Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases developing in childhood. The incidence of the disease in children increases for unknown reasons at a rate from 3 to 5% every year worldwide. The background of T1DM is associated with the autoimmune process of pancreatic beta cell destruction, which leads to absolute insulin deficiency and organ damage. Complex interactions between environmental and genetic factors contribute to the development of T1DM in genetically predisposed patients. The T1DM-inducing autoimmune process can also affect other organs, resulting in development of additional autoimmune diseases in the patient, thereby impeding diabetes control. The most common T1DM comorbidities include autoimmune thyroid diseases, celiac disease, and autoimmune gastritis; additionally, diabetes can be a component of PAS (Polyglandular Autoimmune Syndrome). The aim of this review is to assess the prevalence of T1DM-associated autoimmune diseases in children and adolescents and their impact on the course of T1DM. We also present suggestions concerning screening tests.
Diabetes is the most common chronic metabolic disease diagnosed in children and adolescents. Although it is not contagious, the disease is the first and only condition regarded by the United Nations as an epidemic of the 21st century [
In most parts of the world, type 1 diabetes is the most prevalent chronic disease in the population under 18 years of age although there are no reliable data available from many countries. There are significant differences in the incidence of the disease among different countries, with the lowest rates reported from China and Venezuela (0,1 per 100 000 people per year) and the highest in Finland and Sardinia (37 per 100 000 people per year) [
The results of international research (DIAMOND and EURODIAB) reveal an increasing trend in diabetes prevalence in most regions of the world, with the highest growth dynamics in the youngest age group [
The global increase in T1DM prevalence is a well-known fact; the incidence of type 1 diabetes in children worldwide has been growing at a rate from 3 to 5% per year since the 1960s, with the highest rate reported from fast developing countries [
The background of T1DM is probably associated with the autoimmune process of destruction of pancreatic beta cells by autoantibodies, which leads to absolute insulin deficiency and organ damage. However, there is no evidence that the destruction of the pancreatic beta cells is caused by the autoantibodies. The etiopathogenesis of this disease is complex and multifactorial. Most probably, the presence of many factors initiating or modulating the immune response leads to development of the disease [
As reported by literature, genetic factors have a crucial effect on the development of T1DM [
Genetic predisposition is related to genes located in the major histocompatibility complex (MHC) on chromosome 6p21.3, accounting for at least 40% of the family history of the disease. Depending on the age of the disease onset, between 30% and nearly 50% of individuals with type 1 diabetes have a specific heterozygous genotype comprising alleles HLA-DQA
However, environmental (quantitative or qualitative) factors seem to have a major effect on the growing T1DM incidence observed over the last decade, as it is unlikely that genetic factors can operate within such a short time [
More frequently, T1DM is diagnosed in patients with low genetic predisposition. Therefore, environmental factors seem to be the major trigger initiating the disease by stimulation of immune response against beta cells or overloading already affected beta cells, thereby accelerating the disease process, or by mitigation of the protective effect of environmental factors [
Despite the decades of research, environmental factors promoting the development of pancreatic islet autoimmunity have not been elucidated yet [
Some publications emphasize the impact of viral infections or vitamin D3 deficiency on the development of autoimmunity in pancreatic beta cells. As documented in a TRIGR study, breast-feeding or, if this is not possible, administration of casein hydrolysates reduces the risk of development of pancreatic beta-cell autoimmunity in genetically predisposed children [
Currently, it is believed that there is a subclinical disease period (prediabetes) before the onset of clinical symptoms prior to destruction of approx. 90% of pancreatic beta cells. It is associated with the onset of autoimmune response and appearance of autoantibodies, sometimes many years before the manifestation of the disease [
In recent decades, significant progress has been achieved in clarification of the involvement of autoantigens in autoimmune processes. A number of receptors, enzymes, and hormones have been identified as target antigens in organ-specific autoimmune diseases [
“Islet autoantibodies” is a general term for any group of antibodies directed against Langerhans islets or, in some circumstances, against insulin-producing beta cell autoantigens. The list of autoantibodies and autoantigens that have been discovered is long (see “
Selected autoantibodies in T1DM are as follows, adapted from [
Insulin, insulin processing, and insulin Storage: Carboxypeptidase H autoantibodies. Insulin autoantibodies (IAA). Proinsulin autoantibodies. Zinc transporter 8 protein (ZnT8A).
Protein tyrosine phosphatases: Insulinoma 2- (IA-2-) associated autoantibodies (IA-2A). IA-2
Enzymes: Carbonic anhydrase II. Chymotrypsinogen-related 30 kDa pancreatic autoantibody. DNA topoisomerase II autoantibodies. Glutamic acid decarboxylase (GAD) autoantibodies (GADA). 51 kDa aromatic-L-amino-acid decarboxylase autoantibodies.
Miscellaneous: Aminoacyl-tRNA synthetase autoantibodies. Glima 38 autoantibodies. GLUT2 autoantibodies. Glycolipid autoantibodies. GM2-1 islet ganglioside autoantibodies. Heat shock protein autoantibodies. Islet cell surface autoantibodies (ICSA). Islet cell-specific 38 kDa autoantibodies. Islet-cell cytoplasmic autoantibodies (ICA). 52 kDa RIN (rat insulinoma) autoantibodies.
It has been evidenced that the development of type 1 diabetes increases the risk of other autoimmune diseases. This is related to genetic susceptibility to development of these diseases. The autoimmune process progressing in pancreatic beta cells can also affect other organs, resulting in development of organ-specific autoimmune diseases, or various nonspecific tissues and organs, leading to development of organ-nonspecific autoimmune diseases [
The most frequent comorbidities of type 1 diabetes include Hashimoto’s thyroiditis and Graves’ disease collectively referred to as autoimmune thyroid diseases (15–30%), celiac disease (4–9%), autoimmune gastritis/pernicious anemia (5–10%), Addison’s disease (0,5%), and vitiligo (2–10%). The frequency of occurrence of these diseases is increased in children and adolescents with T1DM in comparison to healthy children [
Analysis of T1DM loci on the basis of genome-wide linkage analyses and loci for occurrence of other autoimmune diseases in the same region [
Locus | Other autoimmune disease |
---|---|
IDDM1 | All autoimmune diseases |
IDDM3 | Celiac disease |
IDDM5 | Rheumatoid arthritis |
IDDM6 | Rheumatoid arthritis, AITD, SLE |
IDDM8 | Rheumatoid arthritis |
IDDM9 | Rheumatoid arthritis |
IDDM12 (CTLA4) | Rheumatoid arthritis, multiple sclerosis, AITD, Addison disease |
IDDM13 | Rheumatoid arthritis |
16q22–q24 | Psoriasis, asthma, celiac disease |
DXS998 | Rheumatoid arthritis |
The aim of this paper is to review the literature on autoimmune diseases associated with type 1 diabetes in children and adolescents.
Hashimoto’s thyroiditis and Graves’ disease, referred to as autoimmune thyroid diseases (AITD), are the most prevalent autoimmune diseases in children and adolescents with type 1 diabetes [
Their incidence is 2–4-fold higher than in the general population [
AITD is characterized by lymphocytic infiltration caused by loss of immunological tolerance to thyroid autoantigens, which is manifested in production of autoantibodies. Consequently, thyroid exhibits various degrees of function impairment. The autoantibodies are directed against specific thyroid proteins, thyroglobulin (ATG), thyroxin peroxidase (ATPO), and TSH receptor (A-TSHR) [
AITD more often produces signs of hypothyroidism (Hashimoto’s thyroiditis) and less frequently of hyperthyroidism (Graves’ disease or the hyperactive phase of Hashimoto’s thyroiditis).
In patients with T1DM, the presence of haplotypes HLA-DQA
Physiological effects of the action of thyroid hormones include enhanced intestinal glucose absorption, glycogenolysis, and insulin catabolism in the liver. These mechanisms have a hyperglycemic effect, and even slight changes in the levels of thyroid hormones can increase the risk of hypoglycemia [
On the other hand, no effect of subclinical hypothyroidism on the growth, BMI, and glycemia control in T1DM patients has been reported by other researchers [
Nevertheless, subclinical hypothyroidism in patients with T1DM may be associated with an adverse lipid profile; therefore, early treatment reduces the risk of development of hyperlipidemia and atherosclerotic cardiovascular diseases [
Hyperthyroidism in Graves’ disease or in Hashimoto’s hyperactive phase (Hashitoxicosis) is less frequent than hypothyroidism in T1DM patients; yet, its incidence is higher than in the general population. Investigations have shown a reduced level of TSH and increased levels of T4 and T3, as well as the presence of anti-TSH receptor antibodies in Graves’ disease. Dost et al. have demonstrated that hyperthyroidism in children with T1DM is associated primarily with acute diabetes complications, for example, ketoacidosis or hypoglycemia, and arterial hypertension. However, no effect on long-term metabolic control and insulin demand has been reported [
As already mentioned, no antithyroid antibodies are usually detected at the time of diagnosis of T1DM; they appear later in the course of the disease [
Celiac disease (gluten-dependent celiac disease) is a chronic autoimmune enteropathy occurring in genetically predisposed individuals and caused by intolerance to gluten, that is, a mixture of plant proteins contained in certain European cereals (wheat, rye, and barley). Gluten induces a specific immune reaction and production of autoantibodies (antireticulin (ARA), antiendomysial (EmA), antigliadin (AGA), and anti-tissue transglutaminase (ATG)) as well as atrophy of intestinal villi [
In children with T1DM, the CD incidence is higher and ranges from 0,6 to 16,4% [
Most probably, there is a multifactorial relationship between both diseases. A key genetic factor in both cases is the presence of genotypes HLA-DQ8 (DQB
The diagnosis of celiac disease is based on determination of specific antibodies and confirmation of the disease by a biopsy of the small intestine. Antiendomysial (EMA) and anti-tissue transglutaminase (ATG) antibodies are the two most important antibodies in the diagnosis of celiac disease. Currently, determination of antigliadin antibodies is not recommended in the diagnostics of CD, as they are less sensitive and less specific than EMA and TTG [
Due to the higher incidence of IgA deficiency in patients with celiac disease than in the general population, the levels of total IgA should be determined and, if these are low, IgG antibodies should be assessed [
Determination of antibodies present in celiac disease is crucial, since most cases are asymptomatic. In children with T1DM, celiac disease is most often diagnosed in the silent or potential phase, prior to the onset of clinical symptoms of the disease [
The treatment of celiac disease involves introduction of a strict, lifelong gluten-free diet [
Recent studies have revealed that the gluten-free diet in patients with type 1 diabetes has drawbacks as well. For instance, the cooperation in compliance with the diet is poorer in patients affected by both diseases. In turn, the role of the diet in optimization of metabolic control is debatable. Gluten-free diet can result in increased weight and BMI in patients with T1DM as a consequence of consumption of great amounts of saturated fatty acids in foods with a high glycemic index and decreased amounts of protein and fiber. This, in turn, can contribute to development of microvascular complications and impair metabolic control. For all these reasons, it is essential that gluten-free diet should be introduced with care and under supervision of experienced specialists [
On the other hand, poor compliance with gluten-free diet in patients with celiac disease may lead to unexplained hypoglycemia episodes [
Guidelines issued by various diabetic societies do not provide uniform recommendations for CD screening in patients with T1DM.
In the 2014 guidelines, the American Diabetes Association (ADA) recommends determination of ATG or EMA of the IgA class shortly after diagnosis of diabetes and exclusion of IgA deficiency. Screening should be carried out in children with a family history of CD, presenting with atypical or typical symptoms of celiac disease (stunted growth, absence of weight gain, weight loss, diarrhea, tympanites, and abdominal pain), symptoms of malabsorption and frequent unexplained episodes of hypoglycemia, or deteriorated glycemia control [
The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends determination of TTG and EMA of the IgA class at the time of diagnosis of the disease and annual determination over the first five years of the disease followed by biennial tests. The determinations should be performed more frequently in the presence of clinical symptoms suggesting CD or occurrence of CD in first-degree relatives [
In turn, according to the recommendations of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPEGHAN), an intestinal biopsy may be waived if the diagnosis of CD is based on typical symptoms, presence of specific autoantibodies, a particularly high level of TTG IgA (10-fold higher than the upper limit), and a specific genotype (HLA-DQ2/DQ8). The decline in the antibody titer and the clinical response to gluten-free diet confirm the diagnosis. Gluten provocation tests and repeated biopsies are necessary only in some patients with an uncertain diagnosis or a high probability of disease in the absence of antibodies. Moreover, in groups with an increased risk of celiac disease, diagnostics can start with a genetic test, if this is possible. In the case of a negative result, celiac disease can virtually be excluded and diagnostics can be terminated at this stage. In turn, when a positive result is obtained, determination of TTG antibodies is recommended. However, due to its cost, the determination is not carried out routinely in clinical practice [
Autoimmune gastritis is an asymptomatic and common disease with higher prevalence among children with T1DM than in the general population. Clinical symptoms appear as a consequence of progression of the disease and development of atrophic gastritis with iron and vitamin B12 deficiency (pernicious anemia). Atrophic gastritis may be a cause of carcinoid tumors and gastric cancer. Laboratory diagnosis of autoimmune gastritis is based on determination of serum biomarkers, for example, anti-parietal cell autoantibodies (APCA) and antibodies directed against an inner factor, and in the case of atrophic gastritis, on determination of the concentration of pepsinogen and gastrin [
Literature reports controversies concerning the impact of other factors, for example, age, sex, or duration of the disease, on the presence of APCA. The presence of APCA is associated with an older age of T1DM patients, longer duration of the disease [
Damage to gastric parietal cells by APCA leads to autoimmune gastritis characterized by hypo- or achlorhydria, hypergastrinemia, and a reduced level of pepsinogen I. Chronic hypergastrinemia induces hyperplasia in the parietal mucosa of enterochromaphilic cells (ECL), which can cause dysplasia (atrophic gastritis) and gastric carcinoid tumors [
Patients with T1DM and serum APCA are at a greater risk of gastric autoimmunity, anemia with iron deficiency, and/or pernicious anemia. Yet, overt autoimmune gastritis is rare in children with T1DM [
Periodic examinations detecting autoimmune gastritis are particularly crucial in T1DM patients with serum GAD and/or anti-thyroid antibodies, as they help prevent and introduce early treatment of iron and vitamin B12 deficiencies as well as precancerous and cancerous lesions [
Unfortunately, there are no guidelines for management of patients with diagnosed APCA. Since autoimmune gastritis is usually asymptomatic, annual determinations of blood morphology, ferritin, vitamin B12, and gastrin levels are recommended in patients with APCA [
In developed countries, approx. 80% of primary adrenal insufficiency, Addison’s disease (AD), is caused by an autoimmune process [
Adrenal damage leads to impaired production of glucocorticosteroids, mineralocorticoids, and androgens accompanied by high serum levels of ACTH and high plasma renin activity [
It rarely occurs in the general population, with an incidence rate from 90 to 140 people per million. Over half of patients with AD present with other autoimmune diseases, for example, as components of Polyglandular Autoimmune Syndromes (PAS) [
The incidence of ACA in adult T1DM patients is 0–4% [
AD can be suspected based on typical clinical symptoms of adrenal insufficiency, for example, fatigue (due to orthostatic hypotension and hypoglycemia), weight loss, decreased appetite, nausea, desire to consume salty foods, and discoloration of the skin and mucous membranes. Moreover, unexplained hypoglycemic episodes may occur and insulin demand may be decreased in patients with T1DM [
Currently, there are no guidelines available for management of patients with diabetes and possible adrenal autoimmunity. Routine determination of ACA is not recommended; hence the risk and period of adrenal autoimmunity development in these patients are not predictable [
Another autoimmune disorder associated with T1DM is vitiligo. The disease is characterized by loss of epidermal melanocytes leading to appearance of delimited discoloration of the skin. The etiopathogenesis of the disease is not clear. Probably, the development of vitiligo is influenced by both genetic and environmental factors. Three major hypotheses concerning the pathogenesis of vitiligo have been proposed. The “neural” hypothesis suggests that accumulation of toxic neurochemical substances released from the nerve endings damages melanocytes, which results in reduced melanin production. According to the “biochemical” hypothesis, the self-destruction of pigment cells is a result of accumulation of intermediate toxic products of melanin synthesis, impairment of defense against free radicals, and accumulation of excessive amounts of hydrogen peroxide. The third hypothesis emphasizes the important role of autoimmunity [
The incidence of vitiligo in the general population is 0,5%–1% [
Diabetes can be a component of Polyglandular Autoimmune Syndromes (PAS), a heterogeneous group of rare diseases defined as functional disorders in at least two of the endocrine glands and, possibly, in other organs. They occur in genetically predisposed individuals after activation of a factor that triggers abnormal immune response. Individual endocrinopathies may develop at different times and their symptoms are preceded by the presence of specific autoantibodies in serum. The first classification was proposed by Neufeld and Blizzard in 1980 [
Characteristics of PAS, adapted from Betterle et al. [
PAS | Major components and autoantigen targets | Minor components and autoantigen targets | Genetic | ||
---|---|---|---|---|---|
I | Addison’s disease | 21-Hydroxylase | Gonadal failure | P450 side-chain cleavage enzyme, 17a-hydroxylase | AIRE gene mutations (chromosome 21) |
Chronic hypoparathyroidism | Calcium-sensing receptor | Vitiligo | SOX9, SOX10, tyrosinase | ||
Alopecia | Tyrosine hydroxylase | ||||
II | Addison’s disease (always present) | 21-Hydroxylase | Atrophic gastritis | H+/K+ pump ATPase | Polygenic inheritance (HLA-DR3, chromosome 6) |
Pernicious anaemia | Intrinsic factor | ||||
Thyroid autoimmune diseases | TSH-receptor | Celiac disease | Transglutaminase | ||
Autoimmune hepatitis | P450 (IID6, IA2) | ||||
Type 1 diabetes mellitus | Glutamic acid decarboxylase | Hypophysitis and so forth | 68, 49, 43 kD from human | ||
III | Thyroid autoimmune diseases associated with endocrinopathy other than Addison’s disease | TSH-receptor | Celiac disease | Transglutaminase | Polygenic inheritance (HLA-DR3, chromosome 6) |
Autoimmune hepatitis | P450 (IID6, IA2) | ||||
Myasthenia gravis and so forth | Acetylcholine receptor | ||||
IIIA | Autoimmune thyroiditis | Thyroid peroxidase | |||
Type 1 diabetes mellitus | Glutamic acid decarboxylase | ||||
IIIB | Autoimmune thyroiditis | Thyroid peroxidase | |||
Pernicious anaemia | Intrinsic factor | ||||
IIIC | Autoimmune thyroiditis | Thyroid peroxidase | |||
Vitiligo | SOX9, SOX10, tyrosinase | ||||
Alopecia | Tyrosine hydroxylase | ||||
Other organ-specific autoimmune disease | |||||
IV | Combination of organ-specific autoimmune diseases that do not fall in the previous types | Gonadal failure | P450 side-chain cleavage enzyme, 17a-hydroxylase | Polygenic inheritance (HLA-DR3, chromosome 6) | |
Vitiligo | SOX9, SOX10, tyrosinase | ||||
Alopecia | Tyrosine hydroxylase | ||||
Atrophic gastritis | H+/K+ pump ATPase | ||||
Pernicious anaemia | Intrinsic factor | ||||
Celiac disease | Transglutaminase | ||||
Autoimmune hepatitis | P450 (IID6, IA2) | ||||
Hypophysitis and so forth | 68, 49, 43 kD from human |
Type 1 PAS, referred to as Blizzard’s syndrome in literature, usually develops in 3–5-year-old children or younger adolescents. The diagnosis of PAS-1 requires the presence of at least two of the following conditions: Addison’s disease, hypoparathyroidism, mucocutaneous candidiasis, and an evidenced AIRE gene mutation [
Schmidt’s syndrome (type 2 PAS) is the most prevalent type of PAS afflicting adults. The elements of this syndrome include Addison’s disease, IgA deficiency, autoimmune thyroid diseases, primary hypothyroidism, hypogonadism, hypopituitarism, type 1 diabetes, Parkinson’s disease, myasthenia gravis, celiac disease, vitiligo, alopecia, pernicious anemia, stiff person syndrome, malabsorption, hepatitis, and asplenia [
PAS-3 comprises the same spectrum of endocrine gland diseases as PAS-2, though without adrenal insufficiency. Three subtypes have been distinguished: (1) Hashimoto’s disease with type 1 diabetes; (2) Hashimoto’s disease with pernicious anemia; and (3) Hashimoto’s disease with vitiligo and/or alopecia and/or other organ-specific and organ-nonspecific autoimmune diseases (celiac disease, hypogonadism, myasthenia gravis, sarcoidosis, rheumatoid arthritis, and Sjögren’s syndrome). Similar to PAS-2, PAS-3 is characterized by polygenic inheritance and is associated with the HLA class II System [
In literature, PAS-4 is distinguished when comorbid polyendocrinopathies cannot be classified as PAS-1, PAS-2, or PAS-3 [
The incidence of type 1 diabetes in the syndromes is 4–18% in PAS-1, 60% in PAS-2, and 14,5% in PAS-3. Although clinical manifestations of the disease are usually observed in the third decade of life, the first symptoms may appear in childhood. Therefore, every pediatrician should know PAS symptoms, especially in relation to multiple autoimmune comorbidities accompanying type 1 diabetes [
In patients with type 1 diabetes,organ-nonspecific autoimmune diseases can develop, for example, juvenile idiopathic arthritis (JIA), Sjögren’s syndrome, or psoriasis [
JIA is the most common organ nonspecific autoimmune disease in children. Diabetes onset occurs earlier in children with JIA: a median of 7.2 years versus 8.3 years in children without arthritis. Also, 88% of children with arthritis developed diabetes first, with the age median of diabetes onset of 5 years earlier than the age of arthritis diagnosis. A multicenter German and Austrian study involving 54 911 patients under 16 years of age with type 1 diabetes demonstrated a 0,19% incidence of JIA in these patients, which was a significantly higher value than that in the general population (0,05%). The disease was shown to affect girls twice as often as boys [
The T1DM and JIA comorbidity has increased in recent decades [
Furthermore, the coexistence of T1DM and JIA increases the risk of development of AITD and CD [
Psoriasis is a chronic inflammatory disease of the skin, nails, and joints with an immune background, affecting 2.0–3.5% of the world population [
Sjögren’s syndrome is a systemic autoimmune disease mostly affecting lacrimal and salivary glands. The spectrum of the disease ranges from dryness syndrome to systemic disease of exocrine glands [
The impact of T1DM-associated autoimmune diseases on the course of T1DM and suggestion concerning screening tests are shown in Table
Impact of T1DM-associated autoimmune diseases on the course of T1DM and suggestion concerning screening tests.
T1DM-associated autoimmune diseases | Influence on the glucose metabolism | Impact on the course of T1DM | Suggestion of screening tests |
---|---|---|---|
Hashimoto thyroiditis hypothyroidism | ↓intestinal glucose absorption | Hypoglycemia | TSH, fT4, TPO Ab, and Tg Ab every year |
| |||
Graves’ disease hyperthyroidism | ↓intestinal glucose absorption | Hypoglycemia | TSH, fT4, fT3, and TSI by signs and symptoms thyrotoxicosis or by unexplained hypoglycemias |
| |||
Celiac disease | ↓intestinal glucose absorption | Hypoglycemia | Anti-transglutaminase antibodies TTG or IgA EMA over the years of the disease followed by biennial tests |
| |||
Autoimmune gastritis | Pernicious anemia | — | — |
| |||
Addison disease | ↑insulin sensitivity | Hypoglycemia | ACTH and cortisol levels by unexplained hypoglycemias or every 2-3 years |
| |||
JIA, psoriasis, Sjogren syndrome, and other autoimmune diseases during corticosteroid therapy | ↓insulin sensitivity | Hyperglycemia | — |
The conclusions of this paper are as follows: T1DM enhances the risk of development of other autoimmune diseases in children and adolescents. Coexistence of type 1 diabetes and other autoimmune diseases impairs glucose metabolism, impedes effective insulin therapy, and deteriorates diabetes control. Monitoring of autoimmune responses in patients with autoimmune diseases is crucial, as these responses may affect other organs.
The authors declare that they have no competing interests.