Maureen M. Leonard

US perspective on gluten-related diseases

The incidence of allergy and autoimmune disease in the US and other industrialized nations is increasing, and gluten-related disorders are no exception. The US has documented a profound rise in celiac disease that cannot be fully explained by improved serological techniques or better recognition by physicians. Non-celiac gluten sensitivity, a condition only recently recognized by the medical community, has become a commonly diagnosed entity. Proteins, including gluten are increasingly being identified as a source of wheat allergy. Although the gluten free diet represents a safe and effective treatment for these conditions, there is still much to be learned about the development of gluten-related disorders and the apparent increase in incidence within the US. In this article, we present a review of current knowledge on the epidemiology of gluten-related disorders within a global context, with a focus on diagnostic trends and the evaluation of potential risk factors.

Celiac Disease and Nonceliac Gluten Sensitivity: A Review

Importance The prevalence of gluten-related disorders is rising, and increasing numbers of individuals are empirically trying a gluten-free diet for a variety of signs and symptoms. This review aims to present current evidence regarding screening, diagnosis, and treatment for celiac disease and nonceliac gluten sensitivity. Observations Celiac disease is a gluten-induced immune-mediated enteropathy characterized by a specific genetic genotype (HLA-DQ2 and HLA-DQ8 genes) and autoantibodies (antitissue transglutaminase and antiendomysial). Although the inflammatory process specifically targets the intestinal mucosa, patients may present with gastrointestinal signs or symptoms, extraintestinal signs or symptoms, or both, suggesting that celiac disease is a systemic disease. Nonceliac gluten sensitivity is diagnosed in individuals who do not have celiac disease or wheat allergy but who have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion of gluten-containing grains, with symptomatic improvement on their withdrawal. The clinical variability and the lack of validated biomarkers for nonceliac gluten sensitivity make establishing the prevalence, reaching a diagnosis, and further study of this condition difficult. Nevertheless, it is possible to differentiate specific gluten-related disorders from other conditions, based on currently available investigations and algorithms. Clinicians cannot distinguish between celiac disease and nonceliac gluten sensitivity by symptoms, as they are similar in both. Therefore, screening for celiac disease must occur before a gluten-free diet is implemented, since once a patient initiates a gluten-free diet, testing for celiac disease is no longer accurate. Conclusions and Relevance Celiac disease and nonceliac gluten sensitivity are common. Although both conditions are treated with a gluten-free diet, distinguishing between celiac disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with celiac disease should be followed up closely for dietary adherence, nutritional deficiencies, and the development of possible comorbidities.

Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) Study Design: Approach to the Future of Personalized Prevention of Celiac Disease.

In the past it was believed that genetic predisposition and exposure to gluten were necessary and sufficient to develop celiac disease (CD). Recent studies however suggest that loss of gluten tolerance can occur at any time in life as a consequence of other environmental stimuli. Many environmental factors known to influence the composition of the intestinal microbiota are also suggested to play a role in the development of CD. These include birthing delivery mode, infant feeding, and antibiotic use. To date no large-scale longitudinal studies have defined if and how gut microbiota composition and metabolomic profiles may influence the loss of gluten tolerance and subsequent onset of CD in genetically-susceptible individuals. Here we describe a prospective, multicenter, longitudinal study of infants at risk for CD which will employ a blend of basic and applied studies to yield fundamental insights into the role of the gut microbiome as an additional factor that may play a key role in early steps involved in the onset of autoimmune disease.

Value of Iga ttg in Predicting Mucosal Recovery in Children With Celiac Disease on a Gluten-free Diet

Objectives: Our objective was to determine the rate of mucosal recovery in pediatric patients with celiac disease on a gluten-free diet. We also sought to determine whether immunoglobulin A tissue transglutaminase (tTG) correlates with mucosal damage at the time of a repeat endoscopy with duodenal biopsy in these patients. Methods: We performed a retrospective chart review of 103 pediatric patients, younger than 21 years, with a diagnosis of celiac disease defined as Marsh 3 histology, and who underwent a repeat endoscopy with duodenal biopsy at least 12 months after initiating a gluten-free diet. Results: We found that 19% of pediatric patients treated with a gluten-free diet had persistent enteropathy. At the time of the repeat biopsy, tTG was elevated in 43% of cases with persistent enteropathy and 32% of cases in which there was mucosal recovery. Overall the positive predictive value of the autoantibody tTG was 25% and the negative predictive value was 83% in patients on a gluten-free diet for a median of 2.4 years. Conclusions: Nearly 1 in 5 children with celiac disease in our population had persistent enteropathy despite maintaining a gluten-free diet and immunoglobulin A tTG was not an accurate marker of mucosal recovery. Neither the presence of symptoms nor positive serology were predictive of a patients histology at the time of repeat biopsy. These findings suggest a revisitation of monitring and management criteria of celiac disease in childhood.

Genetics and celiac disease: the importance of screening

The prevalence of celiac disease (CD) is increasing. Despite an increased awareness and an improvement in diagnostic testing, the majority of individuals with CD remain undiagnosed. Currently, genetic testing in screening for CD is used only to exclude a diagnosis or reinforce a strong clinical suspicion. In this paper, we review the most current literature regarding genetic testing in CD. In response to important data revealing that an individual’s HLA haplotype is one of the strongest known predictors of CD, we propose genetic screening for at-risk infants to stratify individuals based on genetic risk to ultimately create genetic specific screening algorithms.

Managing coeliac disease in patients with diabetes

The association between coeliac disease and type 1 diabetes has long been established. The combination of genetic susceptibility along with a potential role for gluten in the pathogenesis of autoimmunity makes defining glutens role in type 1 diabetes extremely important. Evidence supporting the role of a gluten‐free diet to improve complications associated with type 1 diabetes is not robust. However there is evidence to support improved growth, bone density and potentially the prevention of additional autoimmune diseases in patients with coeliac disease and type 1 diabetes. The gluten free diet is expensive and challenging to adhere to in people already on a modified diet. Early identification of those who have coeliac disease and would benefit from a gluten‐free diet is of utmost importance to prevent complications associated with type 1 diabetes and coeliac disease.

Proinflammatory cytokine interferon‐γ and microbiome‐derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg) are CD4+CD25++forkhead box protein 3 (FoxP3+) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down‐regulate the Th17‐driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non‐coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate‐producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)‐γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial‐derived metabolites.

CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 14-2016. A 37-Year-Old Woman with Adult-Onset Psychosis.

Dr. Maureen M. Leonard: A 37-year-old woman was admitted to a psychiatric hospital for adult-onset psychosis. The patient had been healthy and studying for a doctoral degree when she began having symptoms of psychosis. Her first symptom was a belief that “people were talking about her” as part of a larger “conspiracy” in which family, friends, and random people were part of a “game” and acting out “scenes” for her. She had had stress associated with her schooling and had contemplated changing schools. However, she had not had other symptoms of anxiety or depression, neurovegetative symptoms, or auditory or visual hallucinations. A few months later, the patient’s apartment was burglarized and vandalized; her parents were the only other people with a key, and she believed they were involved. Because of threats she made against family members, she was admitted to an inpatient state psychiatric facility. A diagnosis of psychotic disorder, possibly paranoid schizophrenia, was rendered. An evaluation for causes of the disorder revealed evidence of marked iron-deficiency anemia, including an iron level of 18 μg per deciliter (3 μmol per liter; reference range, 45 to 182 μg per deciliter [8 to 33 μmol per liter]), a ferritin level of 6 ng per milliliter (reference range, 11 to 306), and a transferrin saturation of 3.7% (reference range, 11.0 to 50.0). The evaluation also revealed vitamin deficiencies, including a vitamin B12 level of 167 pg per milliliter (reference range, 182 to 803) and a vitamin D2 level of 10 ng per milliliter (reference value, >32). Before admission to the state psychiatric facility, the patient had had no history of psychiatric disease. She had a remote history of a left-foot fracture and had undergone a right oophorectomy at 17 years of age for torsion of the ovary. She took no medications. Her mother recalled her being a “perfectionist,” especially during her late teenage years. The patient had reported an unintentional weight loss of 9 kg over an unspecified period of time, despite self-described polyphagia and some hair thinning. She did not have diarrhea. There was no history of head injury or seizure, menopausal symptoms after the oophorectomy, or social withdrawal. Her mother had systemic lupus erythematosus, her sister had hypothyroidism From the Departments of Medicine (H.K.D.), Pediatrics (M.M.L., A.F.), and Pathology (V.N.), Massachusetts General Hospital, and the Departments of Medi‐ cine (H.K.D.), Pediatrics (M.M.L., A.F.), and Pathology (V.N.), Harvard Medical School — both in Boston.

Screening for Celiac Disease in a Pediatric Primary Care Setting

Celiac disease (CD) is an autoimmune enteropathy in genetically predisposed individuals triggered by the ingestion of gluten. The prevalence in adults in the United States is increasing. Despite recognition of asymptomatic patients that benefit from screening and improved diagnostics, the majority of patients remain undiagnosed. The purpose of this study is to determine the prevalence of CD in at-risk and not-at-risk pediatric patients in a primary care practice routinely screening for CD. The records of 2325 pediatric patients who underwent serological testing with immunoglobulin A tissue transglutaminase (tTG) during a 5-year period were reviewed. Patients were categorized as at-risk or not-at-risk for CD. The prevalence of CD in at-risk patients was 1:26, the prevalence of CD in not-at-risk patients was 1:111. Our results suggest that the prevalence of CD in children approximates that of US adults and that the true prevalence in children without known risk factors may be increasing.

Case 14-2016

Dr. Maureen M. Leonard: A 37-year-old woman was admitted to a psychiatric hospital for adult-onset psychosis. The patient had been healthy and studying for a doctoral degree when she began having symptoms of psychosis. Her first symptom was a belief that “people were talking about her” as part of a larger “conspiracy” in which family, friends, and random people were part of a “game” and acting out “scenes” for her. She had had stress associated with her schooling and had contemplated changing schools. However, she had not had other symptoms of anxiety or depression, neurovegetative symptoms, or auditory or visual hallucinations. A few months later, the patient’s apartment was burglarized and vandalized; her parents were the only other people with a key, and she believed they were involved. Because of threats she made against family members, she was admitted to an inpatient state psychiatric facility. A diagnosis of psychotic disorder, possibly paranoid schizophrenia, was rendered. An evaluation for causes of the disorder revealed evidence of marked iron-deficiency anemia, including an iron level of 18 μg per deciliter (3 μmol per liter; reference range, 45 to 182 μg per deciliter [8 to 33 μmol per liter]), a ferritin level of 6 ng per milliliter (reference range, 11 to 306), and a transferrin saturation of 3.7% (reference range, 11.0 to 50.0). The evaluation also revealed vitamin deficiencies, including a vitamin B12 level of 167 pg per milliliter (reference range, 182 to 803) and a vitamin D2 level of 10 ng per milliliter (reference value, >32). Before admission to the state psychiatric facility, the patient had had no history of psychiatric disease. She had a remote history of a left-foot fracture and had undergone a right oophorectomy at 17 years of age for torsion of the ovary. She took no medications. Her mother recalled her being a “perfectionist,” especially during her late teenage years. The patient had reported an unintentional weight loss of 9 kg over an unspecified period of time, despite self-described polyphagia and some hair thinning. She did not have diarrhea. There was no history of head injury or seizure, menopausal symptoms after the oophorectomy, or social withdrawal. Her mother had systemic lupus erythematosus, her sister had hypothyroidism From the Departments of Medicine (H.K.D.), Pediatrics (M.M.L., A.F.), and Pathology (V.N.), Massachusetts General Hospital, and the Departments of Medi‐ cine (H.K.D.), Pediatrics (M.M.L., A.F.), and Pathology (V.N.), Harvard Medical School — both in Boston.