Celiac Disease: Clinical Perspective Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
Celiac Disease and Endocrine Autoimmunity George J. Kahaly a Detlef Schuppan b–d a
Department of Medicine I, and b Institute for Translational Immunology and Research Center for Immunotherapy, Johannes Gutenberg University Medical Center, Mainz, Germany; c Division of Gastroenterology, Beth Israel Deaconess Medical Center, and d Harvard Medical School, Boston, Mass., USA
Abstract Background: Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. Key Messages: Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison’s disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLADQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this ab-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0155$39.50/0 E-Mail [email protected] www.karger.com/ddi
sence does not significantly affect these patients’ incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk. Conclusions: The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives. © 2015 S. Karger AG, Basel
Celiac Disease
Celiac disease (CD) is defined as a lifelong intolerance to dietary gluten that results in small-intestinal inflammation, villous atrophy, crypt hyperplasia and often malabsorption. The ingestion of certain cereal grains, mainly wheat, rye and barley drives this T cell-driven autodestructive process within the small-intestinal mucosa which usually recovers when these cereals are rigorously withdrawn from the diet. Both endoscopic-histological diagnosis and the presence of circulating IgA antibodies (Ab) to tissue transglutaminase (TG2) confirm the diagnosis. These Ab ultimately disappear in most patients with CD who follow a gluten-free diet. Susceptibility to CD is determined to a significant extent by genetic factors Prof. George J. Kahaly Johannes Gutenberg University Medical Center Langenbeckstrasse 1 DE–55101 Mainz (Germany) E-Mail Kahaly @ ukmainz.de
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Key Words Celiac disease · Autoimmune thyroid disease · Endocrine autoimmunity · Polyglandular autoimmune syndrome · Type 1 diabetes
Autoantigens
Autoimmune disease
TG2 TPO, Tg TSH receptor, TPO Islet cells, GAD, IA2, insulin P450 cytochromes: 21-OH, 17-OH, SCC 17-OH Calcium-sensing receptor
CD HT GD T1D AD Hypogonadism Hypoparathyroidism
17-OH and 21-OH = 17- and 21-α-hydroxylase (steroid P450 enzymes); SCC = side chain cleavage enzyme (steroidogenic P450 enzyme); Tg = thyroglobulin.
localized within the HLA region. Approximately 90–95% of CD patients share the HLA DR3/DQ2, mainly HLA DQA1*0501-DQB1*0201, the rest carries HLA DR4/ DQ8, or both haplotypes. However, HLA DR4/DQ8 can be the prevalent predisposition in e.g. indigenous populations of South America. The prevalence of HLA DQ2 in most populations is 25–30%, but only a minority of these will ever develop CD. This implies the involvement of additional, non-HLA-linked genes and environmental triggers in the pathogenesis of CD. The ubiquitous enzyme TG2, the CD autoantigen, is central to the pathogenesis of CD since it can deamidate specific glutamine residues in certain gluten peptides that reach the subepithelial small-intestinal lamina propria, thereby increasing their affinity to DQ2 or DQ8 on antigen-presenting cells like dendritic and B cells, favoring the subsequent gluten-specific destructive T cell response. The coexistence of CD and endocrine autoimmune diseases, e.g. type 1 diabetes (T1D), could be explained by sharing a common genetic factor in the HLA region, such as DR3 or DR4 (in association with DQ2 and DQ8, respectively), or by molecular mimicry by which gliadin or TG2 would activate T cells that are cross-reactive with autoantigens relevant to T1D. During active β-cell destruction, TG2, which is expressed in pancreatic islets, might be presented in an immunogenic form. In view of the high frequency of CD in patients with the HLA DQA1*0501-DQB1*0201 haplotype, this presentation may be facilitated by these alleles. Such inflammatory responses may have the capacity to persist in genetically susceptible hosts and lead to chronic organ-specific autoimmune disease. Furthermore, it has been suggested that in the development of autoimmunity in T1D the fail156
Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
ure to achieve tolerance to autoantigens derives from the gut. The prevalence of CD in Western countries is estimated at 0.5% in Germany and 2.5% in elderly Fins. It ranges between 3 and 8% in patients with T1D. Conversely, between 3 and 12% of patients with CD have T1D. Also, at least 5% of patients with CD have autoimmune thyroid disease (AITD), and between 2 and 4% of patients with AITD are affected by CD. In more than 50% of today’s newly detected patients with CD, clinical features are subtle, with mild abdominal discomfort and bloating, weight loss, fatigue, but also growth abnormalities mimicking constitutional growth delay, infertility, recurrent aphthous stomatitis, low bone mineralization and hypocalcemia with vitamin D deficiency and compensatory hyperparathyroidism. Late complications like refractory CD type II, a premalignant condition and overt enteropathyassociated T-cell lymphoma are rare. Iron or folic acid deficiency with or without anemia is the most common laboratory finding. Hypoglycemia, a reduction of insulin requirements and brittle diabetes may indicate the presence of CD in T1D (table 1). CD is considered sufficiently prevalent, and the benefits of diagnosis and treatment by gluten withdrawal are such that it is advocated to screen all T1D patients for this disorder. When serological screening is used, most cases of CD will be detected within 1 year after onset of T1D. Current recommendations for screening subjects with T1D and AITD are to measure TG2 autoantibodies at diagnosis and with symptoms of CD. When positive, subjects should have a smallintestinal biopsy to confirm diagnosis [1–7].
Autoimmune Thyroid Diseases
AITD include Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). HT is the most prevalent autoimmune disease associated with other autoimmune endocrinopathies and is defined by the presence of thyroid peroxidase (TPO) or thyroglobulin Ab and either normal or elevated TSH concentrations in the absence of medications. Although many subjects with HT are hypothyroid, there is a subgroup of thyroid Ab-positive cases who are euthyroid. It may take years for those subjects to develop thyroid dysfunction. TPO-Ab are predictive of thyroid failure with an annual incidence of 4.3% in subjects with an initial elevated TSH level (>5.0 mU/l). TSH alone predicts thyroid failure since at a TSH level of 5 mU/l, the probability of hypothyroidism is 0.5% per year, and rates of progression increase with higher initial serum TSH or Kahaly/Schuppan
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Table 1. Autoantigens in patients with CD and autoimmune endocrine syndromes
thyroid Ab concentrations. TPO-Ab are present in 15– 30% of adults and in 5–22% of children with T1D, compared with 2–10% and 1–4%, respectively, in matched controls. The prevalence of subclinical hypothyroidism in T1D patients is estimated at 13–20% compared with 3–6% in a nondiabetic population, with preponderance for older female patients. Up to 50% of TPO-Ab-positive T1D patients progress to overt AITD. Cross-sectional analysis has shown that hypothyroidism is present in 4–18% of subjects with T1D. Long-term follow-up suggests that as many as 30% of patients with T1D will develop AITD. T1D subjects with glutamate decarboxylase (GAD) Ab positivity, in contrast to tyrosine phosphatase (IA2) Ab-positive patients, are more prone to have TPOAb. T1D patients with persisting islet cell Ab positivity for more than 3 years or with GAD-Ab-positivity are at increased risk of thyroid autoimmunity. Other factors such as age, T1D duration, and gender (female preponderance) influence the link between T1D and AITD. At-risk haplotypes for HT are the HLA DQA1*0301 (linked to DR4), DQB1*0301 (linked to DR5) and DQB1*0201 (linked to DR3). The HLA haplotype DR3-DQB1*0201 contributes to the genetic susceptibility to T1D, AITD and the polyglandular autoimmune syndrome (PAS). Other loci may also contribute to the clustering and may influence disease phenotype and severity. A symmetric, painless goiter is usually the first presentation in HT, although about 10% of patients have atrophic thyroid glands. Treatment of hypothyroidism is important because the decrease in basal metabolism may cause weight gain, hyperlipidemia, atherosclerotic heart disease, and may affect diabetes control, growth, menses, and increase the risk of adverse pregnancy outcome. Even more, the presence of Ab may be associated with an increased likelihood of spontaneous abortion, even in the absence of overt disease. Although thyroid lymphoma is very rare, the risk of this disease is increased ∼67-fold in patients with HT. Treatment of HT-induced hypothyroidism consists of supplementation of levothyroxine sodium. The goal of replacement therapy is to normalize serum TSH levels. Current recommendations are to screen T1D patients for dysthyroidism using TSH after stabilization at onset of T1D, or in case of symptoms of hypothyroidism or hyperthyroidism, and every 1–2 years thereafter. Since patients who are TPO-Ab positive have an 18-fold increased risk of developing thyroid disease compared with patients who are TPO-Ab negative, it is suggested to screen T1D patients using TPO-Ab, TSH and T4 levels at onset of T1D and yearly thereafter.
Autoimmune hyperthyroidism is less common. Graves’ hyperthyroidism is caused by thyroid-stimulating Ab that bind to and activate the TSH receptor (TSHR) on thyroid cells. These Ab not only cause hypersecretion of thyroid hormone but also promote hypertrophy and hyperplasia of thyroid follicles, resulting in a goiter. GD shares many immunological features with HT, including high serum concentrations of Ab against thyroglobulin and TPO. Thyroid function tests reveal a suppressed TSH level, elevated levels of serum T4 and T3, and positive TSH-R-Ab. GD affects approximately 1% of the general population and is the underlying cause of 50– 80% of cases of hyperthyroidism. Subclinical hyperthyroidism can be diagnosed in 6–10% of T1D patients, compared with 0.1–2% in the nondiabetic population. The incidence of overt hyperthyroidism in persons with a suppressed serum TSH is calculated at 2–4% per year. Women are 5–10 times more at risk of developing GD than men. Stress may trigger the disease. At-risk haplotypes for GD are DQA1*0501 (linked to DR3 and to DR5) and DQB1*0302 (linked to DR4). The severity and duration of GD and the age of the patient determine the manifestations of hyperthyroidism: nervousness, emotional lability, disturbed sleep, fatigue, palpitations and atrial fibrillation, heat intolerance, weight loss, and orbitopathy. Among T1D patients treated with insulin, hyperthyroidism increases insulin requirements. Hyperthyroidism may aggravate glucose intolerance by mechanisms which include increased hexose intestinal absorption, increased glucose production (gluconeogenesis and glycogenolysis), and decreased responsiveness to insulin. Current treatment of GD consists of antithyroid drugs (ATD), radioactive iodine, and surgery. ATD inhibit thyroid hormone production and decrease the levels of TSH-R-Ab. In older subjects, consensus exists regarding the treatment of subclinical hyperthyroidism with ATD to prevent atrial fibrillation [8–20].
Celiac Disease and Endocrine Autoimmunity
Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
T1D is a T cell-mediated autoimmune disease that develops in genetically susceptible individuals and results in destruction of insulin-producing β-cells. In up to one third of patients, the autoimmune attack is not limited to β-cells, but expands into a PAS. Of T1D subjects, 15–30% have AITD, 0.5% have Addison’s disease (AD), and 3–12% present with CD. The association between T1D and organ-specific autoimmune disease can be explained by sharing a common genetic background, but also by a 157
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Type 1 Diabetes
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Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
pression of HLA DR2 is decreased in persons with T1D. Certain combinations of HLA alleles are found with a frequency greater than expected and are thus not randomly distributed within the general population. This phenomenon is called linkage disequilibrium. Particularly, HLA DQA1*0301-DQB1*0302 (in linkage disequilibrium with DR4) and DQA1*0501-B1*0201 (in linkage disequilibrium with DR3) haplotypes confer a high diabetogenic risk. The absolute risk of a child with this DR3/DR4 genotype developing T1D from the general population is similar to a first-degree relative of a T1D patient (1 in 20). DQB1*0602 and DQA1*0102 alleles are associated with dominant protection. The model of T1D as a chronic autoimmune disorder begins with environmental triggers in genetically susceptible persons, progressing to autoimmunity with appearance of β-cell Ab, further evolving towards metabolic dysregulation with loss of first-phase insulin response, increasing HbA1c within the normal range, impaired fasting glycemia or impaired glucose tolerance, and finally resulting in overt T1D and loss of C-peptide. The first-phase insulin response measured by i.v. glucose tolerance testing is the sum of insulin levels at the 1st and 3rd min after administration of an i.v. glucose load. Many subjects with T1D had a low first phase before the diagnosis of T1D, and this may persist for years before clinical disease onset. These data suggest that subjects go through a phase of decreasing β-cell mass. The exact β-cell mass at diagnosis is poorly defined. For patients with longterm T1D, it is usually decreased to less than 1% of normal. Residual β-cell function can also be analyzed according to the measurement of C-peptide release as induced by a hyperglycemic clamp procedure. Low first-phase Cpeptide response specifically predicts impending T1D, while a low second-phase response probably reflects an earlier disease stage. A typical de novo T1D patient presents with hyperglycemia and polyuria, polydipsia and weight loss. Ketoacidosis is common and Ab status at the moment of T1D diagnosis should be verified [21–30].
Addison’s Disease
AD is the most frequent cause of primary adrenal insufficiency. It results from destruction of the adrenal cortex with an ensuing deficiency of cortisol, aldosterone, and in females of adrenal androgens. AD affects 1 in 10,000 in the general population and results from destruction of the adrenal cortex by cytotoxic T lymphocytes. In the active phase of the disease, there is a wideKahaly/Schuppan
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defective immunoregulation. T1D is characterized by the appearance of insulitis and the presence of β-cell Ab. Several lines of evidence support the autoimmune nature of the β-cell destructive process: (a) infiltration of the pancreatic islets by lymphocytes and macrophages (insulitis), (b) presence of Ab to islet cell antigens (ICA), IA2, glutamic acid decarboxylase-65 (GAD), insulin (IAA), and zinc transporter ZnT8 (Slc30A8), (c) a preferential occurrence of T1D in persons carrying specific allelic combinations at immune response loci within the HLA gene complex, (d) increased prevalence of organ-specific autoimmune disorders in T1D, (e) the disease can be transferred by spleen or bone marrow cells, and finally (f) animal models of T1D that show a defect in immunoregulation contributing to the onset of disease. One or more β-cell Ab are present in approximately 90% of new-onset patients with T1D. They appear to develop sequentially. Insulin-Ab are often the first expressed, especially in younger children. GAD-Ab positivity is suggested to represent a propensity for general autoimmunity, while IA2-Ab positivity may be a more specific marker of β-cell destruction. β-Cell Ab also represents important preclinical markers of the disease as they may be present for years before T1D diagnosis. The risk of T1D for a first-degree relative depends on the number and type of Ab that are present. Family members who express insulin, GAD and IA2-Ab have a 75% risk of developing T1D within the next 5 years, as compared with a 10–25% 5-year risk in those expressing only one of the Ab. The general 5-year risk for T1D is 34% in subjects positive for ≥3 Ab. Progression to T1D amounted to 12% within 5 years among siblings positive for IAA, 20% for ICA, 19% for GAD but 59% for IA-2-Ab. IA-2-Ab were detected in 1.7% of all siblings and in 56% of the prediabetic subjects on first sampling. Among genes associated with T1D, the HLA gene complex on chromosome 6p21 is the genetic factor with the strongest association. Another gene located on chromosome 11p15 in the upstream region of the insulin gene also confers susceptibility to T1D. Multiple additional genes also contribute to T1D susceptibility. One of these is IDDM12 on chromosome 2q33, which contains two autoimmune disease candidate genes: CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and CD28, encoding for T-cell receptors involved in controlling T-cell proliferation. Other important genes include the MHC I-related gene A (MIC-A) and the protein IA2 nonreceptor type 22 (PTPN22). Ninety percent of Caucasian T1D patients express the HLA DR3 and/or DR4 alleles. These HLA alleles are expressed in 30–40% of the general white population. Ex-
spread mononuclear cell infiltrate. There is loss of normal three-layer structure of the adrenal cortex, and adrenocortical cells show necrosis and pleomorphism. The cytochrome P450 enzyme steroid 21-hydroxylase (21-OH) has been identified as a major antigen for the Ab. Also in AD, screening for 21-OH-Ab identifies subjects who are at risk to develop AD before clinical presentation. Clinical disease can either present as isolated AD or in combination with other autoimmune diseases as part of the PAS. In T1D, the prevalence of 21-OH-Ab ranges between 1 and 3%, compared with 1 and 0.5% in first-degree relatives and controls, respectively. A small number of Abpositive subjects have been followed for the development of AD, and a yearly incidence of AD of approximately 20% has been observed. Adrenal-Ab are more frequent in female subjects and in T1D patients with persisting islet cell Ab. Furthermore, AD is frequently associated with other autoimmune endocrinopathies, particularly with HT. In patients with AD, as many as 70% with 21-OH-Ab also expressed thyroid autoimmunity. Genetic susceptibility for AD has also been linked to the MHC complex on chromosome 6, as CD, AITD and T1D. The HLA DRB1*0404/DQ8-DRB1*0301/DQ2 genotype occurs at an increased frequency in individuals with isolated AD and in those with AD and T1D. A second locus within the MHC, the MHC class I-related MIC-A, has been linked to AD. Homozygosity for MICA5.1 (allele 5.1) was associated with an 18-fold increased risk for AD. Adrenal insufficiency may cause persistent vomiting, anorexia, hypoglycemia, and unexplained weight loss in an adult, malaise, ill-defined fatigue, muscular weakness, hypotension, and craving for salt. The most specific sign of primary AD is generalized hyperpigmentation of the skin and mucosal surfaces, which is due to the high plasma concentrations of melanocyte-stimulating activity of β-lipotropin, which derives from the same precursor as ACTH. Laboratory tests can aid in the diagnosis: hyponatremia, hyperkalemia, and acidosis. In addition, hypocorticism may, by reducing the insulin needs, cause frequent attacks of hypoglycemia. Patients with symptomatic AD should be treated with hydrocortisone and with fludrocortisone as a substitute for aldosterone. Patients with suspected AD and hypothyroidism should be evaluated and treated for adrenal insufficiency prior to replacement of thyroid hormone to avoid an Addison crisis, since thyroxine may increase hepatic corticosteroid metabolism. The natural history of the progression of the disease follows a typical pattern (different stages) which can be correlated with clinical symptoms. One discriminates a potential phase (genetic
PAS form different clusters of autoimmune disorders and are rare endocrinopathies characterized by the coexistence of at least two glandular autoimmune-mediated diseases. Two major subtypes of PAS, types I and II, are distinguished according to age at presentation, characteristic patterns of disease combinations, and different modes of inheritance. PAS I, also known as autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy or multiple endocrine deficiency autoimmune candidiasis syndromes, usually manifests in infancy or childhood at age 3–5 years or in early adolescence and, therefore, is also called juvenile autoimmune polyendocrinopathy. It is defined by a persistent fungal infection (chronic mucocutaneous candidiasis), the presence of acquired hypoparathyroidism, and AD. In most patients, mucocutaneous candidiasis precedes the other immune disorders, usually followed by hypoparathyroidism. The female-to-male ratio varies from 0.8:1 to 2.4:1. The highest prevalences of PAS I have been found in populations characterized by high degree of consanguinity or descendant of small founder populations, particularly in Iranian Jews and Finns. PAS I is a monogenic disease with autosomal recessive inheritance caused by mutations in the autoimmune regulatory gene on chromosome 21. PAS II is more common and occurs in adulthood, mainly in the third or fourth decade (table 2). It is characterized by AD with AITD and/or T1D. AD may precede other endocrinopathies. Vitiligo and gonadal failure are more rarely associated with PAS II than with type I. Especially in adults, the presence of one autoimmune endocrine disease is associated with an increased risk of developing autoimmunity to other tissues. Each of these disorders is characterized by several stages beginning with
Celiac Disease and Endocrine Autoimmunity
Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
susceptibility and/or 21-OH-Ab), a latent phase [elevated plasma renin activity (PRA) and normal basal cortisol and ACTH levels], and a clinical phase (a diminished basal cortisol and elevated ACTH concentration). These parameters constitute the endocrine evaluation of adrenal function: PRA, ACTH, cortisol and corticotropin stimulation testing. Screening for 21-OH-Ab at diagnosis of T1D and then every 2 years seems to be a good practice. If Ab are positive, one has to evaluate morning baseline ACTH, cortisol and PRA levels (supine position) and perform a corticotropin stimulation test. However, in the absence of symptoms, an annual basal cortisol and ACTH may be sufficient [31–34].
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Polyglandular Autoimmune Syndromes
Table 2. Characteristics of the PAS
Incidence Male:female ratio Age at onset Autoimmune Endocrine Diseases Concomitant Disease
PAS type I
PAS type II
Celiac Disease and Endocrine Autoimmunity George J. Kahaly a Detlef Schuppan b–d a
Department of Medicine I, and b Institute for Translational Immunology and Research Center for Immunotherapy, Johannes Gutenberg University Medical Center, Mainz, Germany; c Division of Gastroenterology, Beth Israel Deaconess Medical Center, and d Harvard Medical School, Boston, Mass., USA
Abstract Background: Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. Key Messages: Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison’s disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLADQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this ab-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0155$39.50/0 E-Mail [email protected] www.karger.com/ddi
sence does not significantly affect these patients’ incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk. Conclusions: The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives. © 2015 S. Karger AG, Basel
Celiac Disease
Celiac disease (CD) is defined as a lifelong intolerance to dietary gluten that results in small-intestinal inflammation, villous atrophy, crypt hyperplasia and often malabsorption. The ingestion of certain cereal grains, mainly wheat, rye and barley drives this T cell-driven autodestructive process within the small-intestinal mucosa which usually recovers when these cereals are rigorously withdrawn from the diet. Both endoscopic-histological diagnosis and the presence of circulating IgA antibodies (Ab) to tissue transglutaminase (TG2) confirm the diagnosis. These Ab ultimately disappear in most patients with CD who follow a gluten-free diet. Susceptibility to CD is determined to a significant extent by genetic factors Prof. George J. Kahaly Johannes Gutenberg University Medical Center Langenbeckstrasse 1 DE–55101 Mainz (Germany) E-Mail Kahaly @ ukmainz.de
Downloaded by: NYU Medical Center Library 128.122.253.228 - 4/30/2015 2:28:18 PM
Key Words Celiac disease · Autoimmune thyroid disease · Endocrine autoimmunity · Polyglandular autoimmune syndrome · Type 1 diabetes
Autoantigens
Autoimmune disease
TG2 TPO, Tg TSH receptor, TPO Islet cells, GAD, IA2, insulin P450 cytochromes: 21-OH, 17-OH, SCC 17-OH Calcium-sensing receptor
CD HT GD T1D AD Hypogonadism Hypoparathyroidism
17-OH and 21-OH = 17- and 21-α-hydroxylase (steroid P450 enzymes); SCC = side chain cleavage enzyme (steroidogenic P450 enzyme); Tg = thyroglobulin.
localized within the HLA region. Approximately 90–95% of CD patients share the HLA DR3/DQ2, mainly HLA DQA1*0501-DQB1*0201, the rest carries HLA DR4/ DQ8, or both haplotypes. However, HLA DR4/DQ8 can be the prevalent predisposition in e.g. indigenous populations of South America. The prevalence of HLA DQ2 in most populations is 25–30%, but only a minority of these will ever develop CD. This implies the involvement of additional, non-HLA-linked genes and environmental triggers in the pathogenesis of CD. The ubiquitous enzyme TG2, the CD autoantigen, is central to the pathogenesis of CD since it can deamidate specific glutamine residues in certain gluten peptides that reach the subepithelial small-intestinal lamina propria, thereby increasing their affinity to DQ2 or DQ8 on antigen-presenting cells like dendritic and B cells, favoring the subsequent gluten-specific destructive T cell response. The coexistence of CD and endocrine autoimmune diseases, e.g. type 1 diabetes (T1D), could be explained by sharing a common genetic factor in the HLA region, such as DR3 or DR4 (in association with DQ2 and DQ8, respectively), or by molecular mimicry by which gliadin or TG2 would activate T cells that are cross-reactive with autoantigens relevant to T1D. During active β-cell destruction, TG2, which is expressed in pancreatic islets, might be presented in an immunogenic form. In view of the high frequency of CD in patients with the HLA DQA1*0501-DQB1*0201 haplotype, this presentation may be facilitated by these alleles. Such inflammatory responses may have the capacity to persist in genetically susceptible hosts and lead to chronic organ-specific autoimmune disease. Furthermore, it has been suggested that in the development of autoimmunity in T1D the fail156
Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
ure to achieve tolerance to autoantigens derives from the gut. The prevalence of CD in Western countries is estimated at 0.5% in Germany and 2.5% in elderly Fins. It ranges between 3 and 8% in patients with T1D. Conversely, between 3 and 12% of patients with CD have T1D. Also, at least 5% of patients with CD have autoimmune thyroid disease (AITD), and between 2 and 4% of patients with AITD are affected by CD. In more than 50% of today’s newly detected patients with CD, clinical features are subtle, with mild abdominal discomfort and bloating, weight loss, fatigue, but also growth abnormalities mimicking constitutional growth delay, infertility, recurrent aphthous stomatitis, low bone mineralization and hypocalcemia with vitamin D deficiency and compensatory hyperparathyroidism. Late complications like refractory CD type II, a premalignant condition and overt enteropathyassociated T-cell lymphoma are rare. Iron or folic acid deficiency with or without anemia is the most common laboratory finding. Hypoglycemia, a reduction of insulin requirements and brittle diabetes may indicate the presence of CD in T1D (table 1). CD is considered sufficiently prevalent, and the benefits of diagnosis and treatment by gluten withdrawal are such that it is advocated to screen all T1D patients for this disorder. When serological screening is used, most cases of CD will be detected within 1 year after onset of T1D. Current recommendations for screening subjects with T1D and AITD are to measure TG2 autoantibodies at diagnosis and with symptoms of CD. When positive, subjects should have a smallintestinal biopsy to confirm diagnosis [1–7].
Autoimmune Thyroid Diseases
AITD include Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). HT is the most prevalent autoimmune disease associated with other autoimmune endocrinopathies and is defined by the presence of thyroid peroxidase (TPO) or thyroglobulin Ab and either normal or elevated TSH concentrations in the absence of medications. Although many subjects with HT are hypothyroid, there is a subgroup of thyroid Ab-positive cases who are euthyroid. It may take years for those subjects to develop thyroid dysfunction. TPO-Ab are predictive of thyroid failure with an annual incidence of 4.3% in subjects with an initial elevated TSH level (>5.0 mU/l). TSH alone predicts thyroid failure since at a TSH level of 5 mU/l, the probability of hypothyroidism is 0.5% per year, and rates of progression increase with higher initial serum TSH or Kahaly/Schuppan
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Table 1. Autoantigens in patients with CD and autoimmune endocrine syndromes
thyroid Ab concentrations. TPO-Ab are present in 15– 30% of adults and in 5–22% of children with T1D, compared with 2–10% and 1–4%, respectively, in matched controls. The prevalence of subclinical hypothyroidism in T1D patients is estimated at 13–20% compared with 3–6% in a nondiabetic population, with preponderance for older female patients. Up to 50% of TPO-Ab-positive T1D patients progress to overt AITD. Cross-sectional analysis has shown that hypothyroidism is present in 4–18% of subjects with T1D. Long-term follow-up suggests that as many as 30% of patients with T1D will develop AITD. T1D subjects with glutamate decarboxylase (GAD) Ab positivity, in contrast to tyrosine phosphatase (IA2) Ab-positive patients, are more prone to have TPOAb. T1D patients with persisting islet cell Ab positivity for more than 3 years or with GAD-Ab-positivity are at increased risk of thyroid autoimmunity. Other factors such as age, T1D duration, and gender (female preponderance) influence the link between T1D and AITD. At-risk haplotypes for HT are the HLA DQA1*0301 (linked to DR4), DQB1*0301 (linked to DR5) and DQB1*0201 (linked to DR3). The HLA haplotype DR3-DQB1*0201 contributes to the genetic susceptibility to T1D, AITD and the polyglandular autoimmune syndrome (PAS). Other loci may also contribute to the clustering and may influence disease phenotype and severity. A symmetric, painless goiter is usually the first presentation in HT, although about 10% of patients have atrophic thyroid glands. Treatment of hypothyroidism is important because the decrease in basal metabolism may cause weight gain, hyperlipidemia, atherosclerotic heart disease, and may affect diabetes control, growth, menses, and increase the risk of adverse pregnancy outcome. Even more, the presence of Ab may be associated with an increased likelihood of spontaneous abortion, even in the absence of overt disease. Although thyroid lymphoma is very rare, the risk of this disease is increased ∼67-fold in patients with HT. Treatment of HT-induced hypothyroidism consists of supplementation of levothyroxine sodium. The goal of replacement therapy is to normalize serum TSH levels. Current recommendations are to screen T1D patients for dysthyroidism using TSH after stabilization at onset of T1D, or in case of symptoms of hypothyroidism or hyperthyroidism, and every 1–2 years thereafter. Since patients who are TPO-Ab positive have an 18-fold increased risk of developing thyroid disease compared with patients who are TPO-Ab negative, it is suggested to screen T1D patients using TPO-Ab, TSH and T4 levels at onset of T1D and yearly thereafter.
Autoimmune hyperthyroidism is less common. Graves’ hyperthyroidism is caused by thyroid-stimulating Ab that bind to and activate the TSH receptor (TSHR) on thyroid cells. These Ab not only cause hypersecretion of thyroid hormone but also promote hypertrophy and hyperplasia of thyroid follicles, resulting in a goiter. GD shares many immunological features with HT, including high serum concentrations of Ab against thyroglobulin and TPO. Thyroid function tests reveal a suppressed TSH level, elevated levels of serum T4 and T3, and positive TSH-R-Ab. GD affects approximately 1% of the general population and is the underlying cause of 50– 80% of cases of hyperthyroidism. Subclinical hyperthyroidism can be diagnosed in 6–10% of T1D patients, compared with 0.1–2% in the nondiabetic population. The incidence of overt hyperthyroidism in persons with a suppressed serum TSH is calculated at 2–4% per year. Women are 5–10 times more at risk of developing GD than men. Stress may trigger the disease. At-risk haplotypes for GD are DQA1*0501 (linked to DR3 and to DR5) and DQB1*0302 (linked to DR4). The severity and duration of GD and the age of the patient determine the manifestations of hyperthyroidism: nervousness, emotional lability, disturbed sleep, fatigue, palpitations and atrial fibrillation, heat intolerance, weight loss, and orbitopathy. Among T1D patients treated with insulin, hyperthyroidism increases insulin requirements. Hyperthyroidism may aggravate glucose intolerance by mechanisms which include increased hexose intestinal absorption, increased glucose production (gluconeogenesis and glycogenolysis), and decreased responsiveness to insulin. Current treatment of GD consists of antithyroid drugs (ATD), radioactive iodine, and surgery. ATD inhibit thyroid hormone production and decrease the levels of TSH-R-Ab. In older subjects, consensus exists regarding the treatment of subclinical hyperthyroidism with ATD to prevent atrial fibrillation [8–20].
Celiac Disease and Endocrine Autoimmunity
Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
T1D is a T cell-mediated autoimmune disease that develops in genetically susceptible individuals and results in destruction of insulin-producing β-cells. In up to one third of patients, the autoimmune attack is not limited to β-cells, but expands into a PAS. Of T1D subjects, 15–30% have AITD, 0.5% have Addison’s disease (AD), and 3–12% present with CD. The association between T1D and organ-specific autoimmune disease can be explained by sharing a common genetic background, but also by a 157
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Type 1 Diabetes
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pression of HLA DR2 is decreased in persons with T1D. Certain combinations of HLA alleles are found with a frequency greater than expected and are thus not randomly distributed within the general population. This phenomenon is called linkage disequilibrium. Particularly, HLA DQA1*0301-DQB1*0302 (in linkage disequilibrium with DR4) and DQA1*0501-B1*0201 (in linkage disequilibrium with DR3) haplotypes confer a high diabetogenic risk. The absolute risk of a child with this DR3/DR4 genotype developing T1D from the general population is similar to a first-degree relative of a T1D patient (1 in 20). DQB1*0602 and DQA1*0102 alleles are associated with dominant protection. The model of T1D as a chronic autoimmune disorder begins with environmental triggers in genetically susceptible persons, progressing to autoimmunity with appearance of β-cell Ab, further evolving towards metabolic dysregulation with loss of first-phase insulin response, increasing HbA1c within the normal range, impaired fasting glycemia or impaired glucose tolerance, and finally resulting in overt T1D and loss of C-peptide. The first-phase insulin response measured by i.v. glucose tolerance testing is the sum of insulin levels at the 1st and 3rd min after administration of an i.v. glucose load. Many subjects with T1D had a low first phase before the diagnosis of T1D, and this may persist for years before clinical disease onset. These data suggest that subjects go through a phase of decreasing β-cell mass. The exact β-cell mass at diagnosis is poorly defined. For patients with longterm T1D, it is usually decreased to less than 1% of normal. Residual β-cell function can also be analyzed according to the measurement of C-peptide release as induced by a hyperglycemic clamp procedure. Low first-phase Cpeptide response specifically predicts impending T1D, while a low second-phase response probably reflects an earlier disease stage. A typical de novo T1D patient presents with hyperglycemia and polyuria, polydipsia and weight loss. Ketoacidosis is common and Ab status at the moment of T1D diagnosis should be verified [21–30].
Addison’s Disease
AD is the most frequent cause of primary adrenal insufficiency. It results from destruction of the adrenal cortex with an ensuing deficiency of cortisol, aldosterone, and in females of adrenal androgens. AD affects 1 in 10,000 in the general population and results from destruction of the adrenal cortex by cytotoxic T lymphocytes. In the active phase of the disease, there is a wideKahaly/Schuppan
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defective immunoregulation. T1D is characterized by the appearance of insulitis and the presence of β-cell Ab. Several lines of evidence support the autoimmune nature of the β-cell destructive process: (a) infiltration of the pancreatic islets by lymphocytes and macrophages (insulitis), (b) presence of Ab to islet cell antigens (ICA), IA2, glutamic acid decarboxylase-65 (GAD), insulin (IAA), and zinc transporter ZnT8 (Slc30A8), (c) a preferential occurrence of T1D in persons carrying specific allelic combinations at immune response loci within the HLA gene complex, (d) increased prevalence of organ-specific autoimmune disorders in T1D, (e) the disease can be transferred by spleen or bone marrow cells, and finally (f) animal models of T1D that show a defect in immunoregulation contributing to the onset of disease. One or more β-cell Ab are present in approximately 90% of new-onset patients with T1D. They appear to develop sequentially. Insulin-Ab are often the first expressed, especially in younger children. GAD-Ab positivity is suggested to represent a propensity for general autoimmunity, while IA2-Ab positivity may be a more specific marker of β-cell destruction. β-Cell Ab also represents important preclinical markers of the disease as they may be present for years before T1D diagnosis. The risk of T1D for a first-degree relative depends on the number and type of Ab that are present. Family members who express insulin, GAD and IA2-Ab have a 75% risk of developing T1D within the next 5 years, as compared with a 10–25% 5-year risk in those expressing only one of the Ab. The general 5-year risk for T1D is 34% in subjects positive for ≥3 Ab. Progression to T1D amounted to 12% within 5 years among siblings positive for IAA, 20% for ICA, 19% for GAD but 59% for IA-2-Ab. IA-2-Ab were detected in 1.7% of all siblings and in 56% of the prediabetic subjects on first sampling. Among genes associated with T1D, the HLA gene complex on chromosome 6p21 is the genetic factor with the strongest association. Another gene located on chromosome 11p15 in the upstream region of the insulin gene also confers susceptibility to T1D. Multiple additional genes also contribute to T1D susceptibility. One of these is IDDM12 on chromosome 2q33, which contains two autoimmune disease candidate genes: CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and CD28, encoding for T-cell receptors involved in controlling T-cell proliferation. Other important genes include the MHC I-related gene A (MIC-A) and the protein IA2 nonreceptor type 22 (PTPN22). Ninety percent of Caucasian T1D patients express the HLA DR3 and/or DR4 alleles. These HLA alleles are expressed in 30–40% of the general white population. Ex-
spread mononuclear cell infiltrate. There is loss of normal three-layer structure of the adrenal cortex, and adrenocortical cells show necrosis and pleomorphism. The cytochrome P450 enzyme steroid 21-hydroxylase (21-OH) has been identified as a major antigen for the Ab. Also in AD, screening for 21-OH-Ab identifies subjects who are at risk to develop AD before clinical presentation. Clinical disease can either present as isolated AD or in combination with other autoimmune diseases as part of the PAS. In T1D, the prevalence of 21-OH-Ab ranges between 1 and 3%, compared with 1 and 0.5% in first-degree relatives and controls, respectively. A small number of Abpositive subjects have been followed for the development of AD, and a yearly incidence of AD of approximately 20% has been observed. Adrenal-Ab are more frequent in female subjects and in T1D patients with persisting islet cell Ab. Furthermore, AD is frequently associated with other autoimmune endocrinopathies, particularly with HT. In patients with AD, as many as 70% with 21-OH-Ab also expressed thyroid autoimmunity. Genetic susceptibility for AD has also been linked to the MHC complex on chromosome 6, as CD, AITD and T1D. The HLA DRB1*0404/DQ8-DRB1*0301/DQ2 genotype occurs at an increased frequency in individuals with isolated AD and in those with AD and T1D. A second locus within the MHC, the MHC class I-related MIC-A, has been linked to AD. Homozygosity for MICA5.1 (allele 5.1) was associated with an 18-fold increased risk for AD. Adrenal insufficiency may cause persistent vomiting, anorexia, hypoglycemia, and unexplained weight loss in an adult, malaise, ill-defined fatigue, muscular weakness, hypotension, and craving for salt. The most specific sign of primary AD is generalized hyperpigmentation of the skin and mucosal surfaces, which is due to the high plasma concentrations of melanocyte-stimulating activity of β-lipotropin, which derives from the same precursor as ACTH. Laboratory tests can aid in the diagnosis: hyponatremia, hyperkalemia, and acidosis. In addition, hypocorticism may, by reducing the insulin needs, cause frequent attacks of hypoglycemia. Patients with symptomatic AD should be treated with hydrocortisone and with fludrocortisone as a substitute for aldosterone. Patients with suspected AD and hypothyroidism should be evaluated and treated for adrenal insufficiency prior to replacement of thyroid hormone to avoid an Addison crisis, since thyroxine may increase hepatic corticosteroid metabolism. The natural history of the progression of the disease follows a typical pattern (different stages) which can be correlated with clinical symptoms. One discriminates a potential phase (genetic
PAS form different clusters of autoimmune disorders and are rare endocrinopathies characterized by the coexistence of at least two glandular autoimmune-mediated diseases. Two major subtypes of PAS, types I and II, are distinguished according to age at presentation, characteristic patterns of disease combinations, and different modes of inheritance. PAS I, also known as autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy or multiple endocrine deficiency autoimmune candidiasis syndromes, usually manifests in infancy or childhood at age 3–5 years or in early adolescence and, therefore, is also called juvenile autoimmune polyendocrinopathy. It is defined by a persistent fungal infection (chronic mucocutaneous candidiasis), the presence of acquired hypoparathyroidism, and AD. In most patients, mucocutaneous candidiasis precedes the other immune disorders, usually followed by hypoparathyroidism. The female-to-male ratio varies from 0.8:1 to 2.4:1. The highest prevalences of PAS I have been found in populations characterized by high degree of consanguinity or descendant of small founder populations, particularly in Iranian Jews and Finns. PAS I is a monogenic disease with autosomal recessive inheritance caused by mutations in the autoimmune regulatory gene on chromosome 21. PAS II is more common and occurs in adulthood, mainly in the third or fourth decade (table 2). It is characterized by AD with AITD and/or T1D. AD may precede other endocrinopathies. Vitiligo and gonadal failure are more rarely associated with PAS II than with type I. Especially in adults, the presence of one autoimmune endocrine disease is associated with an increased risk of developing autoimmunity to other tissues. Each of these disorders is characterized by several stages beginning with
Celiac Disease and Endocrine Autoimmunity
Dig Dis 2015;33:155–161 DOI: 10.1159/000369535
susceptibility and/or 21-OH-Ab), a latent phase [elevated plasma renin activity (PRA) and normal basal cortisol and ACTH levels], and a clinical phase (a diminished basal cortisol and elevated ACTH concentration). These parameters constitute the endocrine evaluation of adrenal function: PRA, ACTH, cortisol and corticotropin stimulation testing. Screening for 21-OH-Ab at diagnosis of T1D and then every 2 years seems to be a good practice. If Ab are positive, one has to evaluate morning baseline ACTH, cortisol and PRA levels (supine position) and perform a corticotropin stimulation test. However, in the absence of symptoms, an annual basal cortisol and ACTH may be sufficient [31–34].
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Polyglandular Autoimmune Syndromes
Table 2. Characteristics of the PAS
Incidence Male:female ratio Age at onset Autoimmune Endocrine Diseases Concomitant Disease
PAS type I
PAS type II
