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## The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease

*Maiara Botosso, Renatta Damasceno and Priscila Farage*

#### **Abstract**

Celiac disease (CD) is an autoimmune disorder that can lead to serious health consequences, including cancer. The gluten-free diet (GFD) is the primary treatment for CD and has been shown to lead to clinical remission of the disease. However, the effect of the GFD on cancer development in CD patients is not well understood. This narrative review analyzed observational studies investigating the association between cancer development and adherence to the GFD in CD patients. The most common cancer identified was non-Hodgkin's lymphoma, followed by others such as colon carcinoma and thyroid cancer. Late diagnosis, type of cancer, and type of CD were factors relevant to the protective role of the GFD. However, there is still no consensus in the scientific literature regarding the GFD's role in cancer development in CD. While some studies suggest a protective role, others have not identified an association between the GFD and cancer. More research is needed to understand the relationship between the GFD and cancer development in CD patients. Nonetheless, the GFD is essential for the clinical, serological, and histological remission of CD and improved quality of life.

**Keywords:** celiac disease, malignancy, cancer, gluten-free diet, gluten

#### **1. Introduction**

Celiac disease (CD) is an autoimmune systemic disorder with multiple clinical manifestations triggered by the ingestion of gluten in genetically predisposed individuals [1]. The only available effective treatment so far consists of excluding gluten-protein fractions found in wheat, rye, barley, and hybrids like kamut and triticale—from the diet [2]. CD may occur at all ages and present a variety of signs and symptoms such as stunted growth/short stature, weight loss, abdominal pain, diarrhea/constipation, irritability, osteoporosis, iron-deficiency anemia, among others [3]. Moreover, CD has been associated with increased mortality due to long-term complications such as lymphoproliferative malignancy [4].

Cancer is defined as a chronic multifactorial disease characterized by the uncontrolled growth of cells, and it represents the second leading cause of death worldwide, with the expectation that the number of cases will increase significantly in the coming decades [5, 6]. One of the most serious possible complications of CD is the development of malignancies. In a retrospective population-based cohort in Sweden, Lebwohl et al. [4] evaluated the association between CD and mortality risk in 49.829 patients compared to control participants in the general population matched by age, sex, county and calendar period (n = 246.426). The authors found that CD patients displayed increased risk of death from cancer (2.7 vs. 2.2 per 1000 person-years; HR, 1.29 [95% CI, 1.22–1.36]).

The precise risk of malignancy in adult celiac patients is difficult to assess. However, studies indicate that untreated patients with severe histological intestinal damage are more susceptible to developing cancer [2]. In the retrospective cohort study by Ludvigsson et al. [7], the mortality in CD was examined according to small-intestinal histopathology. The authors identified the highest hazard ratio (HR) in the first year after biopsy with an HR of 3.78 for death due to malignancy (95% CI, 3.14–4.55). After 5 years of follow-up, death from malignancy was only moderately increased (HR, 1.17; 95% CI, 1.03–1.33), which might be explained by the longer duration of treatment at this point, as mucosal inflammation may persist up to a year after implementation of the gluten-free diet (GFD).

The benefits of the GFD on the health and clinical manifestations of CD patients are well established in the literature. A large proportion of these individuals respond completely to the GFD and have a normal life expectancy. However, variables such as late diagnosis, advanced age and low adherence to the GFD represent risk factors for the development of disease complications [8]. Although it may seem simple to remove gluten from the diet, CD treatment may be compromised due to lack of widespread availability of gluten-free products, their high cost, the risk of cross-contamination, the social burden caused by the restrictive nature of the diet, among other factors. Together, these variables may lead to low adherence to the GFD [9].

In a recent study, Marafini, Monteleone and Stolfi [10] suggested that since nonadherence or non-responsiveness to the GFD may lead to chronic inflammation of the small intestine, it is tempting to speculate that a gluten-containing diet in celiac patients could promote the activation of immune/inflammatory signals and ultimately favor the onset or progression of lymphomas and intestinal carcinomas.

Although CD is a common condition with potentially serious health consequences, including cancer, very few studies specifically address the GFD as a possible protective factor in the development of malignancies in celiac individuals. Therefore, this narrative review discusses the role of the GFD in the onset of malignancies in CD, prevalence and characteristics of the main types of cancer found in these patients and the importance of the diet to the treatment and prevention of complications.

#### **2. Methods**

The literature search was carried out in 2022 and updated in 2023 for articles that analyzed the role of the GFD in the development of malignancies in patients with CD. No time restrictions were applied for publication date. The following electronic databases were used: Scielo (Scientific Electronic Library Online), Lilacs (Latin American and Caribbean Centre on Health Sciences Information), Pubmed (US National Library of Medicine—National Institutes of Health), Google Scholar and the Brazilian Digital Library of Theses and Dissertations. The search was conducted by two researchers independently and without conflicts of interest.

The keywords used were "coeliac/celiac disease", "cancer", "malignancy", "neoplasm", "lymphoma", "gluten-free diet", "dietary adherence", and corresponding terms in Portuguese and Spanish. The Boolean operators AND and OR were used to combine the descriptors.

#### *The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.110858*

Original articles (observational studies: cross-sectional, case control and cohort) that investigated a possible association between the occurrence of malignancies and adherence or not to a GFD in patients with CD were included in this review. The following exclusion criteria were applied: (i) reviews, letters, conference summaries, case reports and books; (ii) studies that did not evaluate the GFD in the context of cancer development and (iii) studies that did not follow the criteria recommended by the European Society for Paediatric Gastroenterology Hepatology and Nutrition for the diagnosis of CD (characteristic mucosal changes observed by intestinal biopsy and serological testing).

For the selection of articles, all the abstracts were read and the ones that met the inclusion criteria were chosen. Studies were analyzed according to the year of publication, origin country, aim, study design, sample characterization, main results and conclusions regarding the role of the GFD in the onset of cancer in patients with CD.

#### **3. Results and discussion**

After reading, analyzing and excluding studies that did not meet the established criteria, eight articles were selected to compose this review (**Figure 1**).

The general characteristics and main data of the studies are described in **Table 1**.

The articles included in this review were published between 2003 and 2014. One study was conducted in Argentina, one is from the United States, one from Sweden, and five are from Italy. Regarding the design of the studies, four were prospective cohorts, two retrospective cohorts, one case control and one retrospective case control. All screened articles were extracted from the PubMed database and written in English.

The American study by Green et al. [11] aimed to estimate the risk of malignancy in a cohort of patients with CD compared to the general population of the United States and to determine whether a GFD would be protective in this regard.

**Figure 1.**

*Flow diagram of literature search and selection criteria.*

*The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.110858*

**Table 1.** *Studies on the role of a gluten-free diet in the development of malignancies in celiac disease patients.* *The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.110858*

Participants were treated between July 1981 and January 2000 at the New York Presbyterian Hospital, which has a reference center for CD. Adherence to the GFD was questioned at the initial contact and at subsequent visits by an investigator, with no further details on the content of the questions. The frequency of conscious/voluntary gluten ingestion in the previous month was evaluated.

Among a total of 381 patients, 64% were women (n = 245). During the study period, 3.4% of participants died (n = 13), eight of them due to cancer. A total of 11.3% (n = 43) were diagnosed with malignancy: nine after CD diagnosis, seven within a month of diagnosis and 27 before diagnosis. The most common neoplasm identified was non-Hodgkin's lymphoma (NHL) (n = 9), followed by breast cancer (n = 5), melanoma (n = 5), small intestine (n = 3), colon (n = 3), esophagus (n = 3), lung (n = 3), chronic lymphocytic leukemia (n = 2), ovarian (n = 2) and cervical cancer (n = 2). The study results revealed an increased risk of malignancy in patients with CD compared to the general population of the United States. This finding is consistent with European studies that reported higher rates of cancer of the small intestine, esophagus and lymphoma among individuals with celiac disease [19].

It is important to emphasize that most of these cancer cases occurred before the diagnosis of CD, and a late diagnosis means longer exposure of the patient to dietary gluten. However, an increased risk of NHL was identified among participants despite their strict adherence to a GFD for about 5 years. Thus, the authors suggest that the increased risk for cancer in general occurs before the diagnosis of CD and that it may be reduced with compliance to the GFD. The risk of non-Hodgkin's lymphoma, however, appears to persist despite adequate dietary treatment [11].

In 2007, Silano and colleagues published a study which may be compared to the work by Green et al. [11]. The objective was to evaluate whether the late diagnosis of CD and the consequent prolonged dietary exposure to gluten would increase the risk of developing neoplasia. The study population consisted of patients diagnosed with CD at the Italian Gastroenterology Centers between January 1982 and March 2005. A total of 1968 individuals were included, of whom 1485 were women (75.4%), with a mean age at CD diagnosis of 36.2 ± 13.8 years [12].

Among 1968 patients, 55 were diagnosed with cancer (2.09%) either before or simultaneously with the diagnosis of CD, compared to 42.1 expected cases, with a standardized morbidity ratio (SMR) of 1.3 (95% CI = 1.0–1.7). The most frequent malignant neoplasm was gastrointestinal non-Hodgkin lymphoma (n = 20), followed by colon carcinoma (n = 7), adenocarcinoma of the small intestine (n = 5), Hodgkin lymphoma (n = 4) and stomach and breast carcinomas (n = 3). Other tumor locations included liver, lung, ovary, thyroid cancer and myeloma (two cases each) and acute leukemia, melanoma and uterus (one case each). No patient developed two or more cancers [12].

The mean age at CD diagnosis for patients who developed cancer was 47.6 ± 10.2 years, which was significantly higher than the age at CD diagnosis for patients who did not develop malignancies (28.6 ± 18.2 years). Therefore, this study suggests that the GFD is a likely protector against the development of malignancies in CD patients, as the older the age at CD diagnosis, the longer the exposure time to gluten and the higher the risk of cancer [12].

Enteropathy-associated T-cell lymphoma (EATL) is a term proposed by [20] to describe the rare form of high-grade non-Hodgkin T-cell lymphoma of the upper small intestine associated with CD. Subsequently, in 1989, Holmes and colleagues pointed out that celiac patients have a high risk of developing malignancy, particularly lymphoma. That is corroborated by the findings of studies such as the one from Green et al. [11] and Silano and colleagues (2007), where the most common

malignancy identified was non-Hodgkin lymphoma. In this context, Silano et al. [13] conducted another study with a different cohort to evaluate whether strict adherence to the GFD would reduce the risk of developing EATL [13].

The study sample consisted of 1757 patients diagnosed with CD between January 1982 and December 2006. Information about adherence to the GFD was obtained through interviews. Participants were classified into four groups according to the degree of gluten exposure reported in the interview. The first group comprised of patients who strictly followed the GFD; the second group was composed of patients who consumed up to four gluten-containing meals per month; the third group consumed five to ten glutencontaining meals per month; and the fourth group consumed more than 10 glutencontaining meals per month. Most patients (n = 1113) reported complete adherence to the GFD, belonging to the first group (63.4%); 16.9% were classified in the second group (n = 296); 9.8% in the third group (n = 172) and 9.9% in the fourth group (n = 173) [13].

A total of nine patients developed LTAE while the expected number, according to the RMP, was only 1.4. Among these individuals, only four followed a strict GFD after the diagnosis of CD. The authors mentioned that the risk of developing intestinal lymphoma is related to the presence of gluten in the diet, regardless of the number of gluten-containing meals:

*"It is likely that the chronic stimulation of T-cells in celiac small-bowel mucosa, one of the mechanisms that are supposed to lead to the development of lymphoma, is induced even by a small amount of gluten, and therefore a few monthly dietary indiscretions are sufficient to induce the carcinogenic stimulation."*

This raises concerns about the possibility of patients withholding information during a consultation due to fear of admitting that they are not following the doctor's or other healthcare professional's advice. Omitting just one meal containing gluten per month, for example, may be harmful to the patient in a situation like this. In conclusion, the study pointed out that strict adherence to a GFD is protective against the development of gastrointestinal lymphoma. The authors highlight that individuals with CD should be adequately educated on the importance of complying with a GFD to prevent the appearance of this neoplasia [13].

In 2009, Tursi and colleagues investigated a different aspect from what had been evaluated in the previous studies mentioned above. The researchers explored the manifestation forms of CD (classic, subclinical and silent CD) while evaluating the incidence of malignant and non-malignant complications in a cohort of celiac patients on a GFD. The authors also assessed whether the occurrence of complications was related to non-adherence to the diet. The definitions used for the classification of CD were those of Green and Cellier [21], which state that classic CD is characterized by the presence of gluten-sensitive enteropathy with gastrointestinal symptoms (abdominal pain, diarrhea, weight loss and malabsorption syndrome). Subclinical CD refers to the presence of gluten-sensitive enteropathy with extraintestinal symptoms (iron-deficiency anemia, alopecia, recurrent abortion, among others) and the absence of gastrointestinal symptoms. The silent form of CD refers to the presence of gluten-sensitive enteropathy without any symptoms identified through screening of high-risk groups (first-degree relatives of celiac individuals, patients with insulindependent diabetes, down syndrome and thyroid disorders) [14].

The sample consisted of 549 Italian patients with CD, included between 1993 and 2006. Adherence to the GFD was evaluated according to an arbitrary quantitative scale based on the patient's interview, considering whether there were: no food

#### *The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.110858*

transgressions, less than one food transgression per month or more than one food transgression per month since the time of diagnosis. Regarding the form of CD manifestation, 251 patients (45.72%) presented the classic form of the disease, 262 (47.72%) the subclinical form and 36 (6.56%) the silent form. Regarding compliance to GFD, 381 patients (69.4%) were fully compliant, 112 patients (20.40%) reported less than one food transgression per month, and 56 patients (10.20%) reported at least one food transgression per month [14].

Eighteen patients developed complications while on a GFD, with 14 of them diagnosed with classical CD (77.7%) and four with subclinical CD (22.22%). None of the patients with silent CD presented complications. The most registered complications were neoplasms, observed in seven patients (38.89%). Unlike the findings of the previously mentioned studies, the most common malignancy was not EATL, but rather adenocarcinoma of the small intestine with three cases (n = 3), followed by EATL with two cases (n = 2) and colon carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma, both with one case each (n = 1). Among individuals with malignancies, six had classical CD, and only one had subclinical CD [14].

Regarding the GFD in patients who developed some type of cancer, results showed that three were compliant with the dietary treatment of CD, while four were not. The authors suggest that adherence to the diet does not seem to be a strong risk factor in the development of complications in celiac patients. Instead, the form of CD manifestation at the time of diagnosis appears to be more important in determining complications, such as in the case of classical CD, where the risk of severe endoscopic and histological damage is higher than in the subclinical and silent forms [14].

In Sweden, Olén et al. [15] also investigated CD characteristics and GFD compliance in regards to the risk of lymphoma. In this case-control study, 59 individuals with CD and lymphoma were identified as cases, and 137 controls which had only a CD diagnosis were matched from a population cohort of 11,650 patients. The degree of adherence to the GFD was evaluated through recorded information (by the patient's nutritionist or physician from CD diagnosis until the end of follow-up) available in the medical records. The degree of GFD compliance was defined as: (i) good compliance (strict adherence to the GFD); (ii) low compliance (occasional exceptions or when the patient did not comply to the GFD) and (iii) compliance unknown (medical records did not contain or had scarce information about the patient's diet) [15].

About 59% of the patients were female (n = 115), and the median age at CD diagnosis was 61 years. There was only one case of Hodgkin lymphoma, while 58 cases of non-Hodgkin lymphoma (NHL). Among the NHL cases, 57% were T-cell type (n = 33), 28% were B-cell type (n = 16), and 15% were unspecified NHL (n = 9). Regarding the location of both Hodgkin lymphoma and NHL, 51% (n = 30) were intestinal, and 42% (n = 27) were extraintestinal. Concerning the degree of compliance with the GFD, 34 (58%) patients in the case group had good compliance, 16 (27%) had poor compliance, and 9 (15%) had compliance unknown. Among the control group patients, 92 (67%) had good compliance, 27 (20%) had poor compliance, and 18 (13%) had compliance unknown [15].

No statistically significant risk of lymphoma in general was found in patients with poor compliance with the GFD. However, individuals with a history of weight loss at the time of CD diagnosis had an increased risk of lymphoma years after this diagnosis. The authors suggest that this may indicate that patients with more severe CD and more pronounced inflammation resulting in weight loss have a higher risk of developing lymphoma [15].

In 2011, Volta, Vicentini and Silano [16] conducted a prospective analysis of the risk of papillary thyroid carcinoma in celiac patients. The study sample included all individuals with CD diagnosed at the Collaborating Centers of the Italian Registry of Celiac Disease between January 1982 and December 2006. A validated form was completed for each patient including demographic data, possible occurrence of thyroid disease and adherence to the GFD. Dietary exposure to gluten was expressed in numerical values from 1 to 4 as follows: "1" for patients who did not consume meals containing gluten, "2" for patients who consumed up to 4 meals containing gluten per month, "3" for patients who consumed 5 to 10 meals containing gluten per month, and "4" for patients who consumed more than 10 meals containing gluten per month [16].

Among the 1757 participants, most were women (n = 1314, 74.7%). The mean age at CD diagnosis was 38.6 ± 12.6 years. A total of six patients were diagnosed with the papillary form of thyroid carcinoma, five of whom were women [16]. The fact that most celiac patients who develop papillary thyroid cancer are female reinforces that both CD and thyroid cancer are more frequent among women [21]. When analyzing the results of this study, it is important to consider that the age at CD diagnosis in patients who developed thyroid carcinoma did not differ statistically from the age of those who did not develop this type of cancer. Moreover, only one patient with carcinoma exhibited poor adherence to the GFD, while the other five had excellent compliance. These findings suggest that early diagnosis of CD and strict adherence to GFD may not confer a protective effect against the development of thyroid malignancy, contrary to what was reported in other studies [16].

In the multicenter retrospective case-control study conducted in four community hospitals in Buenos Aires, Pereyra et al. [17] aimed to determine the risk of colorectal neoplasia among celiac patients by quantifying the prevalence of colorectal polyps, adenomas and advanced neoplastic lesions (ANL) in comparison with healthy patients. Individuals with CD were considered cases, and those without CD were controls. The time since diagnosis and adherence to the GFD were evaluated. To evaluate diet compliance, Biagi's validated questionnaire [22] was used, which is based on four simple questions and provides a final score on five levels (0-IV) that are clinically grouped into three levels: (0) or (I) are individuals who do not follow the GFD; (II) are those who follow the GFD, but with significant errors that require correction; and those with a score of (III) and (VI) follow a strict GFD [17].

During the analyzed period, 118 celiac patients who underwent prior colonoscopy were identified and included in the study as cases, and 236 patients without CD were included as controls. The reason for the colonoscopy was the individual's need to undergo it, which could have been for colorectal cancer (CRC) screening, which is a critical detail in the study. The average age of cases was 56 years. Regarding the GFD compliance of patients with CD, 65% (n = 76) followed a strict GFD (scores III or IV), 20% (n = 23) did not follow a strict GFD (scores 0 or I), and 15% (n = 17) followed a GFD, but with errors that require correction (score II). Concerning the time of CD diagnosis, 41% of patients had been diagnosed for 5 to 10 years (n = 48), 32% had the diagnosis for less than 5 years (n = 37), and 27% had more than 10 years of diagnosis (n = 31). The presence of polyps, adenomas and ANLs in patients with CD was 24 (20%), 18 (15%) and 3 (2.5%), respectively [17].

In this study, the prevalence of colorectal polyps, adenomas and ANLs in celiac patients was not significantly different from that in patients without CD. However, results showed that patients with CD who did not follow a strict GFD had an increased risk for adenomas. Since most patients CD adhered strictly to the GFD, it is uncertain whether the absence of risk for colorectal neoplasia would persist in a larger sample with a higher prevalence of non-adherence to the diet. In conclusion, the authors did not find a higher risk of CRC in patients with CD; however, non-adherence to a strict GFD was an independent predictor for the presence of adenomas [17].

#### *The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.110858*

Finally, the Italian study by Volta et al. [18] aimed to describe the risk of colon carcinoma in a group of celiac patients. The study population consisted of patients diagnosed with CD at the Collaborating Centers of the Italian Register for Celiac Disease Complication between January 1982 and December 2006. A total of 1757 patients were included in the study, of whom 74.8% were female (n = 1314), with a mean age of 38.6 years. Information on compliance with the GFD was obtained through interviews, and the sample was divided into four groups according to the monthly frequency of gluten-containing meals. A total of 1113 patients reported adherence to the GFD (63.4%), 296 consumed gluten-containing meals one to four times a month (16.9%), 172 consumed up to 10 gluten-containing meals a month (9.8%), and 173 followed an unrestricted diet (9.9%).

Six patients (four women and two men) developed colon carcinoma during the follow-up period. Among those, four followed the GFD strictly and two did not. The SMR (observed cases = 6; expected cases = 28.9) overall for colon carcinoma was 0.29 (95% CI = 0.07–0.45). The cases for this type of carcinoma observed within 1 year from the diagnosis of CD were incident cases. Therefore, excluding these cases from the analysis to avoid ascertainment bias, the SMR drops to 0.13 (95% CI = 0.03–0.35) [18].

By stratifying the risk according to gluten intake, the SMR decreases even further to 0.07 (95% CI = 0.009–0.27) for CD patients who adhere strictly to the GFD. Furthermore, it is important to mention that all four patients who developed colon carcinoma, despite good adherence to the GFD, were diagnosed with CD at a much older age than the sample in this study (62.8 ± 8.2 vs. 38.6 ± 12.6; p < 0.05), which indicates that they maintained a gluten-containing diet for a longer time. In conclusion, the authors suggest that CD patients have a lower risk of developing colon carcinoma compared to the general population. This risk decreases during the first year after CD diagnosis, and it is even lower for treated patients who strictly follow the GFD [18].

#### **4. Conclusion**

There is still no consensus in the scientific literature regarding the role of the GFD in the development of malignancies in celiac patients. Some studies suggest that the diet plays a protective role, while others have not found an association between diet and cancer. The most common type of cancer identified in the studies was non-Hodgkin lymphoma, specifically enteropathy-associated T-cell lymphoma, followed by others such as Hodgkin's lymphoma, colon carcinoma, adenocarcinoma of the small intestine and thyroid cancer.

Late CD diagnosis, cancer type and classification of CD form were relevant to the outcomes related to the protective or non-protective role of the GFD. However, it is important to emphasize that the GFD is essential for the clinical, serological and histological recovery of CD patients, also affecting their quality of life, regardless of its effect on the development of neoplasms or not.

This review contributes in pointing out the scarcity of studies that investigated the relation between the GFD and the onset of malignancies in CD and highlights the need to expand research on this topic. In the future, when new articles on the subject are published, the development of a systematic review may provide support for healthcare professionals' recommendations in the prevention of complications associated with CD.

*Celiac Disease and Gluten-Free Diet*

### **Author details**

Maiara Botosso, Renatta Damasceno and Priscila Farage\* Federal University of Goias, Brazil

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Role of the Gluten-Free Diet in the Development of Malignancies in Celiac Disease DOI: http://dx.doi.org/10.5772/intechopen.110858*

#### **References**

[1] Husby S et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. Journal of Pediatric Gastroenterology and Nutrition. 2012;**54**(1):136-160

[2] Bascuñán KA, Vespa MC, Araya M. Celiac disease: Understanding the glutenfree diet. European Journal of Nutrition. 2017;**56**:449-459

[3] Husby S et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition guidelines for diagnosing coeliac disease 2020. Journal of Pediatric Gastroenterology and Nutrition. 2020;**70**(1):141-156

[4] Lebwohl B et al. Association between celiac disease and mortality risk in a Swedish population. Journal of the American Medical Association (JAMA). 2020;**323**(13):1277-1285

[5] Garófolo A et al. Dieta e câncer: Um enfoque epidemiológico. Revista de Nutrição. 2004;**17**(4):491-505

[6] Muscaritoli M et al. ESPEN practical guideline: Clinical nutrition in cancer. Clinical Nutrition. 2021;**40**(5):2898-2913

[7] Ludvigsson JF et al. Small-intestinal histopathology and mortality risk in celiac disease. Journal of the American Medical Association. 2009;**302**(11):1171-1178

[8] Askling J et al. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology. 2002;**123**(5):1428-1435

[9] Makharia GK et al. The global burden of coeliac disease: Opportunities and challenges. Nature Reviews Gastroenterology & Hepatology. 2022;**19**:313-327

[10] Marafini I, Monteleone G, Stolfi C. Association between celiac disease and cancer. International Journal of Molecular Sciences. 2020;**21**(11):4155

[11] Green PH et al. Risk of malignancy in patients with celiac disease. The American Journal of Medicine. 2003;**115**(3):191-195

[12] Silano M et al. Delayed diagnosis of coeliac disease increases cancer risk. BMC Gastroenterology. 2007;**7**(1):1-5

[13] Silano M et al. Effect of a glutenfree diet on the risk of enteropathyassociated T-cell lymphoma in celiac disease. Digestive Diseases and Sciences. 2007;**53**(4):972-976

[14] Tursi A et al. Complications in celiac disease under gluten-free diet. Digestive Diseases and Sciences. 2009;**54**(10):2175-2182

[15] Olén O et al. Coeliac disease characteristics, compliance to a gluten free diet and risk of lymphoma by subtype. Digestive and Liver Disease. 2011;**43**(11):862-868

[16] Volta U, Vincentini O, Silano M. Papillary cancer of thyroid in celiac disease. Journal of Clinical Gastroenterology. 2011;**45**(5):44-46

[17] Pereyra L et al. Risk of colorectal neoplasia in patients with celiac disease: A multicenter study. Journal of Crohn's and Colitis. 2013;**7**(12):672-677

[18] Volta U et al. Low risk of colon cancer in patients with celiac

disease. Scandinavian Journal of Gastroenterology. 2014;**49**(5):564-568

[19] Holmes GK et al. Malignancy in coeliac disease: Effect of a gluten free diet. Gut. 1989;**30**(3):333-338

[20] O'farrelly CLIONA et al. Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T cell lymphoma. British Medical Journal (Clinical Research Edition). 1986;**293**(6552):908-910

[21] Green PH, Cellier C. Celiac disease. New England Journal of Medicine. 2007;**357**(17):1731-1743

[22] Biagi F et al. A gluten-free diet score to evaluate dietary compliance in patients with coeliac disease. British Journal of Nutrition. 2009;**102**(6):882-887

### *Edited by Luis Rodrigo*

Celiac disease is an autoimmune disease that primarily affects the small intestine, causing chronic inflammation and sometimes villous atrophy. It is related to the ingestion of gluten products and affects genetically susceptible people. This book provides a comprehensive overview of celiac disease, presenting information on its diagnosis and management.

Published in London, UK © 2023 IntechOpen © Spring Fed Images / Unsplash

Celiac Disease and Gluten-Free Diet

Celiac Disease and

Gluten-Free Diet

*Edited by Luis Rodrigo*


**2. Materials and Experimental Methods**

*2.1. Materials and Processing*

The tool steel Vanadis 6, with chemical composition as shown in Table 1, was used for the examinations.

**Table 1.** Chemical composition of the experimental steel.

Specimens of the studied steel with a size of 20 mm × 20 mm × 7 mm were gradually heated (step (1) in Figure 1) up to the austenitizing temperature of 1050 ◦C in a vacuum, held there for 30 min (2), and quenched by nitrogen gas to room temperature (3). Then, the specimens were divided to five batches. The first one was immediately subjected to tempering treatment (7, 8). This treatment route is called conventional heat treatment, CHT. Immediately after quenching, the other four sets were moved to the cryogenic system, where they were cooled down at a cooling rate of 1 ◦C/min to a pre-determined

SZT temperature (4). The SZTs were carried out at temperatures of −75, −140, −196, or −269 ◦C, and for 17 h each (5). After that, the material was re-heated to room temperature, at a heating rate of 1 ◦C/min (6). Immediately after re-heating, sub-zero-treated specimens were subjected to tempering. Tempering was carried out at temperatures of 170, 330, 450, or 530 ◦C, 2 times each, for 2 h (7, 8).

**Figure 1.** A schematic of the heat treatment schedules used.


**5. Conclusions**

This paper evaluates the 14 DC-DC boost converters' efficiency, number of components, and stability. The significance of choosing a converter based on load and source requirements is evaluated. The importance of voltage gains and voltage stress factors when connecting solar PV to the grid is discussed. In addition to the non-isolated step up, interleaved and coupled inductors' reliability with respect to solar PV system applications are outlined. The stress on the switches is reduced by coupled inductor with the ZVS operation system to reduce grid instability and synchronization drawbacks. Each converter importance is fully discussed in this review. Microgrids with solar PV will significantly increase the flexibility of the power system, but to make it reliable, it is necessary to choose the proper converters based on corresponding ratings. Selecting a suitable Converter linking PV source and Dc link bus enhances system performance. In addition, the bidirectional interleaved switched capacitor DC-DC converter implemented in grid connection helps reduction of capacitor voltage stress is discussed in this review. This further extends to by interleaved converter use in diminishing the current ripples at low voltage. Even though the converters pose the following merits, many constraints still need to be resolved, such as exceeding duty values to 50% and linear increases of switch voltage stress with increasing duty cycle.

**Author Contributions:** Implementation, Investigation, I.J.; Analysis, Supervision, Proofreading, V.I. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


2.6.5. Diffuse large B cell lymphoma, leg type

It manifests as red or bluish (violaceous) nodules or tumors on one or both legs, usually below the knee; 10–15% develop outside of the lower extremities. Contrary to other cutaneous B cell lymphomas, these tumors frequently disseminate to extracutaneous sites and pursue an aggressive course. MYD88 L265P mutations are seen in ~50% of cases.

#### 2.6.6. Diffuse large B cell lymphoma associated with chronic inflammation

Also known as pyothorax-associated DLBCL, it usually develops in patients with a long standing history of pyothorax; however it may also arise at other sites with chronic inflammation [14]. It is seen worldwide but is more common in Japan and China. Clinically, it is an aggressive tumor. These tumors are almost always EBV-positive and are believed to arise from EBV-infected post germinal center B cells. The pattern of EBV gene expression present in this type of lymphoma (LMPI and EBNA2 positivity) suggests the role of local immunosuppression within the sites of chronic inflammation.

#### 2.6.7. Lymphomatoid granulomatosis

This is also an EBV-positive large B cell lymphoma with a T cell-rich background which is clinically and pathologically distinct from DLBCL [15]. The usual manifestations are cough and fever (60%), rash/nodules (40%), malaise and weight loss (35%), neurological abnormalities and dyspnea (30%), or chest pain (15%) [16]. Extranodal involvement is common. The lungs are commonly affected. Other commonly involved sites include kidney, liver, brain, and skin. Lymph nodes and splenic involvement is rare. Histologically, the infiltrates are either angiocentric or angioinvasive. Often extensive necrosis is present with only a few atypical large B cells in a pleomorphic background of lymphocytes, plasma cells, and histiocytes. The large atypical B cells represent the neoplastic component and show evidence of EBV infection with in situ hybridization. Pulmonary nodules exhibit central necrosis and cavitation.

#### 2.6.8. EBV-positive DLBCL, NOS

EBV-positive DLBCL, NOS is a variant of DLBCL that replaced the entity, EBV-positive DLBCL of the elderly and was added in the 2016 WHO classification. It may affect persons of all ages [17–21]. This is seen in patients without known immunodeficiency or prior lymphoma. It is seen most commonly in Asian countries where it accounts for 8–10% of DLBCL among patients without a known immunodeficiency. The majority of patients present with extranodal disease, with or without nodal involvement. While the initial reports were in adults >50 years old, this entity has been increasingly recognized in younger patients [17, 22].

However, it was not superior in predicting the outcome. In a study on 108 patients, it was shown that Hans and Choi algorithms predicted OS and PFS significantly better than the Tally method [33]. Other algorithms use combinations of other markers (Muris et al.: BCL2, CD10, MUM1 [34]), (Natkunam et al.: LMO2 [35]), (Nyman et al. 50: MUM1, CD10, GCET1, MUM1, FOXP1,

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263 47

However, the utility of IHC methodology is also limited by its poor concordance to GEP, inferior accuracy and reproducibility and a lack of prognostic utility. IHC algorithms do not recognize the 10–15% of tumors and are not always reproducible [37]. Lymph2Cx is a 20-gene version of a Nanostring code set for a COO typing assay of DLBCL. This represents GEP like

Figure 4. Immunohistochemistry algorithms for the characterization of diffuse large B-cell lymphoma on the basis of cell of origin. (a) Hans algorithm; (b) Choi algorithm; (c) Nyman algorithm; (d) Visco-young algorithm; (e) Muris algorithm;

and (f) Tally algorithm.

LMO2 [36]) and have been described in detail in Figure 4.

#### 2.6.9. EBV-positive mucocutaneous ulcer

It is considered a provisional entity in the 2016 revision of the WHO classification. This is characterized by the presence of isolated circumscribed ulcerative lesions, typically affecting elderly individuals [23, 24]. Its association with immunosuppression is not clear. Usually, the oropharynx is affected but lesions may also occur in the skin or in the gastrointestinal tract. Histologically, a polymorphous inflammatory infiltrate mixed with scattered EBV-infected B cells is seen in the lesions, which frequently include cells resembling Hodgkin/Reed-Sternberg cells both morphologically and immunophenotypically. This entity is distinguished from Hodgkin lymphoma by its extranodal presentation and has a benign disease course which is characterized by frequent spontaneous regressions and its excellent response to conservative treatment.

#### 2.7. Molecular subtypes

As noted above, the classification of DLBCL NOS, into GCB vs. ABC subtypes is important for the prognostication. The prognosis of GCB-type DLBCL is considered to be better than ABC-type DLBCL. In the rituximab era the 5-year survival of GC type DLBCL is 87–92% as compared to 44% in the ABC-type DLBCL [7, 25]. Moreover, response to novel therapies may be different for the two subtypes. The classification into GCB- vs. ABC-type is best conducted by genomic expression profiling [26]. The DNA microarray is an effective tool to characterize the molecular features of DLBCL and specific genes associated with response to therapy. Though microarray GEP are gold standard for profiling of DLBCL to determine COO, they are expensive and not readily available. Moreover, they have poor flexibility and reproducibility in evaluating low quality RNA samples from formalin-fixed paraffin-embedded (FFPE) tissues and for high quality data, they require RNA extraction from the frozen tissues [27]. Thus their implementation in the routine clinical practice is limited [28]. IHC-based methods are rapid, cost effective and thus are widely used in the clinical practices. Different algorithms have been developed to improve the accuracy. These algorithms use different combinations of antibodies to identify germinal center or activated B cell-related proteins [4, 7, 29]. The relatively simple and most well-known is the Hans algorithm which is based upon the application of 3 antibodies, CD10, BCL6, IRF4/ MUM1 and has a reasonable correlation with the GEP [30]. Cases are considered positive if 30% or more of the tumor cells are stained with an antibody (CD10, BCL6, and MUM1). The overall concordance with gene expression array is 80%. The Choi algorithm added FOXP1 and GCET 1 to Hans algorithm and showed 93% concordance with GEP [25, 31]. A Tally classifier substituted BCL6 for the LMO2 antibody which predicted COO better than rest of the IHC algorithms [32]. However, it was not superior in predicting the outcome. In a study on 108 patients, it was shown that Hans and Choi algorithms predicted OS and PFS significantly better than the Tally method [33]. Other algorithms use combinations of other markers (Muris et al.: BCL2, CD10, MUM1 [34]), (Natkunam et al.: LMO2 [35]), (Nyman et al. 50: MUM1, CD10, GCET1, MUM1, FOXP1, LMO2 [36]) and have been described in detail in Figure 4.

2.6.8. EBV-positive DLBCL, NOS

46 Hematology - Latest Research and Clinical Advances

2.6.9. EBV-positive mucocutaneous ulcer

2.7. Molecular subtypes

EBV-positive DLBCL, NOS is a variant of DLBCL that replaced the entity, EBV-positive DLBCL of the elderly and was added in the 2016 WHO classification. It may affect persons of all ages [17–21]. This is seen in patients without known immunodeficiency or prior lymphoma. It is seen most commonly in Asian countries where it accounts for 8–10% of DLBCL among patients without a known immunodeficiency. The majority of patients present with extranodal disease, with or without nodal involvement. While the initial reports were in adults >50 years

It is considered a provisional entity in the 2016 revision of the WHO classification. This is characterized by the presence of isolated circumscribed ulcerative lesions, typically affecting elderly individuals [23, 24]. Its association with immunosuppression is not clear. Usually, the oropharynx is affected but lesions may also occur in the skin or in the gastrointestinal tract. Histologically, a polymorphous inflammatory infiltrate mixed with scattered EBV-infected B cells is seen in the lesions, which frequently include cells resembling Hodgkin/Reed-Sternberg cells both morphologically and immunophenotypically. This entity is distinguished from Hodgkin lymphoma by its extranodal presentation and has a benign disease course which is characterized by frequent spontaneous regressions and its excellent response to conservative treatment.

As noted above, the classification of DLBCL NOS, into GCB vs. ABC subtypes is important for the prognostication. The prognosis of GCB-type DLBCL is considered to be better than ABC-type DLBCL. In the rituximab era the 5-year survival of GC type DLBCL is 87–92% as compared to 44% in the ABC-type DLBCL [7, 25]. Moreover, response to novel therapies may be different for the two subtypes. The classification into GCB- vs. ABC-type is best conducted by genomic expression profiling [26]. The DNA microarray is an effective tool to characterize the molecular features of DLBCL and specific genes associated with response to therapy. Though microarray GEP are gold standard for profiling of DLBCL to determine COO, they are expensive and not readily available. Moreover, they have poor flexibility and reproducibility in evaluating low quality RNA samples from formalin-fixed paraffin-embedded (FFPE) tissues and for high quality data, they require RNA extraction from the frozen tissues [27]. Thus their implementation in the routine clinical practice is limited [28]. IHC-based methods are rapid, cost effective and thus are widely used in the clinical practices. Different algorithms have been developed to improve the accuracy. These algorithms use different combinations of antibodies to identify germinal center or activated B cell-related proteins [4, 7, 29]. The relatively simple and most well-known is the Hans algorithm which is based upon the application of 3 antibodies, CD10, BCL6, IRF4/ MUM1 and has a reasonable correlation with the GEP [30]. Cases are considered positive if 30% or more of the tumor cells are stained with an antibody (CD10, BCL6, and MUM1). The overall concordance with gene expression array is 80%. The Choi algorithm added FOXP1 and GCET 1 to Hans algorithm and showed 93% concordance with GEP [25, 31]. A Tally classifier substituted BCL6 for the LMO2 antibody which predicted COO better than rest of the IHC algorithms [32].

old, this entity has been increasingly recognized in younger patients [17, 22].

However, the utility of IHC methodology is also limited by its poor concordance to GEP, inferior accuracy and reproducibility and a lack of prognostic utility. IHC algorithms do not recognize the 10–15% of tumors and are not always reproducible [37]. Lymph2Cx is a 20-gene version of a Nanostring code set for a COO typing assay of DLBCL. This represents GEP like

Figure 4. Immunohistochemistry algorithms for the characterization of diffuse large B-cell lymphoma on the basis of cell of origin. (a) Hans algorithm; (b) Choi algorithm; (c) Nyman algorithm; (d) Visco-young algorithm; (e) Muris algorithm; and (f) Tally algorithm.

platform that can run on FFPE tissue. Twenty genes have been selected out of 93 candidate genes [38, 39] to identify COO using this platform. In NanoString technology, digitally colored code sets are attached to the sequence-specific probes to directly measure mRNA [28, 40]. This technique offers highly sensitive, quantitative and reproducible results on FFPE and frozen tissue samples. This requires a very small amount of RNA and covers a large number of genes enabling complex genetic analysis. Studies have demonstrated strong concordance between patient-matched frozen and FFPE materials. It showed 98% concordance for ABC/GCB and 95% in the unclassifiable cases when compared with GEP [38]. In a study on 82 patients, who were treated with R-CHOP the concordance rate between Lymph2Cx assay and Hans algorithm was 73.6%. The outcome of Lymph2Cx-defined ABC (77.1%) was significantly poor as compared to the GCB type (96.6%). On contrary, there was no difference in the outcome of two groups classified by the Hans algorithm [41].

3.3. Immunophenotype

and 6.2.

3.4. Workup

It is essential for the differentiation of various subtypes of DLBCL. This is established either by flow cytometry or IHC. Flow cytometry can be employed in determining bone marrow involvement [45] when PET/CT is not readily available for staging and in determining CNS involvement by CSF flow cytometry [46]. Immunophenotype findings are usually combined with morphologic findings to arrive at a diagnosis. Tumor cells in DLBCL generally express pan B cell antigens (CD19, CD20, CD22, and CD79a) as well as CD45. The typical immunophenotype is CD20+, CD45+, and CD3. The panel should include CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, and MYC. 50–75% of tumors express surface and cytoplasmic monoclonal immunoglobulin (Ig). The proliferative fraction of cells is usually higher than 40% and may occasionally be >90%. CD5 positive tumors are associated with a more aggressive disease and a higher incidence of CNS involvement and a worse prognosis. CD10+ and BCL6+ indicates GCB lymphoma while MUM1+ indicates ABC lymphoma. The three most common translocations noted in DLBCL include MYC, BCL2 and BCL6. MYC is an oncogene involved in pathogenesis of aggressive lymphomas based on partner gene translocation. MYC protein is a transcription regulator for cellular proliferation acting on metabolic and angiogenic mechanism. Genetic translocation involving MYC are considered primary events in 5–15% of DLBCL [47] and in around 20% on first relapse [48]. In DLBCL frequently the partner gene is BCL-2 or to a lesser extent BCL-6 or both, in the so-called double-hit or triple-hit lymphomas. Overexpression of MYC protein can be tested with IHC which can occur independent of translocation in 30% of cases; however for confirmation of specific translocation FISH studies are required [49]. Both, overexpression and translocation confer adverse outcome as documented in different studies [50]. More information on this translocation and their effect on outcome is detailed in Sections 2.3

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263 49

Initial work up includes thorough physical examination with special attention to node bearing areas and evaluation of performance status (PS) and constitutional symptoms. Appropriate site for excisional/incisional biopsy should be earmarked as stated above.  Additional tests including uric acid and phosphorus, in patients with high tumor burden. Hepatitis B virus (HBV) testing is also warranted as there is an increased risk of HBV reactivation in patients who may require Rituximab. Positron emission tomography (PET)/computed tomography (CT) scan is recommended for initial staging as upstaging can result in altered therapy. Also baseline PET/ CT is necessary to confirm the response on the post treatment PET scans. A systematic review and meta-analysis by Adams et al. showed that sensitivity and specificity of PET/CT for detection of bone marrow involvement ranged from 70.8 to 95.8% and from 99.0 to 100%, respectively [51]. There were 3.1% patients who were PET negative but had bone marrow involvement on bone marrow biopsy. On contrary 12.5% patients with negative bone marrow biopsies had marrow involvement on PET scan and PET/CT [51]. Bone marrow biopsy is not needed if the PET/CT is negative unless finding another concomitant lymphoma is important


**Risk Management Strategies in School Development and the Effect of Policies on Tolerance Education and the Effect of Policies on Tolerance Education**

**Risk Management Strategies in School Development**

DOI: 10.5772/intechopen.70787

Behcet Öznacar Behcet Öznacar Additional information is available at the end of the chapter

image. Decentralization of decision making mechanisms may create another asset for the schools to compete in different cultures. As being private schools in Northern Cyprus, they use a degree of marketing communication tools. For their future survivals, they should consider educational success, quality, learning, and assessments with the integrated educational

Faculty of Communication and Media Studies, Eastern Mediterranean University, Famagusta,

[1] Fill C. Simply Marketing Communications. England: Pearson Education Limited; 2006. p. 1 [2] Keller KL. Mastering the marketing communications mix: Micro and macro perspectives on integrated marketing communication programs. Journal of Marketing Management.

[3] Shimp TA. Advertising, Promotion, and Supplemental Aspects of Integrated Marketing

[4] Clow KE, Baack D. Integrated Advertising, Promotion, and Marketing Communications.

[5] Şahin A. Örgüt Kültürü-Yönetim İlişkisi ve Yönetsel Yetkinlik. Maliye Dergisi. 2010;159:21-35 [6] MacNeil AJ, Prater DL, Busch S. The effects of school culture and climate on student achievement. International Journal of Leadership in Education. 2009;12(1):73-84. DOI:

[7] Mitchell JT, Willower DJ. Organizational culture in a good high school. Journal of Educa-

[8] Jerald CD. School Culture: "The Hidden Curriculum". Issue Brief Center for Comprehensive School Reform and Improvement [Internet]. 2006. Available from: http://files.eric.ed.

[9] TRNC Statistical Year Book 2015 [Internet]. 2017. Available from: http://www.devplan.

[10] TRNC. The Ministry of Education Private School Applications [Internet]. Available from:

Communications. 6th ed. Ohio: Thomson South Western; 2003. p. 10-32

tional Administration. 1992;30(1). DOI: 10.1108/09578239210008781

tools and the use of marketing communication tools.

106 Open and Equal Access for Learning in School Management

\*Address all correspondence to<EMAIL_ADDRESS>
2001;17:819-847. DOI: 10.1362/026725701323366836

3rd ed. New Jersey: Pearson Prentice Hall; 2007. p. 821

gov/fulltext/ED495013.pdf [Accessed: 2017-07-8]

org/ISTYILLIK/IST-YILLIK-2015.pdf [Accessed: 2017-07-08]

http://www.mebnet.net/?q=node/39 [Accessed: 2017-07-10]

Author details

Northern Cyprus, Cyprus

References

Anıl Kemal Kaya\* and Umut Ayman

10.1080/13603120701576241

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70787

#### **Abstract**

Safety schools gain their quality of management by setting up strategies for risk management. The nature of safety schools relies on culture, management, and psychological guidance. In this respect, schools have intensified the need to concentrate on strategic planning for making school managements in quality context. The key term in quality for the school management is to focus on risk management. Risk management covers the potential pitfalls before facing threats. Therefore, strategy and policy establishment are important for managing the risks. In the first step, monitoring risks and examining opportunities and weaknesses are the major attempts to reach out quality. This research encapsulates examination of risk management in schools and current strategies and policies for the risks in the school cultures within qualitative nature. Experiences of headmasters and vice headmasters were gathered through interview. Thematic analysis was conducted to examine themes: culture of schools, strategy and policy of schools, and risk management. Research results revealed that headmasters and vice headmasters are aware of risk management. Schools are not enough to practice policies and strategies for establishing a school culture. It is seen that school culture and quality can be empowered through setting risk management and setting further policies and strategies.

**Keywords:** risk, management, strategies, tolerance, education


**1. Introduction**

Neurodegenerative diseases represent a major public health issue in the world. Indeed, due to the progressive aging of the population and the lack of curative treatments, the number of people suffering from neurodegenerative diseases has increased considerably in recent years and is expected to continue to grow steadily in the years to come. These pathologies are chronic progressive diseases that affect the central nervous system, mainly the neurons that are often the target of therapies. The causes of these pathologies are to be found in genetics or risk factors such as the presence of chemical molecules in food, air, water, houses, and everyday objects. These different risk factors can contribute to oxidative stress, inflammation, and peroxisomal and mitochondrial dysfunctions, ultimately leading to neuronal death [1]. Most therapies target neurons and their function. However, there is an inflammatory component that must also be considered, and thus the involvement of microglia, in these pathologies [2]. Microglial cells are the major resident immune cells in the brain. Microglia activation is often classified into two opposite states: M1 and M2 [3]. The M1 state corresponds to a "classical activation" and is considered to be proinflammatory with a high capacity to present antigens, and high production of nitric oxide (NO) and reactive oxygen species (ROS) as well as pro-inflammatory cytokines. The M2 state includes both "alternative activation" and "acquired deactivation" and expresses the phenotypic markers arginase-1 (Arg1), CD206, interleukin (IL)-10, transforming growth

**Citation:** Charrière, K.; Ghzaiel, I.; Lizard, G.; Vejux, A. Involvement of Microglia in Neurodegenerative Diseases: Beneficial Effects of Docosahexahenoic Acid (DHA) Supplied by Food or Combined with Nanoparticles. *Int. J. Mol. Sci.* **2021**, *22*, 10639. https://doi.org/10.3390/ ijms221910639

Academic Editor: Fabrizio Michetti

Received: 2 September 2021 Accepted: 27 September 2021 Published: 30 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

factor β (TGF-β), and IL-1. This M2 state is considered to be an anti-inflammatory state [4] with the capacity to fine-tune inflammation, debris removal, promotion of angiogenesis, and tissue remodeling and repair. This separation into two opposite states does not reflect all the microglia phenotypes which will depend on the brain injury, its stage, and its location [2,5]. Nevertheless, microglial cells can be neuroprotective or neurotoxic depending on their activation status and the M1/M2 terminology remains useful to describe these two properties, while keeping in mind that it does not allow all reactive states of microglia to be described.

In physiological conditions, microglial cells work as sentinels. When they are activated by injurious stimuli, they can turn into several phenotypes, the two main ones being M1 and M2.

M1 produces pro-inflammatory cytokines that allow neuroprotection by removing pathological agents or recruiting additional cells. In this case, neuro-inflammation caused by microglia is neuroprotective. In contrast, a prolonged neuro-inflammation induces neurotoxicity and leads to neurodegeneration [6]. Briefly, M1 cells act as potent effectors that drive the inflammatory response, can have detrimental effects on neural cells, and participate in neuronal cell death if the switch to the M2 state does not occur in an appropriate time frame [7].

Therefore, modulating the activation state of microglia and their tendency toward the M2 state could be a promising therapeutic approach for central nervous system repair and regeneration.

Given the lack of effective treatment and the difficulty of developing a molecule capable of crossing the blood–brain barrier (BBB), the use of food-derived molecules has been raised as a possible therapeutic option to target the current inflammatory state or to improve the phagocytic activity of microglia. Among these molecules, docosahexaenoic acid (DHA; C22:6 omega-3), an omega-3 polyunsaturated fatty acid, has many advantages.

In this review, we will focus on the potential cytoprotective effects of DHA on oxidative stress, cell death affecting microglia, and on microglia-controlled inflammation. We will also present some human clinical trials that show the benefits of using DHA to improve the therapeutic management of patients with neurodegenerative diseases along with certain limits to the use of DHA in capsules or from food. Finally, we will present different approaches using nanoparticles that could allow for a better availability of DHA at the cerebral level.