**2. Clinical presentations of CD in adults**

In adults, the average age of presentation of CD is 44 years (with a wide age range between 14 and 81 years). It has a clear female predominance (3:1), which has been confirmed in young children. Strikingly, approximately 15–25% of cases are diagnosed in people over 60 years of age [9].

In some cases, there is a recorded history of growth retardation or other symptoms that suggest that CD was present in childhood. The classic presentation of the disease with malabsorption, diarrhoea, weight loss and abdominal distension is less common in adults than in children [10].

Diarrhoea is the main way in which CD presents itself, although it occurs in fewer than 50% of patients; constipation is not uncommon in celiac patients and is accompanied by non-specific gastrointestinal symptoms that overlap considerably with those of functional dyspepsia (FD), irritable bowel syndrome (IBS) and functional diarrhoea [11, 12].

Patients with CD may frequently have symptoms that are also characteristic of IBS, including abdominal pain (77%), abdominal distension (73%), chronic diarrhoea (52%), constipation (17%) and/or the presence of a pattern of alternating bowel movement in an intermediate percentage (24%). This means that IBS is often the initial diagnosis for many patients, before the discovery of CD several years later [13, 14].

The presence of symptoms related to gastroesophageal reflux disease (GERD) that do not respond well to treatment with anti-secretory drugs should make the doctor think that the patient may be celiac. For example, in an Argentine study, Nachman et al. evaluated the presence and intensity of GERD symptoms at the time of diagnosis of CD in adult patients and found a significantly higher mean score of reflux symptoms than in healthy controls. In baseline terms, 30.1% of patients with CD presented moderate or severe GERD symptoms, compared with 5.7% of controls [15]. A study conducted by Usai et al. of cases and controls in patients with CD and associated GERD confirmed that the GFD improved symptoms and was a useful strategy for preventing recurrences [16].

The prevalence of extra-intestinal manifestations is very high among adult patients, especially if a specific search for them is carried out. Anaemia, caused mainly by iron deficiency, osteoporosis, dermatitis herpetiformis, recurrent aphthous stomatitis, hypertransaminasaemia and a series of neuropsychiatric disorders may be a common form of presentation of CD in adults [17, 18].

Serological screening in high-risk groups, especially in families of patients with CD, have increased the frequency of detection of the disease in children and adults, some of whom are asymptomatic or have mild, nonspecific symptoms [19].

## **3. Diagnostic criteria of CD in adults**

The diagnostic strategy for an adult patient with suspected CD is complex, given the diversity of possible clinical scenarios in which it can occur. Determining the specific serology for CD by measuring titres of tissue transglutaminase (tTG), endomysial (EMA) and deamidated gliadin (PGD) antibodies should be the initial diagnostic test, because of its simplicity and low cost. It should be carried out in patients presenting signs, symptoms and/or associated diseases.

When the tTG titres are 10 times higher than their normal values (>100 U/ml), they are considered to be diagnostic of CD by themselves, thereby avoiding taking duodenal biopsies, since the probability of finding associated villous atrophy is very high. Hills et al. confirmed that the finding in adults of tTG values >30 U/ml

**5**

*Introductory Chapter: Celiac Disease - An Overview DOI: http://dx.doi.org/10.5772/intechopen.82723*

1. Clinical symptoms suggestive or compatible with CD

4. Enteropathy compatible with CD in duodenal biopsies

*Criteria of Catassi and Fassano for the diagnosis of CD [22] (five-point rule).*

since their presence reinforces the diagnosis of CD [20].

(N < 10) with the Celikey test has a positive reductive value of 100%. Before deciding against taking biopsies during the endoscopy, the positivity of the EMAs should be confirmed and the presence of the genetic markers (DQ2 and DQ8) determined,

Conversely, when the levels of the tTG antibodies are less than three times the normal values, a gastroscopy should be done with multiple duodenal biopsies (usually six, of which two must be from the bulb). If the histological results reveal enteropathy, a GFD should be initiated and followed strictly and permanently. In patients with CD-compatible enteropathy and negative serology, genotyping of the HLA-DQ2/DQ8 system may be useful, because if both markers are negative, they

Nevertheless, it should be considered that, for any case, neither serological and genetic tests, nor the results of duodenal biopsies are pathognomonic. This means that, in certain cases, it is very difficult to confirm or rule out the presence of CD, given the great variability of possible findings, and it is impossible to simplify the wide range of diagnostic possibilities available for use in the clinical setting.

However, some easily applicable algorithms are available that can be of use. In this regard, in 2010, Catassi and Fassano suggested using a simple five-point rule that is very easy to include and evaluate, assigning a unit value to responses to questions about such items as: clinical symptoms, positivity of serology, the presence of compatible genetic markers, the positivity of histological findings, and the serological and histological responses to the GFD. The presence of four of these five criteria (or three of four if genetic markers are not available) is indicative of a probable diagnosis of CD, if the patient can be or not diagnosed. This system has not yet been

This system is only of indicative value and is little used in clinical practice because, despite its simplicity, it is difficult to interpret and the weight of each of the included items is not taken into account. Under no account should it be applied

Non-celiac gluten sensitivity (NCGS) is an emerging disorder, characterised by the presence of intestinal and extra-intestinal symptoms, related to the consumption of foods containing gluten. It appears in individuals who are not affected by CD or by wheat allergy. Despite the lack of reliable epidemiological data, it is estimated that its prevalence worldwide is between 5 and 10 times that of CD (5–10% in the general population). This has contributed to the great increase (a tripling in the US, for example) in the worldwide consumption of gluten-free food in recent years. NCGS was originally described in 1976 and 1978 [23, 24] and the first series of studies on the subject was published in 1980 [25]. However, it was not until 2010, with the sharp increase in the number of publications, that this apparently novel

with rigid criteria, to conclude whether a particular patient is celiac or not.

prospectively validated, so it is not in general use (**Table 1**) [22].

2. Positive serology with high titres 3. Positive genotyping for HLA DQ2/DQ8

5. Positive response to gluten-free diet

make the diagnosis unlikely [21].

**4. Non-celiac gluten sensitivity**

**Table 1.**


#### **Table 1.**

*Celiac Disease - From the Bench to the Clinic*

**2. Clinical presentations of CD in adults**

diagnosed in people over 60 years of age [9].

useful strategy for preventing recurrences [16].

**3. Diagnostic criteria of CD in adults**

may be a common form of presentation of CD in adults [17, 18].

patients presenting signs, symptoms and/or associated diseases.

common in adults than in children [10].

functional diarrhoea [11, 12].

[13, 14].

In adults, the average age of presentation of CD is 44 years (with a wide age range between 14 and 81 years). It has a clear female predominance (3:1), which has been confirmed in young children. Strikingly, approximately 15–25% of cases are

In some cases, there is a recorded history of growth retardation or other symptoms that suggest that CD was present in childhood. The classic presentation of the disease with malabsorption, diarrhoea, weight loss and abdominal distension is less

Diarrhoea is the main way in which CD presents itself, although it occurs in fewer than 50% of patients; constipation is not uncommon in celiac patients and is accompanied by non-specific gastrointestinal symptoms that overlap considerably with those of functional dyspepsia (FD), irritable bowel syndrome (IBS) and

Patients with CD may frequently have symptoms that are also characteristic of IBS, including abdominal pain (77%), abdominal distension (73%), chronic diarrhoea (52%), constipation (17%) and/or the presence of a pattern of alternating bowel movement in an intermediate percentage (24%). This means that IBS is often the initial diagnosis for many patients, before the discovery of CD several years later

The presence of symptoms related to gastroesophageal reflux disease (GERD) that do not respond well to treatment with anti-secretory drugs should make the doctor think that the patient may be celiac. For example, in an Argentine study, Nachman et al. evaluated the presence and intensity of GERD symptoms at the time of diagnosis of CD in adult patients and found a significantly higher mean score of reflux symptoms than in healthy controls. In baseline terms, 30.1% of patients with CD presented moderate or severe GERD symptoms, compared with 5.7% of controls [15]. A study conducted by Usai et al. of cases and controls in patients with CD and associated GERD confirmed that the GFD improved symptoms and was a

The prevalence of extra-intestinal manifestations is very high among adult patients, especially if a specific search for them is carried out. Anaemia, caused mainly by iron deficiency, osteoporosis, dermatitis herpetiformis, recurrent aphthous stomatitis, hypertransaminasaemia and a series of neuropsychiatric disorders

Serological screening in high-risk groups, especially in families of patients with CD, have increased the frequency of detection of the disease in children and adults,

some of whom are asymptomatic or have mild, nonspecific symptoms [19].

The diagnostic strategy for an adult patient with suspected CD is complex, given the diversity of possible clinical scenarios in which it can occur. Determining the specific serology for CD by measuring titres of tissue transglutaminase (tTG), endomysial (EMA) and deamidated gliadin (PGD) antibodies should be the initial diagnostic test, because of its simplicity and low cost. It should be carried out in

When the tTG titres are 10 times higher than their normal values (>100 U/ml), they are considered to be diagnostic of CD by themselves, thereby avoiding taking duodenal biopsies, since the probability of finding associated villous atrophy is very high. Hills et al. confirmed that the finding in adults of tTG values >30 U/ml

**4**

*Criteria of Catassi and Fassano for the diagnosis of CD [22] (five-point rule).*

(N < 10) with the Celikey test has a positive reductive value of 100%. Before deciding against taking biopsies during the endoscopy, the positivity of the EMAs should be confirmed and the presence of the genetic markers (DQ2 and DQ8) determined, since their presence reinforces the diagnosis of CD [20].

Conversely, when the levels of the tTG antibodies are less than three times the normal values, a gastroscopy should be done with multiple duodenal biopsies (usually six, of which two must be from the bulb). If the histological results reveal enteropathy, a GFD should be initiated and followed strictly and permanently. In patients with CD-compatible enteropathy and negative serology, genotyping of the HLA-DQ2/DQ8 system may be useful, because if both markers are negative, they make the diagnosis unlikely [21].

Nevertheless, it should be considered that, for any case, neither serological and genetic tests, nor the results of duodenal biopsies are pathognomonic. This means that, in certain cases, it is very difficult to confirm or rule out the presence of CD, given the great variability of possible findings, and it is impossible to simplify the wide range of diagnostic possibilities available for use in the clinical setting.

However, some easily applicable algorithms are available that can be of use. In this regard, in 2010, Catassi and Fassano suggested using a simple five-point rule that is very easy to include and evaluate, assigning a unit value to responses to questions about such items as: clinical symptoms, positivity of serology, the presence of compatible genetic markers, the positivity of histological findings, and the serological and histological responses to the GFD. The presence of four of these five criteria (or three of four if genetic markers are not available) is indicative of a probable diagnosis of CD, if the patient can be or not diagnosed. This system has not yet been prospectively validated, so it is not in general use (**Table 1**) [22].

This system is only of indicative value and is little used in clinical practice because, despite its simplicity, it is difficult to interpret and the weight of each of the included items is not taken into account. Under no account should it be applied with rigid criteria, to conclude whether a particular patient is celiac or not.

## **4. Non-celiac gluten sensitivity**

Non-celiac gluten sensitivity (NCGS) is an emerging disorder, characterised by the presence of intestinal and extra-intestinal symptoms, related to the consumption of foods containing gluten. It appears in individuals who are not affected by CD or by wheat allergy. Despite the lack of reliable epidemiological data, it is estimated that its prevalence worldwide is between 5 and 10 times that of CD (5–10% in the general population). This has contributed to the great increase (a tripling in the US, for example) in the worldwide consumption of gluten-free food in recent years.

NCGS was originally described in 1976 and 1978 [23, 24] and the first series of studies on the subject was published in 1980 [25]. However, it was not until 2010, with the sharp increase in the number of publications, that this apparently novel


#### **Table 2.**

*Diagnostic criteria compatible with the presence of an NCGS [26–28].*

entity was brought to the attention of physicians and researchers, presenting a challenge to those working in the field of gluten consumption-related disorders.

It is characterised from the clinical point of view by the presence of digestive and extra-digestive symptoms in relation to the consumption of food containing gluten. No precise diagnostic criteria are available, which is why it is fundamentally diagnosed by the exclusion of CD in patients with similar clinical characteristics. The diagnostic criteria of the NCGS are based on additionally ruling out the presence of symptoms related to wheat allergy. Antibodies to CD are negative or have low titres, and duodenal biopsies may show inflammatory changes, but always without any intestinal villous atrophy being present (**Table 2**) [26–28].

The physiopathology of NCGS is still not fully understood. Several pioneering studies have suggested an important role for innate intestinal immunity in the pathogenesis of NCGS, in contrast to CD, in which an adaptive immune response is activated [29, 30].

No cases of family aggregation, presence of associated diseases or long-term complications have been described in NCGS, unlike what occurs in the case of CD. A diagnosis of NCGS in patients with gluten-dependent symptoms, a family history of CD or associated autoimmune diseases, can call into question whether a case of NCGS is, instead, really a case of mild CD, because their very similar clinical characteristics make them very difficult to distinguish.

## **5. Diseases associated with CD**

The extra-intestinal diseases most frequently associated with CD are iron deficiency anaemia, type 1 diabetes mellitus, osteoporosis, thyroid disorders and dermatitis herpetiformis [31]. Autoimmune diseases are generally between 3 and 10 times more frequent in patients with CD than in the general population.

Some hypotheses have been proposed to explain the increase in the prevalence of autoimmune diseases in patients with celiac disease. One of these is that a longer exposure to gluten prior to diagnosis could be a risk factor for the development and appearance of related diseases [32, 33]. However, other researchers determined that the presence of autoimmune diseases in patients with a late diagnosis of CD is not associated with the duration of gluten consumption [34].

From the immunological perspective, CD is characterised by over-expression of interleukin-15 (IL15) at the level of the mucosal surface of the small intestine. There is some evidence about its importance in the association with autoimmune diseases, because, due to the presence of these increased levels of cytokine, the effector T cells in the intestinal epithelium are not suppressed by the regulatory T cells, which would generate a loss of gluten tolerance and a greater presence of antibodies such as auto-antigens [35].

Vitamin D deficiency is another factor that has been implicated in the pathogenesis of autoimmunity in CD due to it frequently being detected at low levels in the blood of patients with CD and other autoimmune disorders. Vitamin D is an

**7**

*Introductory Chapter: Celiac Disease - An Overview DOI: http://dx.doi.org/10.5772/intechopen.82723*

which it acts have not yet been fully elucidated [36].

that responds effectively to the eradicating treatment.

grams of the majority of anaemic patients with CD [40].

**7. Diabetes mellitus type 1 (DMT1) and associated CD**

patients with CD compared with controls [42, 43].

**6. Ferropenic anaemia and associated CD**

found in 1.8–14.6% of patients [38].

important biological inhibitor of inflammatory hyperactivity, even in the presence of several malignant tumours. Its real role and the details of the mechanisms by

Anaemia without other clinical signs of intestinal malabsorption is one of the most common extra-intestinal manifestations of CD [37]. CD is frequently diagnosed in patients referred for evaluation for iron deficiency anaemia, which is

A prospective study conducted in patients with iron deficiency anaemia published in 2005 [39] reported a 5% prevalence of celiac disease. Subsequent studies have confirmed that between 4 and 6% of patients with refractory iron deficiency anaemia of unknown origin have CD. Associated autoimmune gastritis is found in 20–27% of patients, 50% of whom also have an associated active *H. pylori* infection

The most obvious cause of this anaemia is a decrease in intestinal absorption of iron and other nutrients, including folate and cyanocobalamin. Villous atrophy of the intestinal mucosa is a significant cause of the decrease in iron absorption, as confirmed by the microcytic and hypochromic anaemia revealed in the haemo-

The decreased absorption of iron in CD is also revealed by the failure of the serum iron levels to increase following oral administration of iron supplements, whereas the problem is resolved rapidly when iron is administered parenterally.

In children, the first cases with CD and associated DMT1 were reported in 1969 [41]. Thus, a 10-year controlled longitudinal monitoring study of 335 adult celiac patients, diagnosed between 1980 and 1990, compared with a broad group of age- and sex-matched control subjects with various gastrointestinal symptoms, confirmed the high prevalence of endocrine diseases in patients with CD (11.9% in patients versus 4.3% in the control group; p < 0.003). More recently, other researchers found a higher prevalence of type 1 diabetes mellitus (5.4–7.4%) in

DMT1 is diagnosed in more than 90% of cases before CD is confirmed. Patients with diabetes mellitus and symptoms associated with CD who are following a GFD show a clear overall clinical improvement. In children, an increase in the growth rate and a rise in haemoglobin levels are often observed. Better metabolic control of diabetes mellitus is observed, as clearly confirmed by the reduction in the number of hypoglycaemic episodes, and the reduced need for daily insulin if the patient is following a GFD [44]. Juvenile diabetic patients present an average prevalence of CD of about 5% of cases. This strong association is largely due to the fact that celiac patients with and without diabetes share the same genetic base represented by the presence of the HLA-II haplotype, DR3-DQ2, demonstrating that it is appropriate to systematically screen for CD in patients with T1DM. Strategies for follow-up include periodic serological determinations for specific antibodies, first at the time of diagnosis, then, repeated every 6 months for the first year and at least annually for 5 years or more. Patients with positive responses to specific serological tests and in whom genetic susceptibility markers (HLA-DQ2 and/or HLA-DQ8) are present require duodenal biopsies to be taken to confirm the diagnosis of CD. Although many clinical

*Celiac Disease - From the Bench to the Clinic*

B. Exclusion of wheat allergy C. Serology of negative CD D. Absence of villous atrophy

**Table 2.**

activated [29, 30].

entity was brought to the attention of physicians and researchers, presenting a chal-

It is characterised from the clinical point of view by the presence of digestive and extra-digestive symptoms in relation to the consumption of food containing gluten. No precise diagnostic criteria are available, which is why it is fundamentally diagnosed by the exclusion of CD in patients with similar clinical characteristics. The diagnostic criteria of the NCGS are based on additionally ruling out the presence of symptoms related to wheat allergy. Antibodies to CD are negative or have low titres, and duodenal biopsies may show inflammatory changes, but always

The physiopathology of NCGS is still not fully understood. Several pioneering studies have suggested an important role for innate intestinal immunity in the pathogenesis of NCGS, in contrast to CD, in which an adaptive immune response is

No cases of family aggregation, presence of associated diseases or long-term complications have been described in NCGS, unlike what occurs in the case of CD. A diagnosis of NCGS in patients with gluten-dependent symptoms, a family history of CD or associated autoimmune diseases, can call into question whether a case of NCGS is, instead, really a case of mild CD, because their very similar clinical

The extra-intestinal diseases most frequently associated with CD are iron deficiency anaemia, type 1 diabetes mellitus, osteoporosis, thyroid disorders and dermatitis herpetiformis [31]. Autoimmune diseases are generally between 3 and 10 times more frequent in patients with CD than in the general population.

Some hypotheses have been proposed to explain the increase in the prevalence of autoimmune diseases in patients with celiac disease. One of these is that a longer exposure to gluten prior to diagnosis could be a risk factor for the development and appearance of related diseases [32, 33]. However, other researchers determined that the presence of autoimmune diseases in patients with a late diagnosis of CD is not

From the immunological perspective, CD is characterised by over-expression of interleukin-15 (IL15) at the level of the mucosal surface of the small intestine. There is some evidence about its importance in the association with autoimmune diseases, because, due to the presence of these increased levels of cytokine, the effector T cells in the intestinal epithelium are not suppressed by the regulatory T cells, which would generate a loss of gluten tolerance and a greater presence of antibodies such

Vitamin D deficiency is another factor that has been implicated in the pathogenesis of autoimmunity in CD due to it frequently being detected at low levels in the blood of patients with CD and other autoimmune disorders. Vitamin D is an

lenge to those working in the field of gluten consumption-related disorders.

A. Relationship of their presence with consumption of food containing gluten

*Diagnostic criteria compatible with the presence of an NCGS [26–28].*

without any intestinal villous atrophy being present (**Table 2**) [26–28].

characteristics make them very difficult to distinguish.

associated with the duration of gluten consumption [34].

**5. Diseases associated with CD**

**6**

as auto-antigens [35].

important biological inhibitor of inflammatory hyperactivity, even in the presence of several malignant tumours. Its real role and the details of the mechanisms by which it acts have not yet been fully elucidated [36].
