Celiac Disease in Type Diabetes Mellitus

Introduction

Celiac disease and Type 1 Diabetes Mellitus are both chronic autoimmune diseases are steadily increasing prevalence both in co-occurrence and in alone in the population.1 The purpose of this review is to outline literature and studies conducted on Celiac disease in type 1 diabetes mellitus and the risk factors associated with autoimmune comorbidity. Dietary control is related to both diseases and plays an important role in management of short- and long-term complications.1,2,3 The review will discuss the background of these two auto-immune illness as well as possible explanations for increased prevalence, with a focus on genetic variation. There are several risks associated with celiac disease in T1DM patients, but this review will primarily focus on complications with glycemic control and cardiovascular disease.

Background of Celiac Disease

Celiac disease (CD) is a chronic polygenic autoimmune enteropathy triggered by gluten ingestion resulting in inflammatory damage to small intestine mucosa.1,4,5,6 This is characterized by specific serum antibody response which leads to malabsorptive syndrome.4,5 CD is distinguished by intestinal damage, presence of autoimmune antibodies, and genetic susceptibility.1,4,5 Currently 1-2% of the world population is known to have this autoimmune disease, however, this low percentage may be because only 10-15% of sufferers have been diagnosed.1 At this moment, there is only one treatment which is adherence to a strict gluten-free diet (GFD) which includes avoidance of wheat, rye, barley and oats.1,7 Intestinal villi can repair and serological markers will regularize by removing oral gluten intake from the diet.1

CD is T-cell mediated in which immune cells from lamina propria are activated by gliandin-derived peptides in gluten recruit T lymphocytes to activate Th1 response and consequently augment interferon gamma and interleukin-15 by initiating intraepithelial lymphocyte toxicity.1 Currently know, the most contributing genetic factor is human leukocyte antigen (HLA) system.1,2,3 Classic symptoms of CD are diarrhea, malabsorption, abdominal pain steatorrhea, weight loss, failure to thrive, chronic fatigue bloating, and vomiting.1,2,5 Nonclassical symptoms are ataxia, constipation, heartburn and neuropathy.5 Clinical signs of CD include iron-deficiency anemia, vitamin deficiencies, short stature, low bone density.2,5 Some individuals, however, have silent celiac and are seropositive but do not demonstrate gastrointestinal signs or symptoms.5 Untreated CD can result in osteoporosis, infertility, neurological disorders, adenocarcinoma of the jejunum and enteropathy-associated T-cell lymphoma.2 In order to be diagnosed, it is necessary to maintain a glutenated diet to preserve high sensitivity for serum testing which is found to be reliable.1 Criteria for diagnosis with serum testing includes presence of serum IgG anti-tissue transglutaminase antibodies and IgA deficiency.1

Background of Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus (T1DM) is an autoimmune T-cell-mediated destruction of pancreatic islet beta cells.4,5 Beta cells produce insulin and their destruction results in absolute deficiency, preventing cells from uptake of glucose which is required for normal cell function consequently requiring insulin supplementation to maintain adequate physiological range.1,4,5,8 Common signs and symptoms of T1DM are polyuria, polydipsia, weight loss, fatigue and hyperglycemia.1 Patients with T1DM have higher risk of hyperglymia due to consumption of inexpensive carb-rich processed foods, binge eating and diabetic ketoacidosis which can result in coma and death.1,8

Diagnosis of T1DM is confirmed by fasting blood glucose 126 mg/dL, oral glucose tolerance test  Individuals with first-degree relatives with T1DM or other autoimmune diseases have an increased risk of developing T1DM.8 Also, biochemical data consistent with T1DM will detect presence of islet cell antibodies (ICA), auto-antibodies to insulin (IAA), glutamin acid decarboxylase (GADA) and protein tyrosine phosphatase like protein (IA2).1 Currently treatment guidelines are based on American Diabetes Association’s 2018 Standards of Medical Care in Diabetes8 which focus on screening, diagnostic, and therapeutic actions. The ADA reports that diabetic progression rate is contingent upon age at detection, number, specificity, and titer of antibodies.8 Monitoring and evaluation is dependent upon patient’s ability to self-manage and report with aimed recommendations toward language choice in patient-centered communication.

Genetic Variations Related to Type 1 Diabetes Mellitus and Celiac Disease

HLA, human leukocyte antigen, is a major histocompatibility complex (MHC) containing thousands of allele sequences and presents as the densest portion of genes in the human genome.5,9 It contributes majorly to T cell antigen presentation and overlap in non-HLA and HLA portions possibly describes elevated incidence in comorbidities.5 MHC class II DQ peptides, HLADQ2 and DQ8, overlap in CD and T1DM.  have revealed that haplotype, HLA-DR3/DQ2 is found in 90% of patients with CD, 55% of T1DM patients and in less than 25% of the general population whereas HLA-DQ8 is found in 70% of T1DM patients and 10% of CD.5 With the increasing prevalence of CD in T1DM, a study was conducted by Smigoc Schweiger at al.9 with a goal to discover genetic variance related to concurrent disease. Results showed that both T1DM and CD are associated with HLA- DQA1*05:01-DQB1*02:01 (DQ2) and DQB1*03:01 (DQ8) with increased risk for T1DM for DQ8 and increased risk with DQ2 in CD.9 Results also showed that B*08 and C*07 serotypes were increased in patients with CD and T1DM.9 T cells in HLA class I-restricted CD8 in CD have been found to identify gliadin peptides in gluten which suggest the reason that there is an autoimmune effect in these patients due to their relationship with immune system protecting receptors.9

Cytoplasmic multi-protein complexes are known as inflammasomes.10 Inflammasomes, dependent on NOD-like receptors (NLR), act to control inflammatory caspases-1 and -5 generation.10 NLRP1/NLRP1 and NLRP3/NLRP3/CIAS1 are involved in innate immunity and are related to autoimmune disorder susceptibility.10 They, along with NLRP2 polymorphisms, are also associated with inflammatory diseases.10 A recent study in 2010 by Pontillo et al.10 aimed to find the genetic variations associated with concurrent T1DM and CD due to increased prevalence in diagnosis of CD.10 In a study of 196 Brazilian children, results have shown that NLRP3 SNPs were significantly associated with T1DM (rs10754558) and CD (rs358294199).10 There was also significant less G allele frequency in NLRP3 SNP rs10754558 in T1DM and CD.10 These findings suggest that differences in nucleotide polymorphisms could relate to differences in functionality in the immune system.10

A study done by Gutierrez-Achury et al.11 was conducted to not only find possible associations between T1DM and CD over presence of either; the term for having both diseases was named double-immunity in this study. Samples were taken from three populations: 12,480 patients with T1DM, 3098 patients with CD, and 543 patients with both and were analyzed using EIGENSTRAT.11 A single locus was found to be significantly (P

Prevalence of Celiac Disease in Type 1 Diabetes Mellitus

Currently CD in patients with T1DM is on the rise with more than one in 20 patients with T1DM present with CD.1,6 The occurrence is 5-7 times more prevalent than CD alone in the general population and it is believed to be due to environmental and genetic changes in the population.1,2 Data is inconclusive on the exact prevalence of CD in T1DM but reports have averaged around 6% and percentage range from 2.0% – 12.3% in certain populations.6 A possible explanation is the hygiene hypothesis that states lack of childhood exposure to infections increases predisposition to allergies, however, due to the increase of CD in T1DM in developing nations may disprove this.1 Another plausible reason for increased prevalence could be from increased gluten content in wheat from to genetically modifications in wheat breeding.1 Several environmental variables such as length of breast-feeding, gluten introduction timing or amount could all be possible explanations for increased prevalence.1 Changes in intestinal microflora could also be involved in increase of autoimmune disease development, such as lower diversity of intestinal microflora.1 CD is characterized to have elevated Proteobacteria and Bacteroidetes and both CD and T1DM have lower amounts of Firmucutes.1

Epidemiology

In a systematic review and meta-analysis by Elfstrom et al.6 prevalence and epidemiology was evaluated to discover possible associations between demographics with T1DM and their risk to developing CD. Papers dated after 2000 were sampled due to increased usage of TTG for diagnostics and 27 papers were narrowed down for use in the meta-analysis.6 It is known that CD in more prevalent in females, however, the meta-analysis concluded that between males and females, there is no significant difference in prevalence.6 There is lower CD prevalence in adults than in age-mixed samples of both children and adults.1,6 These findings suggest that there is higher prevalence of CD in children with T1DM and screening procedures may need to be more closely regulated. CD in T1DM prevalence has been calculated for the following countries: 16.4% in Algeria5, 10.5% in Brazil2, 6.4% in Greece2; 11.1% in Germany/Austria5, 11.1% in India2, 8.3% Israel5, 4.4% UK2. Although there is abundant research of CD in Caucasian populations, there is a significant lack of research for CD in African American populations.5

Screening Guidelines

There are several risks involved in uncontrolled CD and in less than 10% of patients with T1DM and CD show gastrointestinal symptoms.2 Diagnosis is currently determined by serological tests for tissue transglutaminase (TTG) IgA, endomysial (EMA) IgA, and deaminated gliandin peptide (DPG) IgG and IgA.5 Previously, anti-alpha-gliandin antibodies (AGA) have been used for diagnosis, but there is variability in accuracy and no longer is recommended.5 Most guidelines recommend TTG IgA or TTG IgG in the case of IgA deficiency in patients for screening because of the high sensitivity, specificity, and accuracy and most experts argue that an esophagoduedenoscopy should be performed for confirmation.4

A small bowl biopsy is the gold standard for screening and produced the highest diagnostic yield.5 During an esophagoduedonoscopy, more than five biopsies should be obtained from the duodenum from the duodenal bulb and second portion of the duodenum.5 Endoscopists should see characteristic CD appearance of flattened villi, atrophy, crypt hyperplasia and increased intraepithelial lymphocytes during endoscopy relating to mucosal damage.5

Currently, there is no consistent recommendation for screening timelines.2,4,5 Some recommendations are to screen T1DM patients for CD at initial diagnosis and subsequently for the first four years post diagnosis and then every two years.5 The International Society for Pediatric and Adolescent Diabetes recommends initial screening at diagnosis and every year following for five years with less encounters after.2 Screening for CD is recommended for children with symptoms characteristic of CD and for those with increased risk factors such as patients w/ T1DM or have first-degree relatives with CD as outlined in the modified Guidelines of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition.2 Further evidence is needed to determine screening frequency guidelines in pediatric and if necessary, adult patients with T1DM.4

Health Risks

There are several health risks and long-term complications associated with both CD and T1DM such as increased risk for other autoimmune diseases such as autoimmune thyroid disorders.2 Untreated CD can lead to osteoporosis, neuropathy, intestinal lymphoma and fertility-related complications.2 Patients with both T1DM and CD are known to have higher prevalence of retinopathy, nephropathy, and peripheral neuropathy.2 In this paper, complications with glycemic index and vascular disease in co-occurrence of CD in T1DM patients will be further discussed.

Glycemic Control

Gluten is the protein found in wheat, rye, barley, and oats that triggers an autoimmune response in patients with CD.1 Components of gluten are gluteniin polymers and gliadin monomers which have high amounts of prolines and glutamines.1 Pro-inflammatory cytokines originating from Th1/Th17 immune response are released from gliadins.1 In CD, oral intake of gluten results in an immune response due to gliadin peptides coming in contact with intestinal mucosa.1 IL-8 and IL-15 are secreted which leads to apoptosis resulting in damage to small intestinal permeability and damage.1

Hypoglycemic risk is increased in untreated CD due to malabsorption of nutrients.4 Bakker et al.4 in a study aimed to evaluate the role and risk of CD in regard to T1DM glycemic control.  Intensive insulin therapy is important for treatment and control of glycemic index.4 Bakker notes that in other research done, the role of CD remains inconclusive with reports of CD diagnosis’s effect on glycemic control. In the study of 31 patients of co-occurring, 16.1% of patients reported symptomatic hypoglycemic events before diagnosis of CD with no impact on HbA1C levels.4 It should be noted that no difference in insulin was needed to control blood glucose levels as reported by study participants.4 In contrast, a study done by Mohn et al.3 to also find the association of CD and glycemic control. 20 patients of 434 screened has CD and T1DM. These patients were reported to significantly have more episodes of hypoglycemia, however, in contrast with the Bakker et al study, patients in this study reported to requiring more insulin before CD diagnosis.3,4 In conclusion to both studies, research is inconclusive in regard to glycemic control and the effects of CD and should be further evaluated for mechanisms related to hypoglycemia in CD patients in order to further monitor patients with this concomitant disease.4,5,7

Adherence to a GFD may have an impact on glycemic control, however, there are several management difficulties with GFD in T1DM and only 59% of patience with co-occurrence of T1DM and CD adhering to a strict GFD.4,7 Good glycemic control is imperative to reduce complications.2,3 Typically, low glycemic foods are recommended for T1DM patients because of their reduction effects on postprandial glycemic excursion.7 Gluten-free foods have high glycemic indexes which possibly can increase insulin resistance henceforth negatively affecting glycemic control.2,7 Interestingly, compliance with GFD may elevate insulin requirements and reduce hypoglycemic episode frequency due to increased absorption whereas untreated and poorly controlled CD resulting in weight loss and appearance of blood glucose improvement, although data is inconclusive.1,3,5,7

Vascular Disease

Patients with T1DM have been shown to have increased risk of micro- and macrovascular complications related to cardiovascular disease in comparison to the general population.4 Development can be delayed by intensive insulin therapy to regulate blood glucose ad reduce HbA1C.4 Microvascular complications include retinopathy, nephropathy and neuropathy.4

In a study by Warncke et al.12 individuals with T1Dm and CD under 20 years old were evaluated to discover what, if any, cardiovascular risks were in patients with co-occurrence of T1DM and CD. Evaluated patients had significantly lower high-density lipoproteins which increases risk for cardiovascular disease, but GFD compliance resulted in HDL increase and decrease of dyslipidemia.12 The function of HDL is to engage in reverse cholesterol transport to remove cholesterol from walls of blood vessels in peripheral tissues back to the liver which aids in cardiovascular health.12 The mechanism is unknown for links between HDL and GFD, however, it is speculated that strict compliance with a GFD may improve chronic inflammation related to CD due to increased absorption of nutrients in the small intestine.12

GFD are related to weight gain with 80% of patients gaining weight and 51% being overweight or obese.7 Gluten-free foods elevate blood glucose levels which can result in hyperglycemia due to their higher glycemic index.7 Hyperglycemia plays a role in oxidative stress due to increased free fatty acids which results in atherlosclerosis.7 Other risk factors increased by T1DM and CD are elevated albumin excretion due to non-compliance with GFD and increased carotid intima-media thickness which may lead to atherosclerotic complications.2,4,7

Summary

Celiac disease is a chronic intestinal autoimmune disease with increasing prevalence Type 1 Diabetes Mellitus, a permanent autoimmune disease related to pancreatic beta cell destruction.1,2,4,5,6,8  Prevalence ranges from 2.0 – 12.3% with increased incidence in younger children.6 T1DM and CD have been shown to be significantly associated by genetic variance in HLADQ2 and DQ8, NLRP2 SNPs, and locus CTLA4.9,10,11 Currently there is no screening frequency recommendation but experts agree that patients with T1DM should be screened for CD by serological testing or biopsy.2,4,5 Several health risks are associated with both diseases with if uncontrolled.4,7,12 Data is inconclusive on how a gluten-free diet, required for CD, affects glycemic index with studies showing possible increased insulin requirement, more frequent hypoglycemic episodes, and concern for hyperglycemia due to high glycemic index of gluten-free foods.3,4 Patients with concurrent T1DM and CD have been shown to have lower HDL relating to increased cardiovascular risks as well as weight gain on GFD associated with possible hyperglycemia which may progress atherosclerosis. 7

Conclusions

Currently celiac disease in type 1 diabetes is increasing in prevalence due to changes in environmental and genetics with CD in T1DM patient seen 5-7 times more in patients than CD alone.1,2 There are known associations between co-occurrence and increased glycemic control complications and vascular risks with a heightened incidence rate in children.6 Future research will include a focus into CD in African Americans, for which currently there is a lack of.5  Further research is also needed to definitively conclude the specific risks to mechanisms of vascular risk and HbA1C effect in order to adapt treatment and education guidelines.12 Due to the heightened risk and the high prevalence rate in children, it is necessary for experts to establish screening processes and frequency recommendations for early detection that can potentially lessen long-term complications.2,5

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