Celiac Disease and Gallbladder: Pathophysiological Aspects - PDF Nutrients 2022

nutrients Review Celiac Disease and Gallbladder: Pathophysiological Aspects and Clinical Issues Dimitri Poddighe 1,2, * , Kuanysh Dossybayeva 1 , Diyora Abdukhakimova 1 , Lyudmila Akhmaltdinova 3 and Aigul Ibrayeva 4 1 Department of Medicine, Nazarbayev U...

nutrients Review Celiac Disease and Gallbladder: Pathophysiological Aspects and Clinical Issues Dimitri Poddighe 1,2, * , Kuanysh Dossybayeva 1 , Diyora Abdukhakimova 1 , Lyudmila Akhmaltdinova 3 and Aigul Ibrayeva 4 1 Department of Medicine, Nazarbayev University School of Medicine, Nur-Sultan 010000, Kazakhstan 2 National Research Center for Maternal and Child Health, Clinical Academic Department of Pediatrics, University Medical Center, Nur-Sultan 010000, Kazakhstan 3 National Research Cardiac Surgery Center, Nur-Sultan 010000, Kazakhstan 4 National Research Center for Maternal and Child Health, Program of Pediatric Gastroenterology, Clinical Academic Department of Pediatrics, University Medical Center, Nur-Sultan 010000, Kazakhstan * Correspondence: [email protected]; Tel.: +7-(17)-2694637 Abstract: Background: Celiac Disease (CD) is an immune-mediated disorder which primarily affects the small intestine; however, extra-intestinal organs are often affected by the pathological process, too. As regards the digestive system, liver alterations in CD patients have been widely described, which can also extend to the biliary tract. Notably, gallbladder function can be altered in CD patients. In this review, we specifically analyze and summarize the main pathophysiological aspects and clinical evidence of gallbladder dysfunction in CD patients, in order to discuss the potential medical complications and clinical research gaps. In addition to some perturbations of bile composition, CD patients can develop gallbladder dysmotility, which mainly expresses with an impaired emptying during the digestive phase. The main pathophysiological determinant is a perturbation of chole- cystokinin secretion by the specific duodenal enteroendocrine cells in response to the appropriate Citation: Poddighe, D.; Dossybayeva, nutrient stimulation in CD patients. This situation appears to be reversible with a gluten-free diet in K.; Abdukhakimova, D.; most cases. Despite this gallbladder impairment, CD patients do not seem to be more predisposed to Akhmaltdinova, L.; Ibrayeva, A. gallbladder complications, such as calculous and acalculous cholecystitis. However, very few clinical Celiac Disease and Gallbladder: studies have actively investigated these clinical aspects, which may not be completely evidenced so Pathophysiological Aspects and far; alternatively, the substantial improvements in the last two decades regarding CD diagnosis, which Clinical Issues. Nutrients 2022, 14, have reduced the diagnostic delay (and related dietary treatment), may have lessened the potential 4379. https://doi.org/10.3390/ clinical consequences of CD-related gallbladder dysfunction. Specific clinical studies focused on these nu14204379 aspects are needed for a better understanding of the clinical implications of gallbladder alterations in Academic Editor: Luis Rodrigo CD patients. Received: 14 September 2022 Keywords: gallbladder; celiac disease; gallbladder dysmotility; cholecystokinin; gluten-free diet; Accepted: 4 October 2022 cholecystitis; gallstones Published: 19 October 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Celiac disease (CD) is an immune-mediated disorder triggered by gluten intake in a minority of individuals harboring a specific genetic HLA-DQ background. Indeed, all patients developing CD basically possess one or more allelic variants related to MHC- Copyright: © 2022 by the authors. DQ2 and/or MHC-DQ8 heterodimers. However, the most relevant alleles for CD Licensee MDPI, Basel, Switzerland. predisposition belong to HLA-DQB1, namely HLA-DQB1*02 and, to a lesser extent (in This article is an open access article terms of allelic frequency in CD patients), HLA-DQB1*0302 [2,3]. Notably, this genetic distributed under the terms and background is necessary, but not sufficient, to develop CD upon gluten dietary exposure. conditions of the Creative Commons Indeed, only 3–4% of these HLA-DQ-predisposed people will be diagnosed with CD over Attribution (CC BY) license (https:// their lives, which means that additional (epi)genetic and/or environmental factors play a creativecommons.org/licenses/by/ substantial role in CD etiopathogenesis at the individual level [4,5]. 4.0/). Nutrients 2022, 14, 4379. https://doi.org/10.3390/nu14204379 https://www.mdpi.com/journal/nutrients Nutrients 2022, 14, 4379 2 of 16 The primary target of CD is the gut, and indeed, the diagnostic hallmark of CD is the demonstration of gluten-sensitive enteropathy characterized by intraepithelial lymphocyte infiltration and variable degrees of villous atrophy of the small intestine; [1,4] however, CD is a systemic disorder, since many other tissues and organs can be affected in >50% of patients. Among the extra-intestinal targets of CD, the liver is one of the most frequently affected organs. Unexplained hypertransaminasemia with non-specific histologic hepatic changes is the most common hepatic presentation of CD; such a “cryptogenic” liver disorder (ranging from a mild to severe liver dysfunction) often leads to CD diagnosis in silent (asymptomatic) patients and disappears within 1 year of gluten-free diet (GFD) in most cases. Conversely, specific autoimmune liver diseases, such as autoimmune hepatitis and autoimmune cholangitis (which are more frequently diagnosed in CD patients than in the general population), are not gluten sensitive. Recently, CD has been proposed to also be a risk factor for non-alcoholic fatty liver disease [6–8]. In addition to the liver, the biliary tract can also be specifically affected in CD patients; in detail, gallbladder function can be altered in these patients. In this minireview, we summarize the main pathophysiological and clinical evidence on this matter and discuss the potential medical consequences in CD patients. 2. Overview of Gallbladder Anatomy and Function The main function of the gallbladder is to accumulate the bile to be poured into the duodenum during the digestive process. However, absorption and secretion processes also occur during the permanence of hepatic bile in the gallbladder; in general, the mucosa can absorb water, sodium, cholesterol, phospholipids, and hydrophilic proteins, whereas it can secrete mucins, hydrogen/chloride ions, and probably immunoglobulins and calcium. The most important effect of these processes is a greater concentration of bile acids in the gallbladder bile compared to hepatic bile. Bile acids are the major lipid components of bile, are synthetized from cholesterol in the liver, and are subsequently conjugated to taurine or glycine, which increases their solubility. Immediately after their synthesis, these (primary) biliary acids are secreted into the bile then concentrated and stored in the gallbladder. Upon food intake, the gallbladder releases the bile into the duodenum, where biliary acids support the digestion and absorption of lipids and fat-soluble vitamins. The gallbladder is located between both hepatic lobes and consists of three anatomic parts: the fundus, corpus, and infundibulum. The gallbladder ends in the cystic duct, which drains into the common bile duct without a sphincteric structure. The common bile duct courses through the head of the pancreas and ends with the sphincter of Oddi, which penetrates the duodenal wall where it forms the ampulla of Vater and opens into the duodenal lumen. The gallbladder wall is formed by a mucosa (with a single layer of epithelial cells and its lamina propria), a single layer of muscle (similar to the muscularis mucosa of the gastrointestinal tract), and a serosal layer. The single muscle layer is innervated by the vagal and splanchnic nerves, which synapse with intramural neurons. Indeed, the biliary tract and, in detail, the gallbladder are functionally integrated with the digestive tract by neuro-hormonal mechanisms in the fasting and digestive phases. In the fasting or inter-digestive phase, the entry of bile occurs through both passive and active mechanisms; the active relaxation allowing the gallbladder to receive the incoming bile is mediated by adrenergic and non-adrenergic fibers. During the three phases of the digestive period (cephalic, antral, and intestinal), the gallbladder is subjected to strong contractions mediated by the aforementioned nerves, but especially by the gut hormone cholecystokinin (CCK). Concomitantly, the sphincter of Oddi becomes relaxed, which allows bile to flow into the duodenum [11,12]. Nervous fibers mainly mediate the cephalic and antral gallbladder emptying, whereas CCK basically induces gallbladder contraction during the intestinal phase, mostly by acting directly on cholinergic neurons. CCK is produced by the I-cells of the intestinal mucosa, which shows the highest number/density in the duodenum and Nutrients 2022, 14, 4379 3 of 16 the proximal jejunum. These cells have an apical membrane in direct contact with the intestinal lumen, so they can sense the luminal content. Indeed, the release of CCK is affected by the meal content and, in detail, stimulated by protein- and fat-rich food. The basal cell region, which is close to capillaries, contains the secretory granules, where a mixture of CCK molecular forms with different lengths are stored. Among them, CCK-33 appears to be the predominant form in the human intestine and circulation, where CCK plasma concentrations can reach the picomolar range. Bioactive CCK peptides potently stimulate their target cells by interacting with one of the two CCK receptors expressed on the cell membrane. In detail, the CCK1 receptor is responsible for gallbladder contraction and relaxation of the sphincter Oddi, in addition to other physiological effects, including hepatic bile secretion, pancreatic enzyme secretion and growth, and inhibition of gastric acid secretion and emptying. The CCK2 receptor is primarily expressed in the brain [11,13,14]. 3. Gallbladder Functioning and Regulation in Celiac Disease Gallbladder functioning in CD has been intensively investigated starting from about 1970. Indeed, the CD diagnostic hallmark is the damage and flattening of the jejunal/ileal mucosa, which could also impair the endocrine cells located in the mucosal crypts, in addition to the enterocytes. Therefore, such a CD-related intestinal injury could impair nutrients digestion and absorption, both directly (by destroying the enterocytes and, in general, the villous architecture of the intestinal mucosa) and indirectly (by interfering with the production and secretion of gut hormones and peptides implicated in the regulation of intestinal motility and functioning of other organs involved in the digestive process, such as the exocrine pancreas and gallbladder). Before discussing the impact of CD on gallbladder function, a few studies highlighting some consequences on the bile production and composition in CD patients have to be mentioned [16,17]. Bile flow rate and the secretion of biliary of its main components, such as cholesterol, phospholipids, and bile acids, were reported to be significantly increased in active CD and be normalized after effective GFD. This enhanced secretion of newly synthesized and/or absorbed cholesterol directly into the bile has been associated with a decrease in serum cholesterol concentration in CD patients, which has been observed both in pediatric and adult clinical studies [20–22]. However, total plasma cholesterol is often associated with a decrease in HDL-cholesterol and, thus, a higher ratio of total cholesterol to HDL-cholesterol, which can also be ameliorated through GFD [22,23]. Specifically concerning the gallbladder function in CD, in Table 1 we summarize the output of our literature research aimed to extract all the original articles investigating gallbladder motility and/or its main regulator mechanisms, namely CCK production and action, in CD patients. Here, the main study characteristics and findings are also reported. In Table 2, we provide some extracts from the original text of the results and discussion/conclusion included in these articles. Indeed, most of them date back before 2000 and could not be easily retrieved by the readers [16,24–41]. Table 1. Summary of the main characteristics and findings of clinical studies investigating gallbladder functioning and regulation in CD patients. N of CD CD Authors, Control Patients Patients’ Year Methods Stimulus Group Main Findings [Disease Age [Ref.] (n) Activity] (Yrs.) -The authors showed that CD patients Low-Beer have a reduced gallbladder Oral 18 Adults Y et al., “fatty meal” contraction/emptying after a meal cholecystography [uCD] (28–78) (36) 1971 compared to controls, which can also impair the normal bile salts recirculation. Nutrients 2022, 14, 4379 4 of 16 Table 1. Cont. N of CD CD Authors, Control Patients Patients’ Year Methods Stimulus Group Main Findings [Disease Age [Ref.] (n) Activity] (Yrs.) -This study confirms the impaired motor activity of the gallbladder in untreated Oral chole-cystography CD patients, in response to a meal. + Low-Beer -This poor gallbladder response appears serum CCK 10 Adults Y et al., “fatty meal” to be related to a resistance of this organ concentration by [uCD] (M:49) (10) 1975 to the action of CCK, rather than to an radio- impaired CCK release by the immunoassay enteroendocrine cells of the small bowel mucosa. -These authors reported a normal Study of bilirubin output following CCK-PZ “gallbladder Mg sulfate stimulation in CD patients with atrophy Colombato evacuation” solution (i.d) of intestinal mucosa, which was 11 Adults Y et al., through analysis of & comparable to controls. Therefore, they [uCD] (26–62) (10) 1977 bile secretion CCK-PZ indirectly suggested an impaired release and (i.v.) of CCK (rather than a gallbladder bilirubin output resistance to CCK) in CD patients with damaged intestinal mucosa. -These authors observed that somatostatin cells, GIP cells, and CCK cells were markedly increased in number Analysis of in the damaged mucosa of CD patients, Sjolund hormone-producing cell 18 Adults Y while the number of secretin cells was et al., types in duodenal N/A [uCD?] (19–60) (24) slightly reduced. 1979 biopsies by -This enteroendocrine cellular pattern immuno-staining returned to normal, along with the morphology of intestinal mucosa, upon GFD. -These authors observed a reduced immuno-reactivity of CCK in the Analysis of amount and intestinal mucosa of CD patients, as well type of CCK in Calam as reduced circulating levels of CCK duodenal extracts and 16 Adults Y et al., N/A after a meal, compared to controls. plasma by radio- [uCD] (M:2) (13) 1982 Therefore, they suggested that the immunoassay impairment of gallbladder function and gel filtration could be related to an impaired production and release of CCK in CD. -This study confirmed the gallbladder Delamarre Real-time 4 Adults motor dysfunction in CD patients by et al., “fatty meal” N ultrasonography [uCD?] (n/a) real-time ultra-sonography, instead of 1984 oral cholecystography. Study of gallbladder -This study further confirmed that CD emptying by patients have an impaired emptying of Maton 99mTc -eHIDA HS 14 the gallbladder in response to a fatty et al., + “emulsion of [uCD = 6] Adults Y meal, by hepatobiliary scintigraphy. 1985 serum CCK arachis oil” [nrCD = 2] (n/a) (6) -These authors also suggested that such concentration by [gfdCD = 6] an occurrence can be due to a reduced radio- release of CCK into the circulation, immunoassay which becomes normalized after GFD. -This study showed an increase of the Analysis of “endocrine enteric endocrine cells in children with cells” 27 Pietroletti active CD, in comparison with in jejunal biopsies [uCD = 9) Children Y et al., N/A normal controls. by using a monoclonal [gfdCD = 10] (2–12) (5) 1986 -CD children treated successfully with antibody to [gcCD = 8] GFD showed enteroendocrine cell chromogranin populations similar to the control group. Nutrients 2022, 14, 4379 5 of 16 Table 1. Cont. N of CD CD Authors, Control Patients Patients’ Year Methods Stimulus Group Main Findings [Disease Age [Ref.] (n) Activity] (Yrs.) -In this study, CD patients required larger doses of cerulein to initiate gallbladder emptying, and there was a Cerulein- correspondingly longer delay from the Brown Study of gallbladder synthetic start of the infusion until emptying 8 Adults Y et al., emptying by CCK began. A slower gallbladder emptying 99mTc -eHIDA HS [uCD] (n/a) (8) 1987 analogue was also observed. Therefore, these (i.v) authors suggested that the abnormal gallbladder contraction in CD is not simply because of impaired release of CCK. Analysis of -No significant differences in mucosal Domschke hormone-producing 5 Adults Y CCK-like immunoreactivity profile was et al., cell types N/A [gfdCD] (n/a) (8) observed between CD patients 1989 in duodenal biopsies and controls. by immuno-staining -These authors reported that gallbladder Study of gallbladder motor response to cerulein in untreated emptying by 99mTc -eHIDA HS Cerulein- and treated CD patients was not Masclee synthetic 12 significantly different from that observed + Adults Y et al., CCK [uCD = 6] in controls. serum CCK (38–55) (9) 1991 analogue [gfdCD = 6] -Therefore, these authors suggested that concentration by (i.v) the impaired gallbladder contraction in radio- CD patients could result from a reduced immunoassay endogenous CCK secretion. -No significant differences in basal and stimulated plasma CCK levels were detected among all the following groups: CD patients with a flat jejunal mucosa, Real-time CD patients with an intact intestinal ultrasonography mucosa on GFD, and in controls. Thimister + 13 -These authors concluded that plasma Bombesin Adults Y et al., serum CCK [uCD = 6] CCK release and gallbladder contraction (i.v) (28–55) (7) 1999 concentration by [gfdCD = 7] in response to bombesin are not reduced radio- in patients with active CD; thus, immunoassay impaired postprandial CCK release and gallbladder contraction in these patients are not related to abnormal CCK-secreting capacity, but to impaired stimulation by (undigested) nutrients. -Gallbladder fasting volume was significantly higher in CD patients at diagnosis than in controls; after a fatty 10 meal, gallbladder emptying was Real-time [“at significantly lower in untreated CD ultrasonography diagnosis patients than in the other two groups. Fraquelli + and after 18 Adults Y -These authors also observed that an oral et al., serum CCK “fatty meal” months of (25–38) (10) fatty meal-induced increase in CCK 1999 concentration by successful plasma levels was significantly lower in radio- gluten-free CD patients at diagnosis than after immunoassay diet”] treatment or in the controls. They suggested a complete restoration of CCK response and normalization of gallbladder contraction after GFD. -In CD patients, integrated plasma CCK serum CCK “pre/un- Wahab 22 concentrations were significantly concentration by digested Adults Y et al., [uCD = 13] increased over basal values in response radio- corn (28–55) (15) 2001 [gfdCD = 9] to predigested fat but not in response to immunoassay oil meal” undigested fat. Nutrients 2022, 14, 4379 6 of 16 Table 1. Cont. N of CD CD Authors, Control Patients Patients’ Year Methods Stimulus Group Main Findings [Disease Age [Ref.] (n) Activity] (Yrs.) -A significant decrease in basal and stimulated CCK plasma was observed in CD patients with a flat mucosa and with the IELs infiltration only, Real-time 20 compared to CD patients with healed ultrasonography [uCD = 8] mucosa upon GFD and volunteers. Deprez + “Liquid [gfdCD = 12: Adults Y Thus, they supported a CCK release et al., serum CCK polymeric normal (32–55) (9) impairment in CD patients. 2002a concentration by meal” mucosa = 6; -Compared to controls, fasting radio- IELs gallbladder volumes were significantly immunoassay presence = 8] higher in CD patients with mucosal atrophy, who also showed a significantly reduced contraction of gallbladder compared to all groups. Analysis of CCK-producing cells 19 -This study suggested that the defective in duodenal biopsies [uCD = 7] release of CCK in CD patients is not by immuno-staining Deprez [gfdCD = 12: related to a decrease in the number of and mRNA expression Adults Y et al., N/A normal CCK cells present in the proximal part + (33–55) (10) 2002b mucosa = 6; of the small intestine but rather to a serum CCK IELs decrease in CCK synthesis mediated by concentration by presence = 6] a decrease in mRNA content. radio- immunoassay serum CCK8 Y -This study supported a poor CCK Nousia- concentration by (62) response to a meal in patients with CD Arvanitakis “fatty 24 Children radio- or, in general, patients having flat et al., meal” [uCD] (2–18) immunoassay * CMPE intestinal mucosa, compared 2006 (12) to controls. -Fasting gallbladder volume was 19 significantly larger in CD patients than Benini [“before in healthy controls, as well as residual Real-time meal with Adults Y et al., (n = 19) postprandial gallbladder volume; this ultrasonography 50% lipids (M:34) (24) 2012 and during gallbladder functional abnormality (n = 14) GFD“] promptly returned to normal after successful GFD. -After strict GFD for a period of 6 99mTc -BrIDA months, both ultrasonography and Das HS hepatobiliary scintigraphy were “fatty 50 Children et al., + N concordant in describing the meal” [uCD] (M:9) 2021 Real-time improvement of gallbladder emptying, ultrasonography fasting volume, and postprandial volume in children affected with CD. * Abbreviations: ref., reference number; n, number; yrs., years; Y, yes; N, no; n/a, not available; N/A, not applicable; M, mean; GFD, gluten free diet; uCD, untreated CD patients; nrCD, non-responsive CD patients; gfdCD, CD patients on gluten-free diet; gcCD, CD patients undergoing gluten challenge; CCK, cholecystokinin; PZ, pancreozymin; GIP, gastric inhibitory peptide; 99mTc -eHIDA HS, 99mTc -labeled diethyl acetanilide-iminodiacetic acid hepatobiliary scintigraphy; 99mTc -BrIDAHS, 99mTc-labelled mebrofenin hepatobiliary scintigraphy; CMPE, cow’s milk protein enteropathy; IELs, intraepithelial lymphocytes; i.v., intravenous administration; i.d., intra- duodenal administration. Low-Beer et al. first reported absent or impaired gallbladder contraction in CD patients after a fatty meal, despite a normal concentration of the contrast medium administered to perform oral cholecystography. The concomitant study of bile salt turn-over showed a “stagnation of bile in the biliary tree”, supporting the poor contraction of gallbladder after a meal in CD patients [16,17,42]. An experimental study by Di Magno et al. in- directly suggested an impaired secretion of CCK in CD patients after a meal as a main pathophysiological explanation. However, Low-Beer et al. first analyzed the kinetics of plasma CCK after a meal and the concomitant gallbladder response by radioisotope cholecystography, which was described in detail in their seminal paper. They observed Nutrients 2022, 14, 4379 7 of 16 an increase of CCK fasting levels, a non-significant rise of CCK levels after a meal and a delayed gallbladder emptying in CD patients compared to controls. Their conclusion was that “at least two factors contribute to the defective gallbladder emptying in patients with coeliac disease. First the rise in serum CCK is less steep than normal. Secondly the gallbladder appears to be less sensitive to the action of CCK, possibly as a result of the abnormally high fasting levels”. This second conclusion was debated by some researchers, but Colombato et al. provided clinical data supporting the main role of deficient CCK production and/or release in CD patients, rather than a resistance of the gallbladder to CCK action. Indeed, these authors observed a normal bile secretory response in CD patients upon exogenous CCK-PZ infusion, which was comparable to that observed in controls. Two additional studies using the pure synthetic CCK analogue caerulein provided conflicting results. Brown et al. reported that their CD patients required a considerably larger dose of caerulein to initiate gallbladder contraction, and its emptying was less complete compared to the controls. Conversely, Masclee et al. found that gallbladder response to cerulein in untreated and treated CD patients was not significantly different from that observed in their controls. Table 2. Original text extracts from results and discussion/conclusion of the clinical studies investi- gating gallbladder functioning and regulation in CD patients. Authors, Year Results Conclusions [Ref.] -“Our finding, in most of the coeliac patients, of a prolonged -“Area of gallbladder shadow after fat, expressed as percentage of taurocholate half-life and a decreased recirculation of Low-Beer resting area, in coeliac patients and controls” was assessed by the metabolites of taurocholate is consistent with stagnation of et al., radiologist and related to the degree of gallbladder contraction. bile in the biliary tree”. 1971 -“in coeliac patients the gallbladder area after “fat is significantly -“... in most patients with coeliac disease the gallbladder greater than normal in relation to the resting value (p < 0.01)”. contracts minimally or not at all in response to a fatty meal”. -“Fasting serum CCK levels were significantly raised in patients with CD (mean 1081 pg/mL ± 250 S.E.M.), being higher than in any -“This study confirms the previous findings of a sluggish of the controls (mean 68 pg/mL ± 28 S.E.M.) in nine of the gallbladder response to food in patients with celiac disease. 10 patients (p < 0.002). In contrast, the peak serum cholecystokinin The poor response, however, does not appear to be due solely levels, and the increments in serum cholecystokinin after fat were to failure of endogenous cholecystokinin release by the both lower in patients with celiac disease, but the difference from abnormal small bowel mucosa, as was previously Low-Beer control subjects did not reach significant levels”. suggested... ” et al., -“Emptying of the gallbladder was less completed in patients with -Peak serum levels after food are normal in patients with 1975 celiac disease, as judged by the percentage reduction in celiac disease. The gallbladder itself appears to be resistant to radioactivity over the gallbladder. After an hour the celiac the action of cholecystokinin, and this resistance may in some gallbladder still retained approximately two thirds of its fasting way to be related to the presence of constantly high levels of activity, as compared with only one third in controls (p < 0.0025)”. this hormone in the blood, the reason for which -The onset of gallbladder emptying was significantly delayed in remains obscure. “ celiac patients”. -“Following CCK-PZ stimulation, 10 normal control subjects -“The patients with atrophy of the small-intestinal mucosa in showed a bilirubin increase from 1.92 ± 1.00 to 26.09 ± 7.72 mg/ the basal state showed a reduced secretion of bile bilirubin, 60 min. In 11 patients with intestinal atrophy bilirubin output and in almost half of the cases, bile in the duodenum was increased from 0.68 ± 0.45 to 41.09 ± 23.54 mg/60 min. The totally absent”. Colombato increase in bilirubin output following CCK-PZ stimulation was not -“These results seem to be related to a deficient release or et al., different in the control and patient groups”. synthesis of endogenous cholecystokinin from a damaged 1977 -“In 10 normal control subjects the bilirubin output increased from small-intestinal mucosa and seems to confirm that 2.02 ± 0.97 to 35.19 ± 18.45 mg/60 min following instillation of small-intestinal mucosa in celiac sprue is incapable, for magnesium sulfate, whereas in 11 patients with intestinal atrophy whatever reason, of responding to a well-known the increase was from 0.76 ± 0.42 to 2.39 ± 1.24 mg/60 min stimulating mechanism”. (p < 0.001)”. -“We found that in the flat mucosa the somatostatin cells, GIP cells, and CCK cells were markedly increased in number, Sjolund -“Cells displaying somatostatin, GIP or CCK immunoreactivity while the number of secretin cells was slightly reduced. The et al., were fairly numerous in all specimens. The number of these cells endocrine cell pattern and the intestinal morphology 1979 was almost doubled in the patients having a flat mucosa”. returned to normal upon withdrawal of gluten (four patients)”. Nutrients 2022, 14, 4379 8 of 16 Table 2. Cont. Authors, Year Results Conclusions [Ref.] -“In normal subjects fasting CCK-like immunoreactivity was 0.05). Mean postprandial intestinal mucosa. The meal-induced increase in CCK plasma values were 1.8492 ± 0.6173 and 2.5792 ± 1.6243 pmol/L in CMPE levels were significantly lower in patients with flat intestinal and CD, respectively. Again, there was no statistical difference mucosa as compared with those having normal mucosa between the 2 groups and the controls (2.0084 ± 1.8570 pmol/L; or controls”. Nousia- p > 0.05). There was significant difference, however, between -“In conclusion, we have demonstrated that plasma CCK Arvanitakis fasting and postprandial values in both groups and the controls release in response to oral nutrients is decreased in patients et al., (p < 0.001)”. having intestinal mucosa atrophy. This may lead to lack of 2006 -“Plasma CCK values obtained from patients with villous exocrine pancreas stimulation. This study supports the atrophy... Mean fasting values were 0.6475 ± 0.3264 and hypothesis that exocrine pancreatic impairment in patients, 0.7383 ± 0.5186 pmol/L in CMPE and CD, respectively. They were who have intestinal mucosal atrophy and are not markedly not statistically different from those of the control group undernourished, may be attributed to reduced CCK secretion (0.7317 ± 0.6709 pmol/L; p > 0.05). Mean postprandial values were from the CCK secreting cells located in the damaged 0.7133 ± 0.3019 and 0.8246 ± 0.5132 pmol/L in CMPE and CD, intestinal mucosa rather than pancreatic acinar dysfunction”. respectively. They were comparable (p > 0.05) but statistically different from those of the control group (2.0084 ± 1.8570 pmol/L; p = 0.001). There was no significant difference between fasting and postprandial values in CMPE, whereas the difference in CD barely reached statistical significance (p = 0.046)”. Nutrients 2022, 14, 4379 11 of 16 Table 2. Cont. Authors, Year Results Conclusions [Ref.] -“Mean fasting GB volume was significantly larger in CD patients than in healthy controls (32.2 ± 19.1 mL vs. 17.6 ± 5.1 mL, respectively, p = 0.0041), as was residual postprandial GB volume (8.5 ± 8.8 mL vs. 2.2 ± 1.7 mL), respectively, p = 0.0038)”. -“Fourteen of the 19 CD patients enrolled in the study have been Benini studied twice, before and during GFD. [... ]GB volume decreased -“Our study confirms a functional alteration of GB motility in et al., in each individual patient and mean value decreased from CD patients, and a prompt return to normality during GFD”. 2012 32.1 ± 1.4 mL at baseline to 20.6 ± 9.6 mL (p = 0.0549) during GFD, a value similar to that observed in healthy controls (17.6 ± 5.1 mL). Postprandial residual volume also decreased in each individual patient and mean value volume decreased from 8.3 ± 8.9 mL at baseline to 2.4 ± 1.7 mL during GFD (p = 0.0134), a value similar to that observed in healthy controls (2.2 ± 1.7 mL)”. -“After a strict GFD for a period of 6 months, repeat HBS and USG were performed to evaluate GBEF in the 8 children who had -“After ensuring GFD for 6 months, the subgroup of children impaired GBEF by HBS at baseline. Apart from a significant with reduced GBEF had significant improvement in GBEF improvement in GBEF on HBS (19% to 74%, p < 0.001), the GBEF parameters as assessed by both HBS (increase to 74% from also improved significantly as assessed by USG parameters after 19%) and USG (increase to 52% from 24%), indicating that a GFD (p < 0.001). The fasting GB volume reduced, with significant GFD can reverse the abnormalities of GB motility in children Das improvement in postprandial percentage GB volume change with CD. GFD results in the reconstitution of normal villous et al., compared to baseline pre-GFD values”. architecture with return of normal CCK cell function, leading 2021 -“A subgroup analysis was done comparing children with normal to an improvement in GB motility”. and reduced GBEF (Table 3). Mean delay in diagnosis (6.5 ± 2.0 vs. -“To conclude, GB dysmotility can occur in children with CD, 2.3 ± 1.2 years, p < 0.001) and OCTT (96.2 ± 14 vs. 56.1 ± 12 min, especially if the diagnosis is delayed, but it is reversible with p < 0.001) were significantly higher in children with reduced GBEF. adherence to GFD. GB hypomotility may translate into [... ] The delay in diagnosis had a significant negative correlation gallstone disease, with its related complications, in adulthood with baseline GBEF on HBS (r = −0.5, p < 0.001) and percentage if CD is left untreated”. postprandial GB volume change on USG (r = −0.3, p < 0.01), [... ]”. Abbreviations: ref., reference number; CCK, cholecystokinin; PZ, pancreozymin; GIP, gastric inhibitory peptide; GB, gallbladder; S.E.M., standard error of the mean; GBEF, gallbladder ejection fraction; CMPE, cow’s milk protein enteropathy; IELs, intraepithelial lymphocytes; i.v., intravenous administration; i.d., intra-duodenal administration; n or N, number. Overall, considering all the available and more recent studies included in Tables 1 and 2, most evidence supports an impaired CCK release into the bloodstream rather than a reduced sensitivity of the gallbladder to CCK. Indeed, several studies also assessed the histological pattern of enteroendocrine cells in the jejunal mucosa and CCK levels of CD patients. Whereas Sjolund et al. and Pietroletti et al. described an increased number of CCK- positive cells in untreated CD patients [26,30], other studies did not confirm this finding and actually found normal or non-significantly reduced CCK-positive enteroendocrine cells in CD patients [27,32,38]. In detail, the study by Calam et al. and especially another one by Deprez et al. further indicated a reduction of CCK plasmatic levels after a meal in CD patients, which can be linked to an impaired production and release of CCK by these specific enteroendocrine cells rather than a decrease in their number [27,37]. Notably, Thimister et al. suggested that such an impaired postprandial CCK release with consequent poor gallbladder contraction in CD patients are not related to general abnormalities in CCK-secreting capacity but to impaired stimulation by nutrients on these enteroendocrine cells. In addition, to further confirm the impairment of CCK secretion in CD patients, Maton et al. provided the first evidence that the impaired CCK release and gallbladder motility can be reversible after GFD. In addition to oral cholecystography and hepatobiliary scintigraphy, “gallbladder iner- tia” has also been demonstrated by real-time ultrasonography. Delamarre et al. performed it for the first time , and all eventual clinical investigations on this matter have relied on this approach since the end of 1990 [34,35,37,40]. Among them, the study by Fraquelli et al. also assessed the somatostatin levels in addition to those of CCK with respect to gallblad- der motility. They observed increased circulating levels of somatostatin in untreated CD patients, which they suggested causing increased gallbladder fasting volume, in addition Nutrients 2022, 14, 4379 12 of 16 to further supporting an impairment of CCK secretion as a main mechanism leading to the defective gallbladder motor response to a fatty meal. There is no additional re- search investigating the somatostatin homeostasis and actions in CD specifically; however, several studies confirmed its inhibitory effect on gallbladder contraction in general, even during the postprandial phase. Indeed, it may reduce the plasmatic levels of several gut hormones, including CCK, [46–48] which plays a major role in gallbladder contractions and is impaired in CD patients, as discussed above. Regarding the potential role of other gut hormones in CCK plasmatic levels and, thus, the gallbladder dyskinesia in CD, Wahab et al. analyzed peptide YY kinetics in CD patients. They found a strong correlation between plasma peptide YY and plasma CCK, and suggested that the release of CCK in response to digested fat could partially contribute to an increase in peptide YY response to digested fat in these patients. Moreover, Hoentgen et al. concluded that peptide YY can suppress the cephalic phase of postprandial gallbladder emptying but not meal-stimulated maxi- mum emptying, according to their study on both healthy volunteers and untreated CD patients. Most clinical studies included adult CD patients only; however, those few and more recent studies on children seem to confirm the observations made in the adult population overall [30,39,41]. Nousia-Arvanitakis et al. confirmed that plasma CCK release in response to oral nutrients is decreased in untreated CD children; notably, they linked this finding to the presence of intestinal mucosal atrophy in general since a similar response was also observed in patients affected with a different disease, namely cow’s milk protein enteropathy. Das et al. documented gallbladder dysmotility in CD children, which was reversible after GFD. 4. Is There Any Clinical Implication of Gallbladder Dysfunction in Celiac Disease? Despite a clear demonstration of CD-related CCK perturbation and gallbladder motor dysfunction, clinical studies focused on gallbladder disease in CD patients are scarce. No- tably, most pathophysiological studies were published before 2005, perhaps indicating a decreased interest in this specific matter in the last two decades for some reasons. Probably, as mentioned in the introduction, researchers paid the most attention to the liver complica- tions and/or comorbidity of CD, which can be definitely more relevant in terms of both severity and frequency compared to gallbladder disorders. Indeed, in addition to the number of studies documenting gallbladder dyskinesia, some research also documented an altered biliary output and bile salt composition in CD patients (as discussed in the previous section), which could theoretically promote the formation of gallstones in these patients. In general, no significant predisposition to gallbladder gallstones and/or calculous cholecystitis has clearly emerged so far. However, very few studies actively investigated these specific aspects in CD, and gallstones- related problems in these patients may have not been completely noticed. Otherwise, we should also consider the great improvement in CD diagnosis and management in the last two decades, which has significantly reduced the diagnostic delay (even in atypical and/or mild forms) and allowed a prompt implementation of GFD, at least in developed countries [51–53]; as a consequence, CD-related gallbladder disease may manifest much less frequently than in the case of a longer clinical history without diagnosis and dietary therapy, which can reverse CCK alterations and gallbladder dysmotility, as previously highlighted. This second hypothesis may be partially or indirectly supported by the study by Freeman, who reported 6 cases (20%) of gallstones in a case series including 30 CD patients diagnosed in the elderly. Notably, all of them were reported to have a “severely abnormal flat small intestinal biopsy”. Therefore, one might speculate that these elderly CD patients could have received a more delayed diagnosis compared to younger patients, which may have contributed to a greater detection rate of gallstones. Indeed, only one case report described a child diagnosed with CD after developing acute calculous cholecystitis. Very recently, Agin et al. investigated the frequency of gallstones in children with CD. Gallstones were detected in 6 out of 120 (5%) of CD children Nutrients 2022, 14, 4379 13 of 16 and in 3 out of 100 (3%) controls: no significant difference was reported. However, the tim- ing of abdominal ultrasonography in the study population is not clearly stated, especially with respect to the GFD. Nonetheless, the authors concluded that the early diagnosis and treatment of CD could play a role in preventing the development of gallstones. Gallbladder disease is not only represented by gallstones formation and their potential complications. Indeed, cholecystitis can also occur in the absence of gallstones. Acalculous cholecystitis is more often detected in critically ill patients and less frequently in patients with immune-mediated comorbidities; however, it can even occur in previously healthy individuals. Infections (especially viral) are often detected in the latter category , whereas bile stasis, gallbladder ischemia, and inflammatory injury have been variably implicated in (critically) ill patients developing acute acalculous cholecystitis. A re- cent study also demonstrated a sluggish to paretic gallbladder emptying in response to a small intestinal lipid meal in most critically ill patients developing acute acalculous cholecystitis. Such a gallbladder motor impairment could promote mucosal injury, hypoperfusion, parietal ischemia, and secondary infection of the gallbladder, which are the main mechanisms considered in the pathogenesis of acute acalculous cholecystitis, as men- tioned above. However, no well-defined acute acalculous cholecystitis cases have been associated with CD in children and adults, despite the gallbladder dyskinesia in untreated patients. Parfenov et al. described a case of “chronic acalculous cholecystitis” in a 40-year CD patient. This disorder is usually defined as a prolonged inflammatory condition affecting the gallbladder, but the diagnostic criteria are variable and thus not well defined. It is usually considered in patients with a variable combination of symptoms, including recurrent biliary pain ranging from colic to vague discomfort in the upper abdominal right quadrant, and nonspecific complaints, such as nausea, reflux, bloating. Ultrasonography could reveal unspecific findings, including cholelithiasis and gallbladder wall thickening in some cases; notably, clinical studies using gallbladder scintigraphy have pinpointed that a gallbladder affected with chronic cholecystitis has an abnormal contraction, and an impaired/reduced gallbladder ejection fraction is consistent with this diagnosis [62–64]. As discussed in the previous section, gallbladder dyskinesia is well demonstrated in CD patients, and the clinical picture of chronic cholecystitis often overlaps with (functional) recurrent abdominal pain and/or dyspeptic syndromes, which are a frequent complaint in CD patients as well [65–67]. Therefore, gallbladder dysfunction might contribute to this kind of manifestation in CD patients. However, there are no specific studies in this specific regard that have assessed the frequency of dyspeptic symptoms and/or right upper abdominal pain at the time of CD diagnosis (rather than the prevalence of CD diagnosis in patients with these complaints) and their correlation with gallbladder contractility after a meal. Very recently, Voss et al. analyzed several hepatobiliary disorders in patients affected with chronic intestinal disorders, including CD, by using the ‘UK biobank’ (UKB), which is a population-based cohort study built up in the United Kingdom from 2006 to 2010. Among 2377 individuals with CD, 6.1% received a diagnosis of cholelithiasis, which was significantly higher than controls (3.9%, p < 0.001); only 1.1% were diagnosed with unspec- ified cholecystitis. This value was greater than that observed in controls (0.7%), but the difference did not reach the statistical significance (p = 0.071). Therefore, although one may speculate that gallbladder dysfunction may contribute to some dyspeptic complaints in CD patients, there are no clinical studies investigating this specific aspect, and no final conclusion can be made in this regard. 5. Conclusions In addition to some perturbations of bile composition, CD patients can develop gall- bladder dysmotility, characterized by an impaired emptying during the digestive phase. The main pathophysiological determinant is a perturbation of CCK secretion by the specific duodenal enteroendocrine cells in response to the appropriate nutrients stimulation in CD patients. This situation appears to be reversible with GFD in most cases. Despite the gallbladder impairment, CD patients do not seem to be more predisposed to gallbladder Nutrients 2022, 14, 4379 14 of 16 complications, such as calculous and acalculous cholecystitis. However, very few clinical studies actively investigated these specific aspects, which may have not been completely evidenced; moreover, the substantial improvements in the last two decades regarding CD diagnosis, which have reduced the diagnostic delay (and related dietary treatment), may have lessened the potential clinical consequences and complications of CD-related gallbladder dysfunction, in terms of additional impairment of digestive processes and/or calculous/acalculous gallbladder disease. Specific clinical studies focused on these aspects are needed for a better understanding of the clinical implications of gallbladder alterations in CD patients. Case–control studies actively investigating gallbladder dysfunction in CD patients could better define the prevalence of this clinical issue in larger cohorts of patients. 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