Ignite Creation Date:
2024-05-06 @ 7:58 PM
Last Modification Date:
2024-10-26 @ 3:18 PM
Study NCT ID:
NCT06206616
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-03-18
First Post:
2024-01-04
Brief Title:
Liver Steatosis in Pediatric CD Patients
Sponsor:
University of Palermo
Organization:
University of Palermo
Study Overview
Official Title:
Liver Steatosis in Pediatric Celiac Disease Patients Exploring the Epidemiological and Pathophysiological Features of an Underestimated Condition
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Celiac disease CD is an autoimmune enteropathy triggered by the intake of gluten characterized by a genetic predisposition Although CD is often associated with malabsorption symptoms a growing number of affected subjects are overweight or frankly obese One of the conditions that is most frequently detected in pauciasymptomatic subjects is an increase in transaminases which often regresses completely after the start of GFD
More recently a specific liver disorder has shown a certain relevance in adult patients suffering from CD so much so that the European Society for the Study of Coeliac Disease ESsCD has cited it among the possible comorbidities which should be screened in CD subjects Non-Alcoholic Fatty Liver Disease NAFLD
In adults a non-random association between CD and NAFLD has been demonstrated showing a CD prevalence rate of 2-14 among patients with NAFLD Few studies have focused on this same aspect in pediatric age reporting contrasting data
Several factors have been advocated as putative responsible of association between CD and NAFLD dietary imbalances intestinal mucosa permeability impairment alterations of the intestinal microbiota
The objectives of this study are
1 define retrospectively the prevalence of NAFLD in a pediatric population affected by CD and study its possible association with GFD
2 define the possible role of the intestinal permeability alteration andor the intestinal mucosa damage andor the proinflammatory status in the development of NAFLD in children affected by CD
More recently a specific liver disorder has shown a certain relevance in adult patients suffering from CD so much so that the European Society for the Study of Coeliac Disease ESsCD has cited it among the possible comorbidities which should be screened in CD subjects Non-Alcoholic Fatty Liver Disease NAFLD
In adults a non-random association between CD and NAFLD has been demonstrated showing a CD prevalence rate of 2-14 among patients with NAFLD Few studies have focused on this same aspect in pediatric age reporting contrasting data
Several factors have been advocated as putative responsible of association between CD and NAFLD dietary imbalances intestinal mucosa permeability impairment alterations of the intestinal microbiota
The objectives of this study are
1 define retrospectively the prevalence of NAFLD in a pediatric population affected by CD and study its possible association with GFD
2 define the possible role of the intestinal permeability alteration andor the intestinal mucosa damage andor the proinflammatory status in the development of NAFLD in children affected by CD
Detailed Description:
Background Celiac disease CD an autoimmune enteropathy triggered by the intake of gluten is a widespread pathology with a worldwide estimated prevalence of approximately 1 characterized by both gastrointestinal and systemic symptoms both in adults and children which are usually resolved by eliminating gluten from the diet Gluten-Free Diet GFD However it still remains an under-diagnosed condition to date the overall prevalence in Italy is 037 and in Sicily 035
Although CD is often associated with malabsorption symptoms steatorrhea weight loss nutritional deficits etc a growing number of affected subjects are overweight or frankly obese One of the conditions that is most frequently detected in pauciasymptomatic subjects is an increase in transaminases which often regresses completely after the start of GFD
More recently a specific liver disorder has shown a certain relevance in patients suffering from CD so much so that the European Society for the Study of Coeliac Disease ESsCD has cited it among the possible comorbidities which should be screened in CD subjects Non-Alcoholic Fatty Liver Disease NAFLD This condition affects approximately 34 of overweight or frankly obese children and is closely related both in children and adults to the traits of metabolic syndrome so much so that today it is preferably referred to as Metabolic Dysfunction-Associated Steatotic Liver Disease MASLD In adults a non-random association between CD and NAFLD has been demonstrated showing a CD prevalence of 2-14 among patients with NAFLD Few studies have focused on this same aspect in pediatric age however reporting that the prevalence of CD among children with NAFLD could be comparable to the prevalence of CD in the general pediatric population Nevertheless a study conducted on 11488 children 0-19 years affected by CD compared with 57029 healthy children supports the hypothesis of a close association between CD and NAFLD in childhood Authors proved a 46 relative risk value of NAFLD in CD patients
Several factors have been advocated as putative responsible for this association 1 dietary imbalances due to the adoption of GFD rich in fats and sugars and low in fiber 2 alteration of intestinal permeability with an increase in the translocation of bacterial substances from the gut which are transported directly to the liver where they are able to generate inflammatory processes mediated by the nuclear factor kappa-light-chain-enhancer of activated B cells NF-kB activated by the Tool-like receptor 4 TLR4-Lipopolysaccharide LPS-LPS Binding Protein LPB complex with production of proinflammatory cytokines Tumor Necrosis Factor TNF-α Interleukine IL-1β IL-6 IL-12 IL-18 3 alterations of the intestinal microbiota
Objectives
Primary objective define retrospectively the prevalence of NAFLD in a pediatric population affected by CD and study its possible association with GFD
Objective 11 identify the prevalence of NAFLD before the introduction of the GFD in an already diagnosed pediatric celiac Objective 12 identify the prevalence of NAFLD after at least 12 months of GFD in an already diagnosed pediatric celiac Objective 13 compare the prevalence of NAFLD before and after at least 12 months the introduction of the GFD in all pediatric celiac patients for whom both pre- and post-GFD data are available Objective 14 establish a possible correlation between the presenceabsence of NAFLD both before and after the adoption of the GFD and clinical laboratory immunological genetic and histological parameters in order to identify a subgroup of celiac children potentially predisposed to the NAFLD development Objective 15 establish any changes in the clinical laboratory immunological genetic and histological parameters of the population referred to in objective 13 and establish whether there is a correlation between these and the possible onsetregression of NAFLD
Secondary objective define the possible role of the intestinal permeability alteration andor the intestinal mucosa damage andor the proinflammatory status in the development of NAFLD in children affected by CD
Objective 21 identify the possible presence of serological markers of altered intestinal permeability andor intestinal mucosa damage in a population of celiac children prospectively enrolled at the Pediatric Clinic of the Childrens Hospital G Di Cristina before the start of the GFD T0
Objective 22 Identify the possible presence of blood markers of inflammation in the population referred to in point 21 at T0
Objective 23 define the existence of an association between the markers of altered intestinal permeability andor mucosal damage andor inflammation and the presence of NAFLD in the population referred to in point 21 at T0
Objective 24 evaluate any changes in serological markers of altered intestinal permeability andor mucosal damage in the population referred to in point 21 after 6 months of strict adherence to the GFD T1
Objective 25 evaluate any changes in blood markers of inflammation in the population referred to in point 21 at T1
Objective 26 define the existence of an association between the markers of altered intestinal permeability andor mucosal damage andor inflammation and the presence of NAFLD in the population referred to in point 21 at T1
Materials and methods Primary objective To achieve the primary objective of the study all the medical records of pediatric patients suffering from CD already diagnosed according to the European Society for Paediatric Gastroenterology Hepatology and Nutrition ESPGHAN criteria at the Pediatric Clinic of the Childrens Hospital G Di Cristina will be retrospectively analyzed
Objectives 11 12 and 13 To achieve objectives 11 and 12 the presence and degree of steatosis diagnosed by abdominal ultrasound will be assessed before the start of the GFD objective 11 or after at least 12 months from the introduction of the GFD objective 12
To achieve objective 13 a sub-analysis of the presence and degree of steatosis will be performed in all those patients who have undergone an abdominal ultrasound both before and after the introduction of GFD
Objectives 14 and 15 To achieve objective 14 clinical sex ethnicity age at diagnosis BMI symptoms duration of GFD laboratory transaminasemia albuminemia total cholesterolemia and subclasses triglyceridemia fasting glycemia insulinemia Homeostasis Model Assessment-Insulin Resistance HOMA-IR Index immunological anti-gliadin antibodies AGA anti-tissue transglutaminase antibodies tTG anti-endomysial antibodies EMA genetic HLA structure and histological Marsh duodenal histological classification presence of eosinophilic infiltration etc data of all included patients will be collect both before target population 11 and after target population 12 the introduction of the GFD
To achieve objective 15 the same clinical laboratory immunological genetic and histological parameters analyzed for objective 14 will be analyzed if available both before and after the introduction of the GFD in order to establish whether there is a correlation between these and the possible onsetregression of NAFLD in the population referred to in objective 13
Secondary objective To achieve the secondary objective of the study pediatric patients affected by newly diagnosed CD according to the ESPGHAN criteria will be prospectively enrolled at the at the Pediatric Clinic of the Childrens Hospital G Di Cristina The number of subjects to be enrolled will be equal to 91 considering in the Province of Palermo Sicily Italy a pediatric population between 0 and 14 years of 170468 subjects a prevalence of CD equal to 1 a confidence level of 95 and a confidence interval of 10 Furthermore as the exact prevalence of NAFLD in children with CD its not clearly defined results derived from the retrospective part of this study objective 11 will be used to maintain a proportion between subjects enrolled without and with pre-GFD NAFLD competitive enrollment
Objectives 21 22 23 To achieve objective 21 all enrolled subjects for whom the same clinical laboratory immunological genetic and histological parameters analyzed for objective 14 must be available the latter only if necessary for diagnosis in order to make a comparison possible will be subjected to blood sampling for the identification of serological markers of altered intestinal permeability zonulin Zo occludin OCLN anti-OCLN antibodies claudin 1 CLDN1 and anti-CLDN1 antibodies and mucosal damage Intestinal Fatty Acid Binding Protein 2 iFABP2 lipopolysaccharide LPS lipopolysaccharide binding protein LPB before starting the GFD T0 The blood sampling will coincide with the one necessary for the diagnostic definition of the patients clinical picture
To achieve objective 22 all enrolled subjects will undergo a blood sample before starting the GFD T0 for the identification of the following inflammatory markers TNF-α IL-1β IL-6 IL-12 IL-18 The blood sampling will coincide with the one necessary for the diagnostic definition of the patients clinical picture
To achieve objective 23 all enrolled subjects before starting the GFD T0 will undergo an abdominal ultrasound to study hepatic steatosis according to the methods previously described and a statistical correlation analysis will be carried out between the presenceabsence of NAFLD and the markers assayed for objective 21 and 22
The assay of intestinal permeability and mucosal damage markers will be carried out using the ELISA method with commercially available kits following the manufacturers instructions
The measurement of inflammation markers will be performed by intracellular staining with flow cytometric method on peripheral blood mononuclear cells PBMC extracted from patients blood samples
Objectives 24 25 26 To achieve objective 24 all enrolled subjects for whom the same clinical laboratory and immunological parameters analyzed at T0 must be available in order to make a comparison possible will be subjected to a blood sample for the identification of serological markers of altered intestinal permeability and mucosal damage already measured at T0 see objective 21 after 6 months of strict adherence to the GFD T1 The blood sampling will coincide with the one necessary to re-evaluate the patients clinical picture after 6 months of adherence to the GFD
To achieve objective 25 all enrolled subjects will undergo a blood sample to identify the inflammation markers already dosed at T0 see objective 22 after 6 months of strict adherence to the GFD T1 The blood sampling will coincide with the one necessary to re-evaluate the patients clinical picture after 6 months of adherence to the GFD
To achieve objective 26 all enrolled subjects after 6 months of strict adherence to the GFD T1 will undergo abdominal ultrasound to study hepatic steatosis according to the methods previously described and a statistical correlation analysis will be carried out between the presenceabsence of NAFLD and the markers assayed for objective 24 and 25
The assessment of adherence to the GFD will be carried out through the monthly compilation by the children andor their parents of a specifically created and validated questionnaire
Although CD is often associated with malabsorption symptoms steatorrhea weight loss nutritional deficits etc a growing number of affected subjects are overweight or frankly obese One of the conditions that is most frequently detected in pauciasymptomatic subjects is an increase in transaminases which often regresses completely after the start of GFD
More recently a specific liver disorder has shown a certain relevance in patients suffering from CD so much so that the European Society for the Study of Coeliac Disease ESsCD has cited it among the possible comorbidities which should be screened in CD subjects Non-Alcoholic Fatty Liver Disease NAFLD This condition affects approximately 34 of overweight or frankly obese children and is closely related both in children and adults to the traits of metabolic syndrome so much so that today it is preferably referred to as Metabolic Dysfunction-Associated Steatotic Liver Disease MASLD In adults a non-random association between CD and NAFLD has been demonstrated showing a CD prevalence of 2-14 among patients with NAFLD Few studies have focused on this same aspect in pediatric age however reporting that the prevalence of CD among children with NAFLD could be comparable to the prevalence of CD in the general pediatric population Nevertheless a study conducted on 11488 children 0-19 years affected by CD compared with 57029 healthy children supports the hypothesis of a close association between CD and NAFLD in childhood Authors proved a 46 relative risk value of NAFLD in CD patients
Several factors have been advocated as putative responsible for this association 1 dietary imbalances due to the adoption of GFD rich in fats and sugars and low in fiber 2 alteration of intestinal permeability with an increase in the translocation of bacterial substances from the gut which are transported directly to the liver where they are able to generate inflammatory processes mediated by the nuclear factor kappa-light-chain-enhancer of activated B cells NF-kB activated by the Tool-like receptor 4 TLR4-Lipopolysaccharide LPS-LPS Binding Protein LPB complex with production of proinflammatory cytokines Tumor Necrosis Factor TNF-α Interleukine IL-1β IL-6 IL-12 IL-18 3 alterations of the intestinal microbiota
Objectives
Primary objective define retrospectively the prevalence of NAFLD in a pediatric population affected by CD and study its possible association with GFD
Objective 11 identify the prevalence of NAFLD before the introduction of the GFD in an already diagnosed pediatric celiac Objective 12 identify the prevalence of NAFLD after at least 12 months of GFD in an already diagnosed pediatric celiac Objective 13 compare the prevalence of NAFLD before and after at least 12 months the introduction of the GFD in all pediatric celiac patients for whom both pre- and post-GFD data are available Objective 14 establish a possible correlation between the presenceabsence of NAFLD both before and after the adoption of the GFD and clinical laboratory immunological genetic and histological parameters in order to identify a subgroup of celiac children potentially predisposed to the NAFLD development Objective 15 establish any changes in the clinical laboratory immunological genetic and histological parameters of the population referred to in objective 13 and establish whether there is a correlation between these and the possible onsetregression of NAFLD
Secondary objective define the possible role of the intestinal permeability alteration andor the intestinal mucosa damage andor the proinflammatory status in the development of NAFLD in children affected by CD
Objective 21 identify the possible presence of serological markers of altered intestinal permeability andor intestinal mucosa damage in a population of celiac children prospectively enrolled at the Pediatric Clinic of the Childrens Hospital G Di Cristina before the start of the GFD T0
Objective 22 Identify the possible presence of blood markers of inflammation in the population referred to in point 21 at T0
Objective 23 define the existence of an association between the markers of altered intestinal permeability andor mucosal damage andor inflammation and the presence of NAFLD in the population referred to in point 21 at T0
Objective 24 evaluate any changes in serological markers of altered intestinal permeability andor mucosal damage in the population referred to in point 21 after 6 months of strict adherence to the GFD T1
Objective 25 evaluate any changes in blood markers of inflammation in the population referred to in point 21 at T1
Objective 26 define the existence of an association between the markers of altered intestinal permeability andor mucosal damage andor inflammation and the presence of NAFLD in the population referred to in point 21 at T1
Materials and methods Primary objective To achieve the primary objective of the study all the medical records of pediatric patients suffering from CD already diagnosed according to the European Society for Paediatric Gastroenterology Hepatology and Nutrition ESPGHAN criteria at the Pediatric Clinic of the Childrens Hospital G Di Cristina will be retrospectively analyzed
Objectives 11 12 and 13 To achieve objectives 11 and 12 the presence and degree of steatosis diagnosed by abdominal ultrasound will be assessed before the start of the GFD objective 11 or after at least 12 months from the introduction of the GFD objective 12
To achieve objective 13 a sub-analysis of the presence and degree of steatosis will be performed in all those patients who have undergone an abdominal ultrasound both before and after the introduction of GFD
Objectives 14 and 15 To achieve objective 14 clinical sex ethnicity age at diagnosis BMI symptoms duration of GFD laboratory transaminasemia albuminemia total cholesterolemia and subclasses triglyceridemia fasting glycemia insulinemia Homeostasis Model Assessment-Insulin Resistance HOMA-IR Index immunological anti-gliadin antibodies AGA anti-tissue transglutaminase antibodies tTG anti-endomysial antibodies EMA genetic HLA structure and histological Marsh duodenal histological classification presence of eosinophilic infiltration etc data of all included patients will be collect both before target population 11 and after target population 12 the introduction of the GFD
To achieve objective 15 the same clinical laboratory immunological genetic and histological parameters analyzed for objective 14 will be analyzed if available both before and after the introduction of the GFD in order to establish whether there is a correlation between these and the possible onsetregression of NAFLD in the population referred to in objective 13
Secondary objective To achieve the secondary objective of the study pediatric patients affected by newly diagnosed CD according to the ESPGHAN criteria will be prospectively enrolled at the at the Pediatric Clinic of the Childrens Hospital G Di Cristina The number of subjects to be enrolled will be equal to 91 considering in the Province of Palermo Sicily Italy a pediatric population between 0 and 14 years of 170468 subjects a prevalence of CD equal to 1 a confidence level of 95 and a confidence interval of 10 Furthermore as the exact prevalence of NAFLD in children with CD its not clearly defined results derived from the retrospective part of this study objective 11 will be used to maintain a proportion between subjects enrolled without and with pre-GFD NAFLD competitive enrollment
Objectives 21 22 23 To achieve objective 21 all enrolled subjects for whom the same clinical laboratory immunological genetic and histological parameters analyzed for objective 14 must be available the latter only if necessary for diagnosis in order to make a comparison possible will be subjected to blood sampling for the identification of serological markers of altered intestinal permeability zonulin Zo occludin OCLN anti-OCLN antibodies claudin 1 CLDN1 and anti-CLDN1 antibodies and mucosal damage Intestinal Fatty Acid Binding Protein 2 iFABP2 lipopolysaccharide LPS lipopolysaccharide binding protein LPB before starting the GFD T0 The blood sampling will coincide with the one necessary for the diagnostic definition of the patients clinical picture
To achieve objective 22 all enrolled subjects will undergo a blood sample before starting the GFD T0 for the identification of the following inflammatory markers TNF-α IL-1β IL-6 IL-12 IL-18 The blood sampling will coincide with the one necessary for the diagnostic definition of the patients clinical picture
To achieve objective 23 all enrolled subjects before starting the GFD T0 will undergo an abdominal ultrasound to study hepatic steatosis according to the methods previously described and a statistical correlation analysis will be carried out between the presenceabsence of NAFLD and the markers assayed for objective 21 and 22
The assay of intestinal permeability and mucosal damage markers will be carried out using the ELISA method with commercially available kits following the manufacturers instructions
The measurement of inflammation markers will be performed by intracellular staining with flow cytometric method on peripheral blood mononuclear cells PBMC extracted from patients blood samples
Objectives 24 25 26 To achieve objective 24 all enrolled subjects for whom the same clinical laboratory and immunological parameters analyzed at T0 must be available in order to make a comparison possible will be subjected to a blood sample for the identification of serological markers of altered intestinal permeability and mucosal damage already measured at T0 see objective 21 after 6 months of strict adherence to the GFD T1 The blood sampling will coincide with the one necessary to re-evaluate the patients clinical picture after 6 months of adherence to the GFD
To achieve objective 25 all enrolled subjects will undergo a blood sample to identify the inflammation markers already dosed at T0 see objective 22 after 6 months of strict adherence to the GFD T1 The blood sampling will coincide with the one necessary to re-evaluate the patients clinical picture after 6 months of adherence to the GFD
To achieve objective 26 all enrolled subjects after 6 months of strict adherence to the GFD T1 will undergo abdominal ultrasound to study hepatic steatosis according to the methods previously described and a statistical correlation analysis will be carried out between the presenceabsence of NAFLD and the markers assayed for objective 24 and 25
The assessment of adherence to the GFD will be carried out through the monthly compilation by the children andor their parents of a specifically created and validated questionnaire
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None