Celiac Disease in Type Diabetes Mellitus

Introduction

Celiac disease and Type 1 Diabetes Mellitus are both chronic autoimmune diseases exhibiting a steadily increasing prevalence, both in co-occurrence and individually, in the population. The purpose of this review is to outline the literature and studies conducted on Celiac disease in Type 1 diabetes mellitus and the risk factors associated with autoimmune comorbidity. Dietary control is significant to both diseases and plays an essential role in the management of short- and long-term complications. This review will discuss the background of these two autoimmune diseases as well as possible explanations for the increased prevalence, with a focus on genetic variation.

While there are several risks associated with celiac disease in T1DM patients, 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 the small intestine mucosa.1,4,5,6 It is characterized by a specific serum antibody response, which leads to malabsorptive syndrome.4,5 CD is distinguished by intestinal damage, the 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, the only treatment is adherence to a strict gluten-free diet (GFD), which includes avoidance of wheat, rye, barley, and oats.1,7 Removing oral gluten intake from the diet can repair intestinal villi, and serological markers will regularize.1

CD is T-cell mediated. Immune cells from the lamina propria, activated by gliandin-derived peptides in gluten, recruit T lymphocytes to activate the Th1 response. Consequently, this augments interferon gamma and interleukin-15 by initiating intraepithelial lymphocyte toxicity.1 The most contributing genetic factor is the human leukocyte antigen (HLA) system, as currently known.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 include ataxia, constipation, heartburn, and neuropathy.5 Clinical signs of CD include iron-deficiency anemia, vitamin deficiencies, short stature, and low bone density.2,5 Some individuals, however, have silent celiac, 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 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 the 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 an absolute deficiency, preventing cells from the uptake of glucose which is necessary for normal cell function. Consequently, this requires insulin supplementation to maintain an 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 a higher risk of hyperglycemia due to the consumption of inexpensive, carb-rich processed foods, binge eating, and diabetic ketoacidosis, which can result in coma and death.1,8

The diagnosis of T1DM is confirmed by fasting blood glucose 126 mg/dL, and an oral glucose tolerance test. Individuals with first-degree relatives with T1DM or other autoimmune diseases have an increased risk of developing T1DM.8 Furthermore, biochemical data consistent with T1DM will detect the presence of islet cell antibodies (ICA), auto-antibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and protein tyrosine phosphatase-like protein (IA2).1

Currently, treatment guidelines are based on the American Diabetes Association's 2018 Standards of Medical Care in Diabetes8, which focus on screening, diagnostic, and therapeutic actions. The ADA reports that the rate of diabetic progression is contingent upon the age at detection, number, specificity, and titer of antibodies.8 Monitoring and evaluation are dependent upon a patient's ability to self-manage and report, with recommendations aimed at 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. It contributes significantly to T cell antigen presentation, and overlap in non-HLA and HLA portions possibly explains the elevated incidence in comorbidities. MHC class II DQ peptides, HLADQ2 and DQ8, overlap in CD and T1DM. It has been revealed that the 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 those with CD. With the increasing prevalence of CD in T1DM, a study was conducted by Smigoc Schweiger et al. with the 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 an increased risk for T1DM for DQ8 and increased risk with DQ2 in CD. Results also showed that B*08 and C*07 serotypes were increased in patients with CD and T1DM. T cells in HLA class I-restricted CD8 in CD have been found to identify gliadin peptides in gluten. This suggests the reason for an autoimmune effect in these patients is due to their relationship with immune system protecting receptors.

Cytoplasmic multi-protein complexes are known as inflammasomes. Inflammasomes, dependent on NOD-like receptors (NLR), act to control inflammatory caspases-1 and -5 generation. NLRP1/NLRP1 and NLRP3/NLRP3/CIAS1 are involved in innate immunity and are related to autoimmune disorder susceptibility. They, along with NLRP2 polymorphisms, are also associated with inflammatory diseases. A recent study in 2010 by Pontillo et al. aimed to find the genetic variations associated with concurrent T1DM and CD due to increased prevalence in the diagnosis of CD. In a study of 196 Brazilian children, results have shown that NLRP3 SNPs were significantly associated with T1DM (rs10754558) and CD (rs358294199). There was also a significantly lesser G allele frequency in NLRP3 SNP rs10754558 in T1DM and CD. These findings suggest that differences in nucleotide polymorphisms could relate to differences in functionality in the immune system.
A study conducted by Gutierrez-Achury et al.11 aimed to find possible associations between T1DM and CD in the presence of either; the term for having both diseases was referred to as double-immunity in this study. Samples were drawn from three populations: 12,480 patients with T1DM, 3,098 patients with CD, and 543 patients with both. They were analyzed using EIGENSTRAT.11 A single locus, CTLA4, was found to be significantly (P < 0.05) associated with both T1D + CD/T1D and T1D + CeD/CD.11 In addition, there was a statistically strong association between T1DM + CD/T1DM and T1DM + CD/CD in the single nucleotide polymorphisms of 1L2RA.11 This research suggests that individuals with double-immunity carry a genetic predisposition that makes them more susceptible to developing both T1DM and CD rather than either disease separately.11 Further research and screening development in this area could facilitate the early identification of both CD and T1DM, thereby minimizing long-term risks.11

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

Epidemiology

In a systematic review and meta-analysis by Elfstrom et al., prevalence and epidemiology were evaluated to discover possible associations between demographics with T1DM and their risk of 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. It is known that CD is more prevalent in females; however, the meta-analysis concluded that between males and females, there is no significant difference in prevalence. There is lower CD prevalence in adults than in age-mixed samples of both children and adults. These findings suggest that there is a 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 Algeria, 10.5% in Brazil, 6.4% in Greece; 11.1% in Germany/Austria, 11.1% in India, 8.3% in Israel, 4.4% in the UK. Although there is abundant research on CD in Caucasian populations, there is a significant lack of research for CD in African American populations.

Screening Guidelines

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

A small bowel biopsy is the gold standard for screening and produces the highest diagnostic yield. During esophagoduodenoscopy, more than five biopsies should be obtained from the duodenum, specifically from the duodenal bulb and the second portion of the duodenum. Endoscopists should look for the characteristic CD appearance of flattened villi, atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes during endoscopy, which relate to mucosal damage.

Currently, there is no consistent recommendation for screening timelines. Some recommendations include screening T1DM patients for CD at initial diagnosis and then every two years for the first four years post-diagnosis.The International Society for Pediatric and Adolescent Diabetes recommends initial screening at diagnosis and annually for the following five years, with fewer screenings afterward. Screening for CD is recommended for children who exhibit symptoms characteristic of CD and for those with increased risk factors such as T1DM patients or those who have first-degree relatives with CD, as outlined in the modified Guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Further evidence is needed to determine screening frequency guidelines in pediatric and, if necessary, adult patients with T1DM.

Health Risks

There are several health risks and long-term complications associated with both CD and T1DM, such as an increased risk for other autoimmune diseases, including autoimmune thyroid disorders. Untreated CD can lead to osteoporosis, neuropathy, intestinal lymphoma, and fertility-related complications. Patients with both T1DM and CD are known to have a higher prevalence of retinopathy, nephropathy, and peripheral neuropathy. In this paper, complications with the glycemic index and vascular disease in the 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 glutenin polymers and gliadin monomers, which have high amounts of prolines and glutamines.1 Pro-inflammatory cytokines originating from the 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 the intestinal mucosa.1 IL-8 and IL-15 are secreted, leading to apoptosis resulting in damage to small intestinal permeability and damage.1
Hypoglycemic risk is increased in untreated CD due to nutrient malabsorption.4 Bakker et al.4 conducted a study to evaluate the role and risk of CD in regard to T1DM glycemic control.  Intensive insulin therapy is important for treatment and control of the glycemic index.4 Bakker notes that in other research conducted, the role of CD remains inconclusive with reports of CD diagnosis' effect on glycemic control. In the study of 31 patients of co-occurrence, 16.1% of patients reported symptomatic hypoglycemic events before the 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 sought to find the association between CD and glycemic control. Of 434 patients screened, 20 had CD and T1DM. These patients significantly reported more episodes of hypoglycemia, however, in contrast with the Bakker et al study, patients in this study reported requiring more insulin before the 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 to better monitor patients with this concomitant disease.4,5,7

Adherence to a GFD may impact glycemic control; however, there are several management difficulties with GFD in T1DM. Only 59% of patients with co-occurrence of T1DM and CD adhere 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 effects on postprandial glycemic excursion.7 Gluten-free foods have high glycemic indexes which can potentially increase insulin resistance, negatively affecting glycemic control.2,7 Interestingly, compliance with GFD may elevate insulin requirements and reduce hypoglycemic episode frequency due to increased absorption. Conversely, untreated and poorly controlled CD could result in weight loss and appearance of blood glucose improvement, although the data remains inconclusive.1,3,5,7

Vascular Disease

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

In a study by Warncke et al., individuals with T1DM and CD under 20 years old were evaluated to discover what, if any, cardiovascular risks were present in patients with a co-occurrence of T1DM and CD. Evaluated patients had significantly lower high-density lipoproteins, which increases the risk for cardiovascular disease, but GFD compliance resulted in an HDL increase and a decrease in dyslipidemia. The function of HDL is to engage in reverse cholesterol transport to remove cholesterol from the walls of blood vessels in peripheral tissues, back to the liver, which aids in cardiovascular health. 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.

GFD is related to weight gain, with 80% of patients gaining weight and 51% being overweight or obese. Gluten-free foods elevate blood glucose levels, which can result in hyperglycemia due to their higher glycemic index. Hyperglycemia plays a role in oxidative stress due to increased free fatty acids, which results in atherosclerosis. 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.

Summary

Celiac disease is a chronic intestinal autoimmune disease with increasing prevalence, as is Type 1 Diabetes Mellitus, a permanent autoimmune disease related to pancreatic beta cell destruction.1,2,4,5,6,8  The prevalence ranges from 2.0 - 12.3%, with an 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 the CTLA4 locus.9,10,11 Currently, there is no recommendation for screening frequency, 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 if uncontrolled.4,7,12 Data is inconclusive on how a gluten-free diet, necessary for those with CD, affects the glycemic index, with studies showing a possible increase in insulin requirements, more frequent hypoglycemic episodes, and concern for hyperglycemia due to the high glycemic index of gluten-free foods.3,4 Patients with concurrent T1DM and CD have been shown to have lower HDL, indicating increased cardiovascular risks, as well as weight gain on a gluten-free diet, which is associated with possible hyperglycemia and may accelerate atherosclerosis.7

Conclusions

The prevalence of celiac disease in type 1 diabetes is currently increasing due to environmental changes and genetics, with CD in T1DM patients being seen 5-7 times more frequently than CD alone.1,2 Known associations exist between co-occurrence and increased complications of glycemic control and vascular risks, with a heightened incidence rate in children.6 Future research will focus on CD in African Americans, for which currently, there is a lack.5 Further research is also needed to definitively conclude the specific risks to mechanisms of vascular risk and the effect of HbA1C 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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