat gluten (De Angelis 2006).
L-carnitine is a compound made in the human body from the amino acids lysine and methionine and also obtained in our diet primarily from animal foods such as meat, fish, and dairy (Higdon 2012a).
In a randomized controlled trial, supplementation with 2 g L-carnitine daily for six months resulted in significant improvement in reported fatigue in adults with celiac disease. The L-carnitine dosage was safe and well tolerated (Ciacci 2007).
L-carnitine is required to shuttle long chain fatty acids into the mitochondria (power plants of the cell) for muscle energy production. The intestinal damage in celiac disease results in a decrease in absorptive surface area, increasing risk of L-carnitine deficiency. In one study, untreated celiac patients were found to have low serum L-carnitine concentrations, which returned to normal with a gluten-free diet (Lerner 1993). Another study found low serum carnitine levels in children with celiac disease (Yuce 2004). L-carnitine deficiency may produce fatigue, weakness, and difficulty gaining weight, all common symptoms in celiac disease (Lerner 1993; Guandalini 2014).
Omega-3 Fatty Acids
Omega-3 fatty acids have important biological anti-inflammatory effects (Skulas-Ray 2015; Yan 2013; Calder 2015). When ingested through food or supplements, omega-3 fatty acids compete with the more pro-inflammatory omega-6 fatty acid arachidonic acid for incorporation into lipid-rich cell membranes (Westphal 2011; Calder 2007; Pischon 2003; Surette 2008).
A study of serum fatty acid composition in adults with newly diagnosed celiac disease found that concentrations of omega-3 fatty acids were significantly lower than those of a control group. After one year on a gluten-free diet and having achieved clinical remission, levels of omega-3 fatty acids increased but still remained well below control values (Solakivi 2009). A study in children with celiac disease and type 1 diabetes mellitus found their omega-3 fatty acid levels—including docosapentaenoic and docosahexaenoic acid (DHA)—were significantly lower than those in a control group (Tarnok 2015).
A study that used cultures of intestinal epithelial cells (enterocytes) supports the potential benefit of oral supplementation with DHA in reducing intestinal inflammation in celiac disease. In response to inflammation triggered by gluten, enterocytes release arachidonic acid. DHA was shown to block this release of arachidonic acid and the resulting inflammatory cascade that furthers disease development (Vincentini 2011; Ferretti 2012). Another mechanism by which omega-3 fatty acids reduce inflammation is through inhibition of nuclear factor-kappaB (NF-ĸB), a pro-inflammatory mediator (Lee 2009). DHA also stimulates a cellular receptor called PPAR-gamma, which activates genes that lessen the production of pro-inflammatory cytokines (Zapata-Gonzalez 2008).
Vitamin C is a water-soluble free radical scavenger that is also essential to the structural integrity of tissues throughout the body (Higdon 2013c). In one experiment, cultured intestinal biopsies from celiac patients were challenged with the gliadin component of gluten with and without the addition of vitamin C. The addition of vitamin C to the cultured cells decreased the secretion of pro-inflammatory cytokines TNF-α, IL-6, and interferon-gamma. Vitamin C also completely inhibited the secretion of the pro-inflammatory cytokine IL-15, which is strongly implicated in the damage that occurs in celiac disease (Bernardo 2012; Gujral 2012).
Glutathione is one of the body’s most powerful defenses against destructive free radicals, and is essential to the liver’s detoxification functions (NLM 2015; Kidd 1997). Several studies have reported significant reductions in glutathione concentrations in the intestinal lining (Stojiljkovic 2009; Stojiljkovic 2012) and peripheral blood (Stojiljkovic 2007; Stojiljkovic 2012) of celiac patients compared with controls. As a result, concentrations of lipid peroxides, or rancid fat, in the intestinal lining increased. Lipid peroxides can promote a cascade of oxidative damage in tissues, contributing to the tissue damage in the intestine that is characteristic of celiac disease, and to the increased risk of cancer in celiac patients (Stojiljkovic 2007; Stojiljkovic 2009; Stojiljkovic 2012).
The body’s glutathione reserves can be increased by means of direct supplementation with glutathione (Richie 2014) or with the use of physiologic precursors such as cysteine (Lee 2013; Sekhar 2011) and N-acetyl cysteine (NLM 2015; Kidd 1997), as well as with alpha-lipoic acid, selenium, and whey protein (Chen 2011; Zavorsky 2007; Jiang 2012).
Exocrine pancreatic insufficiency, a condition in which not enough digestive enzymes are secreted into the small intestine (Toouli 2010), is relatively common in celiac disease patients who do not respond to a gluten-free diet (Ferri 2015). Damage to the small intestine may inhibit the ability of the pancreas to secrete digestive enzymes. One study found that in cases in which diarrhea persisted even after a gluten-free diet, there was a significantly higher prevalence of laboratory signs of pancreatic insufficiency. Patients treated with pancreatic enzymes experienced a 75% reduction in symptoms. Another study found that the severity of villous atrophy in the small intestine was significantly associated with laboratory signs of pancreatic exocrine insufficiency. Pancreatic enzyme insufficiency was found to occur in over half of celiac patients in one study, and to return to normal after one year on a gluten-free diet (Malterre 2009; Evans 2010; Weizman 1987; Regan 1980).
The following interventions have not been thoroughly studied in the context of celiac disease, but may nonetheless be of benefit by helping support intestinal health or combatting inflammatory responses or cellular metabolic derangements, which are thought to underlie several manifestations of celiac disease.
Curcumin. Curcumin is the principal polyphenolic compound in turmeric, a plant used in Indian Ayurvedic medicine for centuries (Higdon 2009). Curcumin has powerful anti-inflammatory and antioxidant properties and has demonstrated in laboratory, animal, and human models an ability to protect against a wide range of conditions including autoimmune disease and IBD (Gupta 2013; Aggarwal 2009; Brumatti 2014; Bright 2007).
Like Crohn’s disease and ulcerative colitis, celiac disease is an inflammatory autoimmune disorder (Ferri 2015). In celiac disease, the inflammatory mediator interferon-gamma promotes enhanced permeability and damage in the small intestine (DiRaimondo 2012; Nilsen 1998). Curcumin has been shown to suppress interferon-gamma, suggesting that curcumin may be beneficial in celiac disease (Fahey 2007).
Interestingly, curcumin may be able to ameliorate psychological manifestations of celiac disease and non-celiac gluten sensitivity as well. In a randomized controlled trial, a highly bioavailable form of curcumin called BCM-95 was found to be as effective as the standard antidepressant medication fluoxetine (Prozac) in the treatment of major depressive disorder (Sanmukhani 2014; Antony 2008). Since depression and other psychological manifestations of celiac disease and non-celiac gluten sensitivity are being recognized with increasing frequency (Peters 2014; Smith 2012; Bushara 2005; Carta 2002; Corvaglia 1999; Addolorato 1996), this is another of curcumin’s benefits that may be valuable in these gluten-related disorders.
Alpha-lipoic acid. Alpha-lipoic acid is a naturally occurring compound centrally involved in energy production within the mitochondria of the cell. It is also a powerful free radical scavenger (Higdon 2012b). In addition, alpha-lipoic acid regenerates other free radical scavengers such as glutathione, vitamin C, vitamin E, and coenzyme Q10 (Chen 2011; Packer 2011; Jones 2002).
Alpha-lipoic acid’s ability to increase levels of glutathione is important in celiac disease, in which low glutathione levels are common (Stojiljkovic 2007; Stojiljkovic 2009; Stojiljkovic 2012). In an animal model, dietary supplementation with alpha-lipoic acid significantly increased both cellular glutathione concentrations and the activity of glutathione peroxidase, a key glutathione-dependent antioxidant enzyme. Compared with controls, levels of oxidized lipids (peroxidation) were significantly lower as well (Chen 2011). Other studies support alpha-lipoic acid’s potential to accelerate glutathione synthesis (Packer 2011; Kolgazi 2007; Suh 2004). In a rodent model of gut inflammation, a feature of celiac disease, treatment of rats with alpha-lipoic acid markedly reduced several measures of damage to the gut lining (Kolgazi 2007).
Boswellia serrata. In recent years, preparations from the gummy resin of Boswellia serrata and other boswellia species have become popular in parts of Europe for the treatment of various chronic inflammatory conditions including chronic bowel diseases. Clinical studies suggest boswellia is safe and effective in the treatment of autoimmune bowel diseases (Crohn’s disease and ulcerative colitis). Boswellic acids, which are active constituents of boswellia, exert anti-inflammatory effects through inhibition of proinflammatory pathways involving 5-lipoxygenase, leukotrienes, and TNF-α (Ammon 2006). In a similar manner, boswellia may help reduce the intestinal inflammation of celiac disease.
Green tea extract (EGCG). Animal studies have indicated that green tea extract and its chief constituent, epigallocatechin-3-gallate (EGCG), are capable of interrupting inflammatory tissue damage that contributes to the symptoms of celiac and other autoimmune disease. Helper T cells are key drivers in many autoimmune diseases including celiac disease (Monteleone 2001). One mechanism for the protective effect of EGCG is suppression of autoreactive T cells and reduced production of pro-inflammatory cytokines. EGCG was also shown to inhibit interferon-gamma, a dominant inflammatory mediator in celiac disease (Wu 2012).
In a human cell-line study, EGCG prevented interferon-gamma from increasing intestinal permeability (Watson 2004). In an animal model of colitis, green tea extract significantly diminished damage to the colon, as evidenced by reduced amounts of inflammatory markers, less diarrhea, and slowing of weight loss (Mazzon 2005).
Glutamine. Glutamine, an amino acid, is especially important for the lining of the gastrointestinal tract, particularly during stress and illness. Glutamine is the most abundant amino acid in the body, and a critical fuel for the cells lining the intestine. In fact, oral glutamine supplementation is capable of increasing the height of intestinal villi, helping the cells of the gut lining to proliferate, and maintaining integrity of the gut lining and preventing excessive permeability (de Vasconcelos 1998; Miller 1999). As a regulator of tight junction proteins that “glue” intestinal cells together (Li 2004), glutamine has been shown to exert a positive effect on gut barrier function (permeability) in a variety of clinical conditions (Beutheu 2013; Sevastiadou 2011; Choi 2007). In a 2012 randomized controlled trial in patients with Crohn’s disease in remission phase, oral glutamine administered at 0.23 g per pound body weight for two months significantly improved intestinal permeability and mucosal integrity (Benjamin 2012).
Glutamine supplementation has yet to be studied in celiac disease. However, since supplementation with glutamine has been demonstrated to safely enhance and maintain gut barrier function, its application in the increased permeability caused by celiac disease is an area of great scientific interest (Kuhn 2010; Beutheu 2013; Choi 2007; Benjamin 2012; Fasano 2011; Clemente 2003; Fasano 2005; Arrieta 2006).
Whey protein. Glutathione forms an integral part of the defense mechanisms that protect the intestinal mucosa (gut lining) from oxidative damage (Stojiljkovic 2009). Whey protein is a rich source of cysteine that is needed for the synthesis of glutathione (Alt Med Rev 2008). Several studies have shown that whey protein is highly effective for increasing glutathione levels in various types of cells (Zavorsky 2007; Vilela 2006; Kent 2003; Grey 2003; Middleton 2004). Additionally, in a 2012 study in patients with Crohn’s disease, whey protein significantly reduced intestinal permeability (Benjamin 2012). This benefit of whey on gut integrity may be useful in celiac disease, and whey protein can easily be incorporated into a gluten-free diet as a source of high-quality protein and glutathione precursors.
Zinc-carnosine. Zinc-carnosine, a free radical scavenger and anti-glycation agent, is composed of zinc and carnosine (Alhamdani 2007). In a randomized crossover trial, healthy participants were given either zinc-carnosine or placebo after five days of indomethacin (Indocin) treatment. The indomethacin caused a 3-fold increase in gut permeability in the placebo group, while zinc-carnosine prevented this rise in permeability in the treatment group. Although more studies are needed, zinc-carnosine appears to help maintain the integrity of the gut barrier (Mahmood 2007).
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