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Adams DW, Moleski S, Jossen J, Tye-Din JA. Clinical Presentation and Spectrum of Gluten Symptomatology in Celiac Disease. Gastroenterology 2024; 167:51-63. [PMID: 38636679 DOI: 10.1053/j.gastro.2024.01.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/31/2023] [Accepted: 01/02/2024] [Indexed: 04/20/2024]
Abstract
Views on the clinical presentation and symptomatology of celiac disease have evolved alongside advances in disease detection and understanding of disease pathogenesis. Although historically regarded as a pediatric illness characterized by malabsorption, it is now better viewed as an immune illness of gluten-specific T cells with systemic manifestations affecting all ages. Its broad presentation, including frequent extraintestinal manifestations and asymptomatic disease, contributes to suboptimal disease detection. Adverse symptoms greatly impact patient quality of life and can result from chronic gluten exposure in untreated disease or those poorly responsive to the gluten-free diet. They can also present as acute symptoms after episodic gluten exposure. Functional gastrointestinal disease is a common comorbidity. Biomarkers like interleukin-2 that are highly sensitive and specific for celiac disease highlight a role for gluten-specific T cells in acute gluten symptomatology. A mechanistic understanding of symptoms will inform approaches to better measure and treat them effectively.
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Affiliation(s)
- Dawn W Adams
- Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Stephanie Moleski
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | - Jacqueline Jossen
- Departments of Medicine and Pediatrics, The Celiac Disease Center at Columbia University, New York, New York
| | - Jason A Tye-Din
- Immunology Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
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De Giuseppe R, Bergomas F, Loperfido F, Giampieri F, Preatoni G, Calcaterra V, Cena H. Could Celiac Disease and Overweight/Obesity Coexist in School-Aged Children and Adolescents? A Systematic Review. Child Obes 2024; 20:48-67. [PMID: 36602771 DOI: 10.1089/chi.2022.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Background: Celiac disease (CD) is a multifactorial, immune-mediated enteropathic disorder that may occur at any age with heterogeneous clinical presentation. In the last years, unusual manifestations have become very frequent, and currently, it is not so uncommon to diagnose CD in subjects with overweight or obesity, especially in adults; however, little is known in the pediatric population. This systematic review aims to evaluate the literature regarding the association between CD and overweight/obesity in school-age children. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. An electronic database search of articles published in the last 20 years in English was carried out in Web of Sciences, PubMed, and Medline. The quality of the included studies was assessed by using the STrengthening the Reporting of OBservational studies in Epidemiology statement. Results: Of the 1396 articles identified, 9 articles, investigating overweight/obesity in children/adolescents affected by CD or screening CD in children/adolescents with overweight/obesity, met the inclusion criteria. Overall, the results showed that the prevalence of overweight or obesity in school-age children (6-17 years) affected by CD ranged between 3.5% and 20%, highlighting that the coexistence of CD with overweight/obesity in children is not uncommon as previously thought. Conclusion: Although CD has been historically correlated with being underweight due to malabsorption, it should be evaluated also in children with overweight and obesity, especially those who have a familiar predisposition to other autoimmune diseases and/or manifest unusual symptoms of CD.
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Affiliation(s)
- Rachele De Giuseppe
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
| | - Francesca Bergomas
- Scuola di Specializzazione in Scienza dell'Alimentazione, Università degli Studi di Milano, Milano, Italy
| | - Federica Loperfido
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
- Scuola di Specializzazione in Scienza dell'Alimentazione, Università degli Studi di Pavia, Pavia, Italy
| | - Francesca Giampieri
- Research Group on Food, Nutritional Biochemistry, and Health, Universidad Europea del Atlántico, Santander, Spain
| | - Giorgia Preatoni
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
| | - Valeria Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Unit, "V. Buzzi" Children's Hospital, Milano, Italy
| | - Hellas Cena
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
- Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, ICS Maugeri IRCCS, Pavia, Italy
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Mędza A, Szlagatys-Sidorkiewicz A. Nutritional Status and Metabolism in Celiac Disease: Narrative Review. J Clin Med 2023; 12:5107. [PMID: 37568509 PMCID: PMC10419423 DOI: 10.3390/jcm12155107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/20/2023] [Accepted: 08/01/2023] [Indexed: 08/13/2023] Open
Abstract
This review summarizes findings from studies assessing the nutritional status of patients with celiac disease (CD). Malnutrition, including over- and undernutrition, may be present in CD, both at diagnosis and while under treatment. Underweight and growth retardation in children, which mostly reflect malabsorption as a consequence of intestinal inflammation, are not a rule. Clinical presentations of CD can vary widely, and each manifestation has its own characteristics. Evaluating various nutritional parameters can be beneficial for CD patients and may improve health outcomes by facilitating an accurate definition of dietary needs and the development of a balanced diet that not only focuses on eliminating gluten but also provides adequate nutrients, alters metabolism, and reduces the risk of other disorders developing. The cornerstone of CD therapy is a gluten-free diet (GFD), which improves nutritional status, but even on a GFD, features of malnutrition may be present. Additionally, overweight and obesity may occur in patients on a GFD, with typical metabolic consequences.
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Affiliation(s)
- Aleksandra Mędza
- Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Copernicus Hospital, Nowe Ogrody 1-6, 80-803 Gdansk, Poland
| | - Agnieszka Szlagatys-Sidorkiewicz
- Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Medical University of Gdańsk, 80-210 Gdansk, Poland;
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Sahin Y. Celiac disease in children: A review of the literature. World J Clin Pediatr 2021; 10:53-71. [PMID: 34316439 PMCID: PMC8290992 DOI: 10.5409/wjcp.v10.i4.53] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/23/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Celiac disease is an immune-mediated systemic disease triggered by intake of gluten in genetically susceptible individuals. The prevalence of celiac disease in the general population is estimated to be 1% in the world. Its prevalence differs depending on geographical and ethnic variations. The prevalence of celiac disease has increased significantly in the last 30 years due to the increased knowledge and awareness of physicians and the widespread use of highly sensitive and specific diagnostic tests for celiac disease. Despite increased awareness and knowledge about celiac disease, up to 95% of celiac patients still remain undiagnosed. The presentations of celiac disease have significantly changed in the last few decades. Classical symptoms of celiac disease occur in a minority of celiac patients, while older children have either minimal or atypical symptoms. Serologic tests for celiac disease should be done in patients with unexplained chronic or intermittent diarrhea, failure to thrive, weight loss, delayed puberty, short stature, amenorrhea, iron deficiency anemia, nausea, vomiting, chronic abdominal pain, abdominal distension, chronic constipation, recurrent aphthous stomatitis, and abnormal liver enzyme elevation, and in children who belong to specific groups at risk. Early diagnosis of celiac disease is very important to prevent long-term complications. Currently, the only effective treatment is a lifelong gluten-free diet. In this review, we will discuss the epidemiology, clinical findings, diagnostic tests, and treatment of celiac disease in the light of the latest literature.
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Affiliation(s)
- Yasin Sahin
- Pediatric Gastroenterology-Hepatology and Nutrition, Medical Park Gaziantep Hospital, Gaziantep 27560, Turkey
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Abstract
OBJECTIVES During the past decades, there has been a shift in the clinical presentation of coeliac disease (CD) to nonclassical, oligosymptomatic, and asymptomatic forms. We assessed clinical presentation of CD in children and adolescents in Central Europe. METHODS Paediatric gastroenterologists in 5 countries retrospectively reported data of their patients diagnosed with CD. Clinical presentation was analyzed and the differences among very young (<3 years) and older children and adolescents were studied. RESULTS Data from 653 children and adolescents (median age 7 years 2 months; 63.9% girls) from Croatia, Germany, Hungary, Italy, and Slovenia were available for the analysis. One fifth (N = 134) of all children were asymptomatic. In symptomatic children, the most common leading symptom was abdominal pain (33.3%), followed by growth retardation (13.7%) and diarrhoea (13.3%). The majority of symptomatic children (47.6%; N = 247) were polysymptomatic. Abdominal pain was the most common symptom in polysymptomatic (66.4%) as well as in monosymptomatic children (29.7%). Comparing clinical presentation of CD in very young children (younger than 3 years) with older children (3 years or older), we found that symptoms and signs of malabsorption were significantly more common in younger (P < 0.001), whereas abdominal pain and asymptomatic presentation were more common in older children and adolescents (both P < 0.001). CONCLUSION In children with CD, abdominal pain has become the most common symptom. However, in younger children, symptoms of malabsorption are still seen frequently. This raises a question about the underlying mechanism of observed change in clinical presentation in favour of nonclassical presentation and asymptomatic disease at certain age.
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Sakhuja S, Holtz LR. Progression of pediatric celiac disease from potential celiac disease to celiac disease: a retrospective cohort study. BMC Pediatr 2021; 21:149. [PMID: 33781221 PMCID: PMC8006356 DOI: 10.1186/s12887-021-02625-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/23/2021] [Indexed: 11/17/2022] Open
Abstract
Background A subset of patients with serology suggesting celiac disease have an initially negative biopsy but subsequently develop histopathologic celiac disease. Here we characterize patients with potential celiac disease who progress to celiac disease. Methods We performed a retrospective analysis of children (0–18 years of age) with biopsy-confirmed celiac disease seen at St. Louis Children’s Hospital between 2013 and 2018. Results Three hundred sixteen of 327 (96%) children with biopsy-confirmed celiac disease were diagnosed on initial biopsy. The 11 children with potential celiac disease who progressed to celiac disease had lower anti-tissue transglutaminase (anti-TTG IgA) concentrations (2.4 (1.6–5) X upper limit of normal (ULN) vs. 6.41 (3.4–10.5) X ULN) at time of first biopsy. Their median anti-TTG IgA concentrations rose from 2.4 (1.6–5) X ULN to 3.6 (3.1–9.2) X ULN between biopsies. Conclusions Four percent of biopsy confirmed celiac patients initially had a negative biopsy, but later developed histopathologic celiac disease. This is likely an underestimate as no surveillance algorithm was in place. We recommend repeat assessment in children whose serology suggests celiac disease despite normal small bowel biopsy. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-021-02625-z.
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Affiliation(s)
- Shruti Sakhuja
- Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid, Campus, Box 8208, St. Louis, MO, 63110, USA
| | - Lori R Holtz
- Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid, Campus, Box 8208, St. Louis, MO, 63110, USA.
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Calcaterra V, Regalbuto C, Manuelli M, Klersy C, Pelizzo G, Albertini R, Vinci F, Larizza D, Leonard MM, Cena H. Screening for celiac disease among children with overweight and obesity: toward exploring celiac iceberg. J Pediatr Endocrinol Metab 2020; 33:/j/jpem.ahead-of-print/jpem-2020-0076/jpem-2020-0076.xml. [PMID: 32653877 DOI: 10.1515/jpem-2020-0076] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/20/2020] [Indexed: 12/31/2022]
Abstract
Background The coexistence of celiac disease (CD) and obesity/overweight is not unusual. Objective We investigate the prevalence and clinical presentation of CD, detected by screening, among children with excessive weight gain. Methods We enrolled 200 children referred for overweight/obesity to our outpatient clinic. Medical history during pregnancy and childhood and lifestyle variables were recorded. Patients were screened for CD with total immunoglobulin A (IgA), IgA anti-transglutaminase (tTG-IgA) and IgA anti-endomysial antibodies (EMA-IgA). In subjects with positive autoantibodies, esophagogastroduodenoscopy (EGDS) was performed and genetic testing for HLA DQ2 and/or DQ8 haplotypes was tested. Results CD positive antibodies (tTg-IgA and EMA-IgA) were detected in eight patients (4%); in all subjects CD diagnosis was confirmed by HLA-DQ2 and/or DQ8 compatibility and EGDS. No association between CD and medical history during pregnancy and childhood or lifestyle variables was noted; however, a dietary difference was identified with those testing positive for CD also reporting a lower weekly consumption of fruits and vegetables (p=0.04). Headache was reported more frequently in patients with than without CD (p=0.04). Familiar positivity for autoimmune diseases was revealed in CD patients (p=0.01). Conclusion CD should be considered in children with excessive weight gain. Familial predisposition to other autoimmune diseases may represent a risk factor for development of CD. Even though the relationship between headache and CD is not well defined, the patients with headache of unknown origin should be screened for CD.
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Affiliation(s)
- Valeria Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Surgery Unit, Children's Hospital "Vittore Buzzi", Milano, Italy
| | - Corrado Regalbuto
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Endocrinologic Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Matteo Manuelli
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
| | - Catherine Klersy
- Biometry & Clinical Epidemiology, Scientific Direction, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Gloria Pelizzo
- Pediatric Surgery Unit, Children's Hospital "Vittore Buzzi", Milano, Italy
- Department of Biomedical and Clinical Science "L. Sacco", University of Milano, Milano, Italy
| | - Riccardo Albertini
- Laboratory of Clinical Chemistry, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Federica Vinci
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Endocrinologic Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Daniela Larizza
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Endocrinologic Unit, Department of Maternal and Children's Health, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maureen M Leonard
- Center for Celiac Research and Treatment, Mass General Hospital for Children, Boston, Massachusetts, USA
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA
| | - Hellas Cena
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
- Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, ICS Maugeri IRCCS, Pavia, Italy
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Parada AC, Méndez C, Aguirre C. Excess weight and gastrointestinal symptoms in Chilean celiac patients at the time of diagnosis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 111:384-387. [PMID: 30859843 DOI: 10.17235/reed.2019.5251/2017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
INTRODUCTION celiac disease is an immune condition that results in histologic changes in the small bowel and produces both digestive and extra-digestive symptoms. Intestinal damage results in malabsorption and impaired weight or impaired optimal weight gain. However, these patients may be overweight or obese in spite of histologic damage. The aim of this study was to determine the prevalence of excess weight in newly diagnosed (adult) celiac patients. METHODS this was a retrospective observational study of patients recently diagnosed with celiac disease according to the standard Marsh classification. Nutritional status was assessed based on body mass index (BMI), as categorized by the World Health Organization (WHO). Clinical presentation was classified as typical or atypical. Potential differences in gastrointestinal symptoms according to nutritional status were also assessed. RESULTS a total of 135 medical records of adult celiac patients (women = 123; men = 12) were reviewed. The average weight and BMI were 61.1 kg and 23.7 kg/m2, respectively. The proportion of typical clinical presentations was 59.2% and of atypical presentations 40.8%. A total of 71.8% of patients had a BMI indicating low or normal weight and 28.1% had a BMI indicative of being overweight or obese. No differences with regard to the presence of gastrointestinal symptoms were found according to nutritional status. CONCLUSIONS further studies are needed to jointly assess energy intake and intestinal absorption in these patients, in order to explain the high rate of excess weight.
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Affiliation(s)
- Alejandra C Parada
- Departamento de Nutrición, Pontificia Universidad Católica de Chile, Chile
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Popp A, Mäki M. Changing Pattern of Childhood Celiac Disease Epidemiology: Contributing Factors. Front Pediatr 2019; 7:357. [PMID: 31555624 PMCID: PMC6727179 DOI: 10.3389/fped.2019.00357] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 08/15/2019] [Indexed: 12/14/2022] Open
Abstract
Up until the 1960s and 1970s, diarrhea, malabsorption syndrome, and failure to thrive were the presenting symptoms and signs of celiac disease (CD) in young infants; however this disease was also at the same time reported to be disappearing. Indeed, clinical childhood CD was seen to transform into a milder form, resulting in an upward shift in age at diagnosis during the 1970s (and years later for many countries). This changing pattern of CD presentation then altered the epidemiology of the disease, with major differences between and within countries observed. An awareness of the changing clinical nature of CD and use of case-finding tools to detect even clinically silent CD became an important factor in this changing epidemiology. Countries report both low and high prevalence but it seems to be on the increase resulting in a population-based level of 1-2%. This paper discusses the potential causes and environmental factors behind these observed clinical changes, identifying new clues from different studies published at the time this transformation took place. For instance, it was found that breastfeeding postponed the diagnosis of the disease but did not altogether prevent it. Moreover, gluten introduction at a young age, specifically at the mean age of 2 months, seemed to also have a clear impact in inducing malabsorption syndrome and failure to thrive in young infants in addition to other factors such as gluten intake volume and type of cereal present in the weaning food. Further, the impact of cow's milk and its high osmolarity might have played an important role; humanized milk formulas were not yet invented. Future epidemiological studies on the contributing environmental factors to the shift in CD presentation are thus recommended for countries in which these changing clinical features are still being observed.
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Affiliation(s)
- Alina Popp
- Faculty of Medicine and Health Technology, Tampere Center of Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
- National Institute for Mother and Child Health “Alessandrescu-Rusescu”, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
| | - Markku Mäki
- Faculty of Medicine and Health Technology, Tampere Center of Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
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Calcaterra V, Regalbuto C, Madè A, Magistrali M, Leonard MM, Cena H. Coexistence of Excessive Weight Gain and Celiac Disease in Children: An Unusual Familial Condition. Pediatr Gastroenterol Hepatol Nutr 2019; 22:407-412. [PMID: 31338317 PMCID: PMC6629591 DOI: 10.5223/pghn.2019.22.4.407] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 09/20/2018] [Accepted: 10/02/2018] [Indexed: 12/27/2022] Open
Abstract
Excessive weight gain in children diagnosed with celiac disease (CD) is becoming more common. We describe 2 siblings (9-year and 6 months-old female and 6-year and 9 months-old male) with obesity showing attenuated gastrointestinal and atypical symptoms in which CD was diagnosed in the absence of a known family history of CD. After children's diagnosis, CD in their parents was also investigated. It was detected in their father affected by overweight. The presentation of patients with CD has changed. While patients with overweight and obesity commonly have symptoms such as abdominal pain, reflux, headache, and constipation due to lifestyle factors, CD should also be considered in patients with or without a family history of CD. Careful nutritional status assessment and follow-up monitoring after the diagnosis of CD are mandatory, especially in subjects who are already overweight at the presentation of this disease.
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Affiliation(s)
- Valeria Calcaterra
- Pediatrics and Adolescentology Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy.,Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Corrado Regalbuto
- Pediatrics and Adolescentology Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy.,Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Alexandra Madè
- Pediatrics and Adolescentology Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy.,Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mariasole Magistrali
- Pediatrics and Adolescentology Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy.,Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maureen M Leonard
- Mass General Hospital for Children, Harvard Medical School, Boston, MA, United States.,Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, MA, United States.,Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, United States of America Celiac Research Program, Harvard Medical School, Boston, MA, United States
| | - Hellas Cena
- Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, ICS Maugeri IRCCS, Pavia, Italy.,Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
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Nardecchia S, Auricchio R, Discepolo V, Troncone R. Extra-Intestinal Manifestations of Coeliac Disease in Children: Clinical Features and Mechanisms. Front Pediatr 2019; 7:56. [PMID: 30891436 PMCID: PMC6413622 DOI: 10.3389/fped.2019.00056] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 02/13/2019] [Indexed: 12/11/2022] Open
Abstract
Celiac disease (CD) is a systemic autoimmune disease due to a dysregulated mucosal immune response to gluten and related prolamines in genetically predisposed individuals. It is a common disorder affecting ~1% of the general population, its incidence is steadily increasing. Changes in the clinical presentation have become evident since the 80s with the recognition of extra-intestinal symptoms like short stature, iron deficiency anemia, altered bone metabolism, elevation of liver enzymes, neurological problems. Recent studies have shown that the overall prevalence of extra-intestinal manifestations is similar between pediatric and adult population; however, the prevalence of specific manifestations and rate of improvement differ in the two age groups. For instance, clinical response in children occurs much faster than in adults. Moreover, an early diagnosis is decisive for a better prognosis. The pathogenesis of extra-intestinal manifestations has not been fully elucidated yet. Two main mechanisms have been advanced: the first related to the malabsorption consequent to mucosal damage, the latter associated with a sustained autoimmune response. Importantly, since extra-intestinal manifestations dominate the clinical presentation of over half of patients, a careful case-finding strategy, together with a more liberal use of serological tools, is crucial to improve the detection rate of CD.
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Affiliation(s)
- Silvia Nardecchia
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University of Naples Federico II, Naples, Italy
| | - Renata Auricchio
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University of Naples Federico II, Naples, Italy
| | | | - Riccardo Troncone
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University of Naples Federico II, Naples, Italy
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Frequency of overweight/obesity among a group of children with celiac disease in Iran. GASTROENTEROLOGY REVIEW 2018; 13:127-131. [PMID: 30002771 PMCID: PMC6040095 DOI: 10.5114/pg.2018.73347] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/10/2017] [Indexed: 02/07/2023]
Abstract
Introduction A small number of overweight and obese children with celiac disease (CD) has been reported. Aim To estimate the prevalence of obesity, underweight and normal weight in a group of Iranian pediatric patients. Material and methods In a retrospective study from 2007 to 2015, 225 children less than 18 years old with biopsy-proven CD were enrolled. Data collected included demographic characteristics, clinical presentation, antibody titers and severity of small-bowel mucosal damage. Body mass index (BMI) profile of subjects was calculated based on the age and gender percentile at presentation. Results The mean ± standard deviation (SD) for age was 7.4 ±3.8 and 62% of patients were female. Fifty-four percent of patients presented with a normal BMI, 43% were underweight, and the remaining patients (3.5%) were overweight/obese. The mean age of underweight and normal weight patients was higher than that of obese/overweight patients. Mean ± SD of TTG titer was higher in overweight/obese and normal weight children compared to underweight subjects. The majority of patients (195/225) had severe enteropathy compatible with Marsh III on duodenal biopsy. Most of the children had gastrointestinal (GI) and extra-intestinal manifestations on presentation. There was no association between severity of histological disease and BMI for age. Five out of eight cases in the obese/overweight group had an index case with CD in their family. Conclusions This study highlights the importance of considering celiac disease in children regardless of their BMI. Failure to diagnose CD in children leads to unnecessary diagnostic delays and long-term adverse health consequences.
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Tolone C, Bellini G, Punzo F, Papparella A, Miele E, Vitale A, Nobili B, Strisciuglio C, Rossi F. The DMT1 IVS4+44C>A polymorphism and the risk of iron deficiency anemia in children with celiac disease. PLoS One 2017; 12:e0185822. [PMID: 29023457 PMCID: PMC5638269 DOI: 10.1371/journal.pone.0185822] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 09/20/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Iron deficiency anemia in celiac disease is related to impaired duodenal mucosal uptake, due to villous atrophy. Iron enters the enterocytes through an apical divalent metal transporter, DMT1. Different DMT1 transcripts have been identified, depending on the presence of an iron-responsive element that allows DMT1 up-regulation during iron starvation. An intronic DMT1 polymorphism, IVS4+44C>A, has been associated with metal toxicity, and the CC-carriers show high iron levels. AIMS This study investigates the association between DMT1 IVS4+44C>A and anemia in a cohort of 387 Italian celiac children, and the functional role of the polymorphism. METHODS AND RESULTS By association analysis, we found that DMT1 IVS4+44-AA genotype confers a four-fold risk of developing anemia, despite of atrophy degree. By analysis of mRNA from gastroesophageal biopsies, we found that total DMT1 is significantly upregulated in presence of mild, but not severe, atrophy, independently from IVS4+44C>A variant, and in normal but not in atrophic CC-biopsies. Moreover, we found that A-allele is associated to preferential expression of the DMT1 transcripts lacking the iron-responsive element, thus limiting the DMT1 overexpression that normally occurs to respond to iron starvation. DISCUSSION Possibly, the IVS4+44-AA-related dysregulation of the iron-induced changes in DMT1 expression is not able to impair iron absorption in physiological condition. However, if exacerbated by the concomitant massive loss of functional absorbing tissue paralleling worsened stages of villus atrophy, it might be ineffective in counteracting iron deficiency, despite of DMT1 overexpression. CONCLUSION We suggest, for the first time, that celiac disease may unmask the contribution of the DMT1 IVS4+44C>A polymorphism to the risk of anemia.
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Affiliation(s)
- Carlo Tolone
- Department of Woman, Child and of General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giulia Bellini
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
- * E-mail:
| | - Francesca Punzo
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Alfonso Papparella
- Department of Woman, Child and of General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Erasmo Miele
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy
| | - Alessandra Vitale
- Department of Woman, Child and of General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Bruno Nobili
- Department of Woman, Child and of General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and of General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy
| | - Francesca Rossi
- Department of Woman, Child and of General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
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Spencer M, Lenhart A, Baker J, Dickens J, Weissman A, Read AJ, Saini S, Saini SD. Primary care physicians are under-testing for celiac disease in patients with iron deficiency anemia: Results of a national survey. PLoS One 2017; 12:e0184754. [PMID: 28931034 PMCID: PMC5607174 DOI: 10.1371/journal.pone.0184754] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 08/30/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Iron deficiency anemia (IDA) is a common extra-intestinal manifestation of celiac disease (CD). Little is known about the frequency with which primary care physicians (PCPs) test for CD in patients with IDA. We aimed to describe how PCPs approach testing for CD in asymptomatic patients with IDA. METHODS We electronically distributed a survey to PCPs who are members of the American College of Physicians. Respondents were asked whether they would test for CD (serologic testing, refer for esophagogastroduodenoscopy [EGD], or refer to GI) in hypothetical patients with new IDA, including: (1) a young Caucasian man, (2) a premenopausal Caucasian woman, (3) an elderly Caucasian man, and (4) a young African American man. These scenarios were chosen to assess for differences in testing for CD based on age, gender, and race. Multivariable logistic regression was used to identify independent predictors of testing. RESULTS Testing for CD varied significantly according to patient characteristics, with young Caucasian men being the most frequently tested (61% of respondents reporting they would perform serologic testing in this subgroup (p<0.001)). Contrary to guideline recommendations, 80% of respondents reported they would definitely or probably start a patient with positive serologies for CD on a gluten free diet prior to confirmatory upper endoscopy. CONCLUSIONS PCPs are under-testing for CD in patients with IDA, regardless of age, gender, race, or post-menopausal status. The majority of PCPs surveyed reported they do not strictly adhere to established guidelines regarding a confirmatory duodenal biopsy in a patient with positive serology for CD.
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Affiliation(s)
- Marisa Spencer
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
- * E-mail:
| | - Adrienne Lenhart
- Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, United States of America
| | - Jason Baker
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Joseph Dickens
- Department of Statistics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Arlene Weissman
- Research Center, The American College of Physicians, Philadelphia, Pennsylvania, United States of America
| | - Andrew J. Read
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Seema Saini
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
- Ambulatory Care, Veterans Affairs Medical Center, Ann Arbor, Michigan, United States of America
| | - Sameer D. Saini
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
- Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan, United States of America
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16
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Changing Clinical Manifestations of Celiac Disease in Children. J Pediatr Gastroenterol Nutr 2016; 63:e25. [PMID: 27159209 DOI: 10.1097/mpg.0000000000001254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Capriati T, Francavilla R, Ferretti F, Castellaneta S, Ancinelli M, Diamanti A. The overweight: a rare presentation of celiac disease. Eur J Clin Nutr 2016; 70:282-284. [PMID: 26508459 DOI: 10.1038/ejcn.2015.169] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 07/05/2015] [Accepted: 07/08/2015] [Indexed: 01/07/2023]
Abstract
We describe the nutritional status of a cohort of celiac disease (CD) children at presentation and during follow-up on gluten-free diet (GFD). Two Italian centers (Rome and Bari) prospectively enrolled 445 biopsy-confirmed CD children, diagnosed between 2009 and 2013. Body Mass Index was used as a measure of nutritional status according to Italian growth charts of Cacciari. The overweight/obese subject was 7.8% at onset and did not significantly increase during follow-up (9.8% at final assessment). The prevalence of overweight/obesity was significantly higher among males than females. Furthermore, overweight/obesity children as compared with those with normal weight were significantly older and had significantly lower levels of tTG antibodies. This study shows that some CD children are obese/overweight at diagnosis; therefore, overweight/obesity can be considered a rare but a possible mode of CD presentation. Thus, CD diagnosis must be considered even in overweight/obese children where this diagnosis can be easily missed.
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Affiliation(s)
- T Capriati
- Gastroenterology-Hepatology and Nutrition Unit, 'Bambino Gesù' Children's Hospital, Rome, Italy
| | - R Francavilla
- Gastroenterology Unit, Pediatric Clinic of University, Bari, Italy
| | - F Ferretti
- Hepato-Metabolic Diseases Unit, 'Bambino Gesù' Children's Hospital, Rome, Italy
| | - S Castellaneta
- Department of Pediatrics, San Paolo Hospital, Bari, Italy
| | - M Ancinelli
- Gastroenterology-Hepatology and Nutrition Unit, 'Bambino Gesù' Children's Hospital, Rome, Italy
| | - A Diamanti
- Gastroenterology-Hepatology and Nutrition Unit, 'Bambino Gesù' Children's Hospital, Rome, Italy
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Wessels MMS, van Veen II, Vriezinga SL, Putter H, Rings EHHM, Mearin ML. Complementary Serologic Investigations in Children with Celiac Disease Is Unnecessary during Follow-Up. J Pediatr 2016; 169:55-60. [PMID: 26547400 DOI: 10.1016/j.jpeds.2015.09.078] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/17/2015] [Accepted: 09/29/2015] [Indexed: 01/14/2023]
Abstract
OBJECTIVES To determine the frequency of nutritional deficiencies and thyroid dysfunction in children with celiac disease (CD) and during follow-up after initiation of a gluten-free diet. Laboratory investigations of hemoglobin, ferritin, calcium, folate, vitamin B12, vitamin D, and thyroid function are regularly ordered in children with CD despite sufficient evidence for these. STUDY DESIGN Between 2009 and 2014, test results of hemoglobin, ferritin, folate, vitamin B12, calcium, vitamin D (25[OH]D), free thyroxin, and thyroid stimulating hormone of children with CD regularly seen at the Leiden University Medical Center were investigated. Laboratory reference ranges were used to define abnormal results. Pearson χ(2) test for trend, unpaired t test, and 1-way ANOVA were used for statistical analysis. RESULTS Of the 182 children evaluated, 119 were newly diagnosed. On average, 17% of results per year were missing because of incomplete blood investigations. Iron deficiency (28%) and iron deficiency anemia (9%) were found at the time of diagnosis of CD. Folate (14%), vitamin B12 (1%), and vitamin D deficiencies (27%) were also seen. No hypocalcemia or thyroid dysfunction was found. At follow-up, iron deficiency, iron deficiency anemia, and folate and vitamin D deficiency were observed in 8%, 2%, 3%, and 25% of patients, respectively. Vitamin B12 deficiency, hypocalcemia, and thyroid disease were not found. CONCLUSIONS Complementary blood investigations are relevant at the time of diagnosis of CD but have little diagnostic yield during follow-up visits once the patient is placed on a gluten-free diet. Thus, we recommend that these variables only be assessed on indication, such as fatigue or abnormal growth.
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Affiliation(s)
| | - Iris I van Veen
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Hein Putter
- Department of Statistics, Leiden University Medical Center, Leiden, The Netherlands
| | - Edmond Henri Herman Maria Rings
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; Department of Pediatrics, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Maria Luisa Mearin
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
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Kivelä L, Kaukinen K, Lähdeaho ML, Huhtala H, Ashorn M, Ruuska T, Hiltunen P, Visakorpi J, Mäki M, Kurppa K. Presentation of Celiac Disease in Finnish Children Is No Longer Changing: A 50-Year Perspective. J Pediatr 2015; 167:1109-15.e1. [PMID: 26316370 DOI: 10.1016/j.jpeds.2015.07.057] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 07/07/2015] [Accepted: 07/29/2015] [Indexed: 12/23/2022]
Abstract
OBJECTIVES To chart trends in the presentation of celiac disease in a large cohort of Finnish children diagnosed over a period of 48 years. STUDY DESIGN Clinical and serologic data, severity of small-bowel mucosal damage, and presence of associated conditions were gathered from 596 children diagnosed with celiac disease in 1966-2013. The children were divided into 4 groups based on the year of diagnosis (before 1980, 1980-1999, 2000-2009, and 2010-2013), and the variables were compared between the periods. The incidence of celiac disease autoimmunity in 2001-2013 was calculated based on the number of new antibody-positive cases in each year. RESULTS Age at diagnosis rose from median 4.3 years before 1980 to between 7.6 and 9.0 years in the later periods. The severity of clinical presentation, in general, became milder and poor growth less common during the entire study period of 50 years. Percentages of children with classical gastrointestinal presentation decreased, and those with atypical or subclinical presentation increased after the 1990s, these changes leveling off in 2000-2013. Similarly, the severity of small-bowel mucosal damage was milder after the 1990s. The incidence of celiac disease autoimmunity increased in the early 2000s but then fluctuated without a clear trend. There were no significant secular changes in sex distribution, presence of anemia, levels of celiac antibodies, or celiac disease-associated conditions. CONCLUSIONS The clinical and histologic presentation of celiac disease in children became milder, especially in the 1980s and 1990s. However, most of these changes have reached a plateau in recent years.
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Affiliation(s)
- Laura Kivelä
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Katri Kaukinen
- Department of Internal Medicine, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland
| | - Marja-Leena Lähdeaho
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Heini Huhtala
- Tampere School of Health Sciences, University of Tampere, Tampere, Finland
| | - Merja Ashorn
- Department of Pediatrics, Lappeenranta Central Hospital, Lappeenranta, Finland
| | - Tarja Ruuska
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Pauliina Hiltunen
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Jarmo Visakorpi
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Markku Mäki
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Kalle Kurppa
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland.
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Abstract
Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet.
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