Celiac disease has been linked to an increased risk of neurological damage


People living with Celiac Disease (CD) have a higher risk of neurological damage according to a new study from the University of Sheffield.

The study found that the brains of people living with CD showed evidence of damage to brain matter and cognitive deficit in the form of slowed reaction times.

Alongside this neurological damage, this group of people also had indications of worsened mental health compared to matched healthy control subjects.

The researchers hope the study will help clinicians to tailor their care to CD patients who may present even the mildest cognitive changes; providing reassurance and motivation for the maintenance of a strict gluten-free diet (GFD), and eradicate any scepticism in the clinical community.

People living with CD have increased sensitivity to gluten and are advised to follow a strict GFD, the only current method of minimising exposure and the immediate risk of damage to their digestive system.

As a result of repeated or uncontrolled exposure, this autoimmune response to gluten can also lead to serious complications and longer term health problems for people living with CD.

These include a higher risk of coronary artery disease, small bowel cancers, deterioration of bone health and damage to the nervous system.

There has long been debate amongst neurologists and gastroenterologists about whether this neurological damage is caused as a result of people having CD, with previous studies finding conflicting evidence.

Seeking to end this debate, researchers from the University of Sheffield conducted a study using independent third party study samples from people with no pre-existing neurological illness from the national UK Biobank.

This data, including cognitive test scores and brain imaging data was used to eliminate any so-called ‘ascertainment bias’ in their study.

Dr Iain Croall, a research fellow from the University of Sheffield’s Department of Infection, Immunity and Cardiovascular Disease, said and Associate Member of Insigneo: “For the first time, the study offers some clarity on the fact that there does appear to be the risk of neurological damage for people living with CD, driven by their autoimmune response to gluten exposure.

“Our independent UK Biobank participants with CD showed meaningful neurological and psychological deficits when compared with control participants.

“The data from the CD group of participants showed a significant reaction time deficit, compared to the control participants; alongside signs of anxiety, health-related unhappiness and depression.”

This shows brain scans from the study

Brain white matter tracts are shown in green in control participants. These parts appear different in the study’s coeliac disease group, which are highlighted in red/orange/yellow; indicating damage to brain tissue in these locations. The image is credited to Iain Croall et al.

Reaction time is an indicator of the cognitive processing speed and people who have compromised white matter tissue frequently show impairments in this area.

Previous research has also highlighted that 50 percent of newly diagnosed CD patients present with clinical neurological symptoms, while population studies have shown living with CD may increase the risk of developing conditions like vascular dementia in older age.

“If previous report findings were due to ascertainment bias, then we would not have found evidence of neuropsychological dysfunction in third party data from the UK Biobank participants,” said Dr Croall.

“What the research shows is that it would be of great benefit for clinicians to support people living with CD to be as vigilant as possible with their gluten-free diet. Reducing any accidental exposure to gluten controls any further brain damage and promotes healing within the digestive system safeguarding a better level of overall health,” said Dr Croall.

Funding: The study was funded by the Sheffield Institute of Gluten Related Disorders, and supported by the National Institute of Health Research (NIHR) Sheffield Biomedical Research Centre and the University of Sheffield Insigneo Institute for in silico Medicine.

The UK Biobank is a valuable international resource that independently holds a wealth of health and demographic data on 500,000 anonymous UK adults, and with consent is made available to health researchers.

Celiac disease (CD) is an autoimmune condition characterized by a specific serological and histological profile triggered by gluten ingestion in genetically predisposed individuals [1].

Gluten is the general term for alcohol-soluble proteins present in various cereals, including wheat, rye, barley, spelt, and kamut [1]. In recent years, there have been significant changes in the diagnosis, pathogenesis, and natural history of this condition [2], with CD undergoing a true ‘metamorphosis’ due to the steady increase in the number of diagnoses identified, even in geriatric patients [2].

This has been mainly attributed to the greater availability of sensitive and specific screening tests, which allow identification of the risk groups for CD and led to a significant raise in diagnoses worldwide [25].

Several theories have suggested that the globalization and ubiquitous spread of ‘false’ or ‘extreme’ versions of the Mediterranean diet including the consumption of very high quantities of gluten (up to 20 g/day), has led to an increased prevalence and incidence of CD [34].

In addition, the quality of gluten itself might also play a contributory role. Indeed, the production of new grain variants due to technological rather than nutritional reasons may have influenced the observed increase in the number of CD diagnoses in recent years [45].

However, these hypotheses have not been confirmed and the real cause of the risk in CD diagnoses remains unknown. Furthermore, the epidemiological observation that similar ‘epidemics’ are reported for other autoimmune diseases in the Western hemisphere [6] suggests that environmental factors other than gluten can be at play.

In this article, we aimed to provide a thorough review on the multifaceted features of CD spanning from its epidemiological, pathogenetic, clinical, and diagnostic aspects to therapeutic strategies using a practical approach in order to help general practitioners, internal medicine physicians, and gastroenterologists in their clinical practice.


CD is one of the most common autoimmune disorders, with a reported prevalence of 0.5–1% of the general population (Table 1), with the exception of areas showing low frequency of CD-predisposing genes and low gluten consumption (e.g., sub-Saharan Africa and Japan) [713].

Studies have shown that most CD cases remain undetected in the absence of serological screening due to heterogeneous symptoms and/or poor disease awareness. CD prevalence is increasing in Western countries. Between the years 1975 and 2000, CD prevalence increased 5-fold in the US, for reasons that are currently unknown [14]. The prevalence of CD is higher in first-degree CD relatives (10–15%) and in other at-risk groups, particularly patients with Down syndrome, type 1 diabetes, or IgA deficiency [1].

Table 1

Serological screening for celiac disease in adults (confirmed with duodenal biopsy) in the general population

First level antibody testNo. of casesAge, yearsCountryPrevalence of celiac disease
Corazza et al., 1997 [6]EmA223720–87Italy0.18%
Ivarsson et al., 1999 [7]EmA189425–74Sweden0.53%
Riestra et al., 2000 [8]EmA117014–89Spain0.26%
Volta et al., 2001 [9]EmA348314–65Italy0.57%
Mustalahti et al., 2010 [10]Anti-tTG, EmA640330–93Finland2.5%
Rubio-Tapia et al., 2012 [11]Anti-tTG, EmA779823–66USA0.71%
Singh et al., 2016 [12]Anti-tTG, EmA43,955Not specifiedAsia0.5%

Anti-tTG anti-transglutaminase antibodies, EmA anti-endomysium antibodies


CD is a unique autoimmune disease in that its key genetic elements (human leukocyte antigen (HLA)-DQ2 and HLA-DQ8), the auto-antigen involved (tissue transglutaminase (tTG)), and the environmental trigger (gluten) are all well defined. A major drawback in CD research has been the lack of a reliable and reproducible animal model, with the possible exception of the Irish setter dog, which may develop a gluten-related disease [15]. Nevertheless, new technologies pertinent to human gut biology and immunology are opening unprecedented opportunities for major research breakthroughs.

As with many other autoimmune diseases, we have witnessed an epidemic of CD, questioning the previous paradigm that gluten is the only key element dictating the onset of the disease in genetically at-risk subjects.

Improved hygiene and lack of exposure to various microorganisms also have been linked with a steep increase in autoimmune disorders in industrialized countries during the past 40 years [116].

The hygiene hypothesis argues that the rising incidence of many autoimmune diseases may partially be the result of lifestyle and environmental changes that have reduced our exposure to pathogens.

With breakthroughs in the role of the gut microbiological ecosystem [17] in dictating the balance between tolerance and immune response leading to autoimmunity, this hypothesis is under scrutiny.

Regardless of whether autoimmune diseases are due to too much or too little exposure to microorganisms, it is generally accepted that adaptive immunity and imbalance between T helper 1 and 2 cell responses are key elements of the pathogenesis of the autoimmune process.

Besides genetic predisposition and exposure to gluten, loss of intestinal barrier function, a pro-inflammatory innate immune response triggered by gluten, inappropriate adaptive immune response, and an imbalanced gut microbiome all seem to be key ‘ingredients’ of the CD autoimmunity recipe.


As with any other autoimmune disease, CD has a strong hereditary component as testified by its high familial recurrence (~ 10–15%) and the high concordance of the disease among monozygotic twins (75–80%) [18].

Also common to other autoimmune diseases is the relevant role of HLA class II heterodimers, specifically DQ2 and DQ8, in the heritability of CD. HLA-DQ2 homozygosis confers a much higher risk (25–30%) of developing early-onset CD in infants with a first-degree family member affected by the disease [1921].

Since HLA-DQ2/HLA-DQ8 is frequent among the general population (25–35%), and only 3% of these HLA-compatible individuals will go on to develop CD [22], it is not surprising that genome-wide association studies have identified more than 100 non-HLA-related genes associated with CD [1823].

The relevance of these additional genes in conferring genetic risk for CD is rather limited, but they may lead to the discovery of key pathways potentially involved in disease pathogenesis.

Gluten as an environmental trigger of CD

Introduced 10,000 years ago during the transition from a nomadic lifestyle to agricultural settlements, gluten-containing grains are a recent addition to the human diet. Moreover, gluten is one of the few digestion-resistant proteins consumed chronically in significant quantities and is constituted by several non-digestible immunogenic peptides.

These two characteristics could help in breaking the tolerance to this food antigen, when the immune system is activated, as can happen during an enteric infection. Gliadins, key components of gluten, are complex proteins unusually rich in prolines and glutamines and are not completely digestible by intestinal enzymes [24].

The final product of this partial digestion is a mix of peptides that can trigger host responses (increased gut permeability and innate and adaptive immune response) that closely resemble those instigated by the exposure to potentially harmful microorganisms [2528].

Gluten trafficking from lumen to lamina propria (paracellular and transcellular)

Studies from our group and others have shown that gliadin can cause an immediate and transient increase in intercellular tight junction permeability of intestinal epithelial cells [2324] (Fig. 1). This effect has been linked to the release of zonulin, a family of molecules that increases paracellular permeability by causing tight junction disassembly [2931].

Gliadin enhances zonulin-dependent increased gut paracellular permeability irrespective of disease status [3239]. Similarly, when tested in C57BL/6 mice duodenal tissues, gliadin caused a myeloid differentiation primary response 88-dependent increase in gut mucosa permeability [40].

We have also identified two alpha-gliadin motifs that can modulate the intestinal barrier function by binding to chemokine receptor 3, with subsequent zonulin release that causes disassembly of the interepithelial tight junction complex [41].

The involvement of the paracellular pathway for gluten trafficking in the lamina propria has also been corroborated by genetic studies identifying an association of some tight junction genes with CD [4244].

There is solid evidence that gluten can also cross the intestinal barrier through the transcellular pathway once tolerance to gluten has been broken [4546]. The transferrin receptor CD71, normally expressed on the basolateral side of enterocytes, is overexpressed on the luminal side of the intestinal epithelium in CD patients during the acute phase of the disease, leading to an apical-to-basal retrotranscytosis of gliadin peptides complexed with secretory IgA [47].

This retrotranscytosis of secretory IgA–gliadin complexes protects gliadin fragments from lysosomal degradation and promotes the entry of harmful gliadin peptides into the intestinal lamina propria [47], thereby perpetuating intestinal inflammation initiated by the paracellular passage of these peptides (Fig. 1).

Because of their resistance, the gluten immunogenic peptides (GIP) can cross the defective epithelial lining, reach the blood stream (thus extending the inflammatory process), and finally be excreted with the urine [48].

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Fig. 1
Celiac disease pathogenesis. Partially digested gliadin fragments interact with chemokine receptor 3 on the apical side of epithelium (1) inducing a myeloid differentiation primary response 88-dependent release of zonulin (2). Zonulin interacts with the intestinal epithelium and triggers increased intestinal permeability (3). Functional loss of the gut barrier facilitates gliadin peptide translocation from lumen to the lamina propria (4). Gliadin peptides trigger release of IL-15, keratinocyte growth factor, and IL-8 (5), with consequent recruitment of neutrophils in the lamina propria (6). Simultaneously, alpha-amylase/trypsin inhibitors engage the Toll like receptor 4–MD2–CD14 complex with subsequent up-regulation of maturation markers and release of proinflammatory cytokines (7). Following innate immune-mediated apoptosis of intestinal cells with subsequent release of intracellular tissue transglutaminase, gliadin peptides are partially deamidated (8). Deamidated gliadin is recognized by DQ2/8+ antigen presenting cells (9) and then presented to T helper cells (10). T helper cells trigger activation and maturation of B cells, producing IgM, IgG, and IgA antibodies against tissue transglutaminase (11). T helper cells also produce pro-inflammatory cytokines (interferon γ and tumor necrosis factor α) (12), which in turn further increase gut permeability and, together with T killer cells, initiate the enteropathy. Damaged enterocytes express CD71 transporter also on their apical side, resulting in retrotranscytosis of secretory IgA-gliadin complexes (13), thus potentiating gluten trafficking from gut lumen to lamina propria. Ultimately, the interaction between CD4+ T cells in the lamina propria with gliadin induces their activation and proliferation, with production of proinflammatory cytokines, metalloproteases, and keratinocyte growth factor by stromal cells, which induces crypt hyperplasia and villous blunting secondary to intestinal epithelial cell death induced by intraepithelial lymphocytes. The hyperplastic crypts (14) are characterized by an expansion of the immature progenitor cells compartment (WNT) and downregulation of the Hedgehog signaling cascade. An increased number of stromal cells known to be part of the intestinal stem cell niche and increased levels of bone morphogenetic protein antagonists, like Gremlin-1 and Gremlin-2, may further contribute to the crypt hyperplasia present in celiac disease

The innate immune response

Innate immunity plays a critical role in initiating CD, and cytokines such as interleukin (IL)-15 and interferon α can prime the innate immune response by polarizing dendritic cells and intraepithelial lymphocyte function [49].

Recent results suggest that specific gliadin peptides may induce epithelial growth factor and an IL-15-dependent proliferation of enterocytes, structural modifications, vesicular trafficking alterations, signaling and proliferation, and stress/innate immunity activation [50].

Alpha-amylase/trypsin inhibitors – molecules conferring pest resistance in wheat – also seem to play a key role in CD innate immune response by engaging the Toll-like receptor 4–MD2–CD14 complex with subsequent up-regulation of maturation markers and release of proinflammatory cytokines in cells from CD patients [51].

These mucosal events, along with the functional breach of epithelial barrier function secondary to the gliadin-mediated zonulin release [2936], the subsequent access of toxic peptides in the lamina propria, and gliadin-induced production of high levels of the neutrophil-activating and chemoattractant chemokine IL-8 [2652], cause the ‘perfect storm’ to initiate CD enteropathy (Fig. 1). More recently, our group showed that gliadin exerts a direct neutrophil chemoattractant effect by interacting with fMet-Leu-Phe receptor 1 [5354].

The adaptive immune response

The erroneous adaptive immune response consequence of a highly specific interplay between selected gluten peptides and major histocompatibility complex class II HLA-DQ2/8-antigen restricted T cells plays a paramount role in CD pathogenesis [55].

Dependent on the post-translational deamidation of gluten peptides by transglutaminase 2 (TG2), this interplay is influenced by the initial imprinting of the innate immune system through IL-15 upregulation that promotes the CD4+ T cell adaptive immune response [5657]. Presentation of gluten to CD4+ T cells carried out by dendritic cells as well as macrophages, B cells, and even enterocytes expressing HLA class II, can cause their recirculation in the lamina propria [58].

The contact of CD4+ T cells in the lamina propria with gluten induces their activation and proliferation, with production of proinflammatory cytokines, metalloproteases, and keratinocyte growth factor by stromal cells, which induces cryptal hyperplasia and villous blunting secondary to intestinal epithelial cell death induced by intraepithelial lymphocytes (IELs) [58].

Additionally, there is an overexpression of membrane-bound IL-15 on enterocytes in active CD causing over-expression of the natural killer (NK) receptors CD94 and NKG2D by CD3+ IELs [59]. CD crypt hyperplasia has been hypothesized to be the consequence of an imbalance between continuous tissue damage due to the mucosal autoimmune insult described above and inability of the stem cells to compensate.

We have recently provided a more mechanistic, evidence-based explanation for hyperplastic crypts in active CD by showing that the celiac hyperplastic crypt is characterized by an expansion of the immature progenitor cell compartment and downregulation of the Hedgehog signaling cascade [60].

These data shed light on the molecular mechanisms underlying CD histopathology and illuminate the reason for the lack of enteropathy in the mouse models for CD. Indeed, lack of consistent CD-like enteropathy in humanized mice [61] supports the concept that the accelerated disruption of enterocytes secondary to the adaptive CD4+ T cell insult cannot fully explain CD pathogenesis, supporting the notion that an intrinsic defect of the stem cell compartment in subjects at risk of CD is a key element of CD enteropathy [6062].

The role of the gut microbiome in the pathogenesis of CD

In Western countries, a rise in the overall prevalence of CD has been well documented, but the reasons for this ‘epidemic’ remain elusive. The combination of epidemiological, clinical, and animal studies suggests that broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life are associated with protection against CD and that pre-, peri-, and post-natal environmental factors may strongly influence the gut ecosystem [17].

Therefore, the hygiene hypothesis concept can be misleading, while an ‘environment-dependent dysbiosis hypothesis’ would more closely reflect the interplay between host and environmental pressure dictating the balance between health and disease. Several studies have shown an association between CD and a change in the microbiome composition [6364].

However, these associative studies do not necessarily imply causation between microbiota composition and CD pathogenesis. Many environmental factors known to influence the composition of the intestinal microbiota are also thought to play a role in the development of CD [1921].

It has been reported that, compared to control infants, neonates at family risk of CD had a decreased representation of Bacteriodetes and a higher abundance of Firmicutes [65]. This study also showed that infants who developed autoimmunity had decreased lactate signals in their stools coincident with a diminished representation in Lactobacillus species in their microbiome, which preceded the first detection of positive antibodies [65].

Early microbiota alterations in infants were also suggested in a recent study comparing microbial communities between DQ2+ and DQ2 infants [66]. However, to move from association to causation, large-scale, longitudinal studies are necessary to define if and how gut microbiota composition and metabolomic profiles may influence the loss of gluten tolerance and subsequent onset of CD in genetically susceptible subjects.

Clinical presentation

CD is diagnosed more frequently in women with a female-to-male ratio ranging from 2:1 to 3:1 [12]. However, based on serological screening, the actual female-to-male ratio is 1.5:1 [67]. The disease can occur at any age from early childhood to the elderly, with two peaks of onset – one shortly after weaning with gluten in the first 2 years of life, and the other in the second or third decades of life. The diagnosis of CD can be challenging since symptoms can vary significantly from patient to patient [68].

In 2011, the Oslo classification of CD identified the following clinical presentations: classic, non-classic, subclinical, potential and refractory [69]. Instead of the ‘classic/non-classic’ categorization, which does not fully reflect current clinical presentations, in this review, we will use a more practical terminology, i.e., intestinal/extraintestinal. These two terms better represent the main clinical phenotypes of CD, which may occur individually (i.e., intestinal vs. extraintestinal) or in combination [70].

The intestinal form of CD is more commonly detected in the pediatric population and children younger than 3 years and is characterized by diarrhea, loss of appetite, abdominal distention, and failure to thrive [71]. Older children and adults may complain of diarrhea, bloating, constipation, abdominal pain, or weight loss [72]. Nonetheless, in adults, the malabsorption syndrome with chronic diarrhea, weight loss and significant asthenia is quite rare. Despite its uncommon detection, this phenotype can cause hospitalization due to cachexia, sarcopenia, significant hypoalbuminemia, and electrolyte abnormalities. Conversely, an irritable bowel syndrome (IBS)-like presentation with constipation or alternating bowel and/or dyspepsia-like symptoms, such as nausea and sometimes vomiting, is more frequent [2].

Extraintestinal symptoms are common in both children and adults [272]. They include iron deficiency microcytic anemia, detectable in up to 40% of cases (by cause of iron malabsorption or chronic inflammation) [73] or, more rarely, macrocytic anemia due to folic acid and/or vitamin B12 deficiency (more frequent in Europe than in the US).

Changes in bone mineral density, including osteopenia or osteoporosis (affecting about 70% of patients at diagnosis), are related to altered absorption of calcium and vitamin D3 [74]. In children, growth retardation and short stature can raise the suspect of an underlying CD. Other signs include tooth enamel defects, aphthous stomatitis (identified in about 20% of undiagnosed CD patients) [75], and hypertransaminasemia (40–50% of untreated patients), which can be ascribed to food and bacterial antigen translocation reaching the liver due to increased intestinal permeability [76].

A wide array of neurological symptoms, such as headache, paresthesia, neuroinflammation, anxiety and depression, can be detectable in CD patients. The clinical presentation may also include changes in reproductive function characterized by late menarche, amenorrhea, recurrent miscarriages, premature birth, early menopause, and changes in the number and mobility of spermatozoa. Notably, these manifestations can be reversed when patients start a strict gluten-free diet (GFD), although fatigue and some neurological manifestation as well as functional gastrointestinal (GI) symptoms can persist for a long period in a subgroup of CD patients [27781].

The subclinical form includes patients with symptoms/signs below the clinical identification threshold and are often recognizable only after the appreciation of the beneficial effects induced by the GFD. A typical example of subclinical cases are those patients undergoing antibody screening due to being relatives of CD patients or cases identified as a result of a screening strategy in the general population [269]. The prevalence of various CD clinical phenotypes observed in our experience is reported in Fig. 2.

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Fig. 2
Prevalence of clinical phenotypes of adult celiac disease in our experience

CD can be associated with different autoimmune and idiopathic diseases, including dermatitis herpetiformis (which, as a single manifestation, should prompt testing for CD), type 1 diabetes mellitus, Hashimoto’s thyroiditis, selective IgA deficiency, alopecia areata, Addison’s disease, connective tissue diseases (mainly Sjogren’s syndrome), chromosomal diseases (Down, Turner, and William’s syndromes), neurological diseases (cerebellar ataxia, peripheral neuropathy, epilepsy with and without occipital calcifications), hepatic autoimmune diseases (primary biliary cholangitis, autoimmune hepatitis, primary sclerosing cholangitis), and idiopathic dilated cardiomyopathy (Table 2) [28293]. The importance of diagnosing CD associated with these concomitant diseases is twofold since a GFD is able to resolve symptoms, prevent complications, and improve some of the CD associated diseases [2].

Table 2

Diseases associated with celiac disease

Type 1 diabetes mellitusDilated cardiomyopathyDown syndrome
Hashimoto’s thyroiditisEpilepsy with or without occipital calcificationsTurner syndrome
Graves’ diseaseCerebellar ataxiaWilliam’s syndrome
Autoimmune hepatitisPeripheral neuropathy
Primary biliary cholangitisMultiple myoclonic seizures
Primary sclerosing cholangitisMultiple sclerosis
Dermatitis herpetiformisCerebral atrophy
VitiligoChronic inflammatory intestinal diseases
Addison’s diseaseSarcoidosis
IgA deficiency
Autoimmune atrophic gastritis
Autoimmune hemolytic anemia
Sjogren’s syndrome
Systemic erythematosus lupus
Rheumatoid arthritis
Myasthenia gravis
IgA nephropathy (Berger’s disease)

The potential form of CD is characterized by positive serological and genetic markers with a normal intestinal mucosa and minimal signs of inflammation such an increase in IELs [69]. Patients with the potential form can manifest with classic and non-classic symptoms or be entirely asymptomatic. The scientific community has not universally agreed on whether or not a GFD should be prescribed for patients with potential CD.

Finally, refractory CD (RCD) is characterized by persistent symptoms and atrophy of the intestinal villi after at least 12 months of a strict GFD. RCD can lead to complications such as ulcerative jejunoileitis, collagenous sprue, and intestinal lymphoma [69].

In recent years, other forms of CD (not included in the Oslo Classification [69]), i.e., seronegative and GFD non-responsive CD, have been identified in the clinical practice. The seronegative form is characterized by the lack of demonstrable serological markers along with clinical signs of severe malabsorption and atrophy of the intestinal mucosa [94].

This form should be included in the differential diagnosis with other diseases that cause atrophy of the intestinal villi. The term non-responsive CD indicates GI symptoms that persist despite a GFD of more than 12 months [95]; however, it does not differentiate between active CD and associated conditions, which can be responsible for symptom persistence (Fig. 3) and alternative terminology is discussed below.

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Fig. 3
Causes of ongoing signs and/or symptoms of celiac disease (CD) despite a gluten-free diet (formerly referred to as ‘non-responsive’ CD). In this review, two clinical phenotypes have been proposed – ongoing active celiac disease (OACD), related to three main causes, and associated celiac disease conditions (ACDC), encompassing a wide array of diseases

Diet and new treatments

Currently, the only effective treatment available for CD is a strict GFD for life since it leads to the resolution of intestinal and extraintestinal symptoms, negativity of autoantibodies, and the regrowth of the intestinal villi.

In addition, the diet offers a partial protective effect towards several complications. However, these crucial advantages are accompanied by some disadvantages, including a negative impact on quality of life, psychological problems, fear of involuntary/inadvertent contamination with gluten (as demonstrated in multicenter GIP studies) [48], possible vitamin and mineral deficiencies, metabolic syndrome, an increased cardiovascular risk, and often severe constipation [171173].

Most of these CD-related drawbacks can be overcome by instructing the patient about the risks of an uncontrolled gluten-free regimen and by providing nutritional recommendations by a dietician with experience in CD.

From a psychological perspective, the support a psychologist could be highly useful in accepting the disease [174].

Due to the relevant burden induced by gluten withdrawal with consequent worsening of quality of life, about 40% of CD patients are unsatisfied with their alimentary regimen and they would be keen to explore alternative treatments [175].

In recent years, researchers have attempted to meet the requests of CD patients seeking therapies different from diet [176]. Clinical trials are currently in progress, but only few have reached later clinical trial phases, namely those with larazotide acetate and gluten-specific proteases from a bacterial mix (ALV003) [177180].

Larazotide acetate is a zonulin antagonist blocking tight junction disassembly, thereby limiting gluten crossing a permeable intestinal mucosal barrier [177]. Larazotide has shown efficacy in gluten-related symptom control rather than in restoring complete epithelial barrier integrity and preventing gluten from crossing the mucosal lining [177].

Taken together, the data so far published indicate that larazotide may be beneficial in allowing patients to tolerate minimal amounts of gluten such as those derived from inadvertent ingestion or probably for ‘gluten-free holidays’, i.e., a short period during which patients are allowed to eat a minimal amount of gluten. ALV003 targets gluten and degrades it into small fragments in the stomach before they pass into the duodenum [178].

This strategy has also been demonstrated to be able to ‘digest’ only small quantities of gluten and thus would be effective against contamination but not to protect patients from the effects driven by large quantities of gluten [178].

However, a recent phase 2b study by Murray et al. [180] showed that ALV003 (or latiglutenase) did not improve histologic and symptoms scores in 494 CD patients with moderate to severe symptoms versus placebo. IL-15 monoclonal antibodies (AMG 714) are being investigated in phase 2 studies in both gluten challenge and RCD type II patients, but additional safety studies are needed for the acquisition and competition of the license.

Finally, vaccination (Nexvax2) is another possible therapeutic strategy aimed at desensitizing patients with CD to gliadin peptides. Although abdominal pain and vomiting were major side effects, the trial passed phase 1. Vaccines could represent a definitive cure for CD should data show actual efficacy [181].

Can CD be prevented?

Several retrospective studies have suggested that breastfeeding, modality of delivery, and time of gluten introduction in the diet of infants at risk for CD may affect the incidence of the disease.

However, the data supporting the role of these factors in the risk of developing CD is limited by their retrospective design and have been criticized by alternative interpretations [182184]. Two recent landmark studies [1921], which prospectively screened infants with a first-degree family member with CD from birth, found that CD develops quite early in life in this risk group, demonstrating that early environmental factors may be crucial in the development of CD.

However, these studies failed to identify possible targets to prevent CD, leading to the gut microbiota as the key element to scrutinize for possible innovative preventive strategies. In this line, viral (e.g., rotavirus) GI infections may potentiate subsequent development of CD. Thus, rotavirus vaccination seems to significantly decrease the risk of CD, in particular among children with early (before 6 months of age) gluten exposure [185].

The ongoing Celiac Disease Genomic, Environment, Microbiome, and Metabolomic study has been designed to identify potential primary prevention targets by establishing microbiome, metabolomic, and/or environmental factors responsible for loss of gluten tolerance, thus switching genetic predisposition to clinical outcome [186].


Although there has been a substantial increase in the number of CD diagnoses over the last 30 years, many patients remain undiagnosed [187]. The flow-chart for identifying CD in adults must always include both serology and intestinal biopsy, whereas genetics should be performed only in selected cases.

Diagnostic criteria should help physicians in avoiding misdiagnosis and missing cases of CD (i.e., seronegative patients with classic symptoms not undergoing biopsy) and preserve people from an unjustified GFD. The treatment for CD is still primarily a GFD, which requires significant patient education, motivation, and follow-up. Slow response occurs frequently, particularly in people diagnosed in adulthood.

Persistent or recurring symptoms should lead to a review of the patient’s original diagnosis, exclude alternative diagnoses, evaluation of GFD quality, and serologic testing as well as histological assessment in order to monitor disease activity. In addition, evaluation for disorders that could cause persistent symptoms and complications of CD, such as refractory CD or lymphoma, should be pursued. The future opens to new therapeutic and preventive strategies, which are expected to improve the patient’s quality of life and pave the way to a definitive cure for this old disease.

Box 1 Causes for the increased number of intraepithelial lymphocytes in the intestinal mucosa with normal villous architecture

Potential celiac disease

Non-celiac gluten sensitivity

Food allergies (cereals, milk proteins, soy derivatives, fish, rice, chicken)

Infectious (viral enteritis, Giardia, Cryptosporidium, Helicobacter pylori)

Bacterial contamination of the small intestine

Drugs (e.g., non-steroidal anti-inflammatory drugs)

Immune system diseases (Hashimoto’s thyroiditis, rheumatoid arthritis, systemic erythematosus lupus, type 1 diabetes mellitus, autoimmune enteropathy)

Common variable immune deficiency

Chronic inflammatory intestinal diseases (Crohn’s disease, ulcerative colitis)

Lymphocytic colitis

University of Sheffield


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