Celiac disease (CD) is a well-known, permanent, genetically determined intolerance to gluten that results in entheropathy, characterized by the typical malabsorption syndrome. After the ingestion of prolamines found in wheat, rye and barley, an altered immune response, dominated by T cells of Th1 type, starts at the gut level and plays an important role in tissue damage. This abnormal response not only results in the entheropathy, but also involves a number of extraintestinal manifestations Citation[1]. In fact, a wide spectrum of symptoms characterizes CD in children and adults, and the classical symptoms are now reported infrequently.
Many studies demonstrate the strict association between CD and endocrine autoimmune diseases. Patients with CD are, in fact, at a greater risk of developing endocrine disorders, such as Type 1 diabetes mellitus (T1DM), autoimmune thyroid disease and pubertal disorders.
The presence of a common genetic predisposition, such as HLA-DQ2 or DQ8 haplotypes, partially seems to explain the association between CD and autoimmune diseases. It has been suggested that the development of multiple autoimmunity may be owing to shared epitopes between an environmental agent and common antigens present in several endocrine tissues. Body proteins can undergo modifications creating epitopes recognized as non-self, in this manner, leading to breakage of immune tolerance and precipitation of autoimmune disease. In CD, the ingestion of gliadin causes an immune response against a unique autoantigen, the enzyme tissue transglutaminase, that could share similar epitopes with other cryptic antigens that are unmasked, especially in endocrine glands Citation[2,3]. This could be the case for T1DM. Indeed, the prevalence of T1DM in patients with CD is approximately 4.5%, 20-times higher than that in the general population. On the other side, in patients with T1DM, CD is currently estimated to affect up to 16.4% in selected populations Citation[4,5]. Usually, even if at the onset of T1DM a temporary rise in antigliadin antibodies (AGAs) is described (in 3–4% of patients) along with the expression of the immunological chaos present at the onset of an endocrine autoimmune disease, in the majority of patients (up to 88.5%), CD is diagnosed months or years after the clinical onset of T1DM Citation[6]. This could depend on the difficulty of suspecting and then diagnosing a silent, atypical or latent CD, thus resulting in the difficulty of pointing out the real timing of the onset of the two pathologies. However, in studies where patients with T1DM are followed yearly through a CD screening, CD is frequently diagnosed during the first year after T1DM onset, but the risk of a retarded serum-conversion (mostly between 2 and 5 years after T1DM onset) imposes in T1DM patients, even in the absence of gastrointestinal symptoms, a restrict follow-up for CD at least every 2–3 years.
The thyroid is also frequently affected in patients with CD, with highly variable percentages of hypo- and hyperthyroidism Citation[4]. Some authors have also demonstrated that early markers of thyroid autoimmune involvement, such as antithyroid peroxidase autoantibodies (anti-TPO) or abnormal ultrasound thyroid pattern with euthyroidism, have a high prevalence in CD, varying from 14.4 to 42.5% Citation[4]. Similarly, CD is also frequent among patients with autoimmune thyroid diseases, especially Hashimoto’s thyroiditis (from 2.8 to 11%) Citation[4].
A higher incidence of autoantibodies (anti-thyroid and antipancreatic gland) has been revealed in patients with untreated CD, when compared with patients (with identical HLA) on a gluten-free diet (GFD) Citation[7]. All these data seem to confirm the role of gliadin as an external and direct trigger of the autoimmune process in genetically predisposed individuals. Indeed, Ventura et al., over a 6-month period, evaluated the presence of autoimmune disorders in 909 adolescents and young adults (mean age: 16.1 years) affected with CD and demonstrated how prolonged gluten exposure in patients with CD increases the risk of contracting autoimmune disease Citation[8]. However, considering age as a confounding factor in this type of study, the effect of long-lasting gluten exposure has not yet been unanimously confirmed Citation[9]. Nevertheless, taking into account the high incidence of endocrine disorders in CD, and that an early diagnosis and treatment of CD might protect against the development of autoimmune conditions, repeated serological screening for CD is recommended every year in all patients with T1DM or other autoimmune endocrine diseases Citation[10]. Further research on the effect of CD treatment on the control of the concomitant endocrine disease may help to understand their shared pathogeneses pathways. In fact, in some patients with autoimmune thyroiditis and CD following a GFD, the dose of the replacement therapy can be progressively reduced and, in a few cases, the diet could normalize a subclinical hypothyroidism. On the other hand, the metabolic response to a GFD in children with T1DM and CD is not considered unanimously positive; in fact, some authors have found a disappearance or reduction of hypoglycemic episodes but, unfortunately, there is no reasonable evidence of a major effect on glycosylated hemoglobin Citation[11].
The presence of CD is also related in some individuals to hypogonadism, leading to a delay in the onset of puberty and to earlier menopause. Some studies have reported not only a significant retarded menarche in untreated CD girls, if compared with those following a GFD, but also negative effects on pregnancy in treated CD, in particular lower birth weight and shorter duration of pregnancy. Similarly, boys are affected by a condition of tissue resistance to androgens characterized by reduced serum level of dihydrotestosterone and by an increased serum level of luteinizing hormone. The pathogenesis of these disorders is still unknown, but a selective malabsorption of micronutrients (e.g., zinc, iron, folic acid and fat-soluble vitamins) essential for the metabolism of carries or receptor proteins for sex hormones or autoimmune mechanisms have been already hypothesized Citation[12]. As with other autoimmune diseases (e.g., systemic lupus erythematosus), hyperprolactinemia, frequently found in untreated patients with CD, could be related to infertility, both because of its inhibiting action in the hypothalamus–pituitary axis and its modulating function in the immunological system. Since reproductive alterations are reversible, adoption of a GFD supported by early diagnosis seems restoring Citation[13].
A growing interest is actually devoted to other related endocrinological implications of CD; first of all, growth hormone (GH) deficiency, where short stature can be the only presenting clinical feature in CD children, even in the absence of gastrointestinal symptoms. In unselected cases admitted for short stature, the prevalence of CD varies from 2.9 to 8.3% and it is associated with delayed bone maturation Citation[4]. GFD usually induces a catch-up growth with recovery of the height in approximately 2 years, depending on the extent of the disease, the age at which it occurs and the extent of the height deficit compared with the target height Citation[14–16]. Some authors have already demonstrated that CD has a negative influence on growth, not only attributable to the impaired intestinal absorption, but also to impaired pituitary function involving somatotrophs cells.
Many years ago, an insufficient GH response to hypoglycemia was found in celiac children restored to normal after the institution of a GFD Citation[14]. A decreased peak of GH (less than -2 standard deviations) was observed in 69% children with active celiac, and low IGF-1 level has been evidenced in celiac children, unrelated to a GH defficiency and resistant to GH therapy, with normalization only under a GFD Citation[14,15]. Sometimes, a GFD is not enough and GH deficiency persists. In fact, a large multicenter study demonstrated a frequency of an associated GH deficiency of approximately 0.3% in patients with CD Citation[17]. Even if several theories have been advanced to explain this association (i.e., hypothalamic dysfunction and abnormal brain monoamines metabolism), no conclusive evidence has been reached.
However, our study in children with concomitant CD and GH deficiency has recently suggested an attractive hypothesis to explain the origin of several cases of GH deficit in CD patients. In fact, we showed that the GH deficiency causing the lack of catch-up growth after a consistent period (at least 12 months) of GFD, despite the reversion to seronegativity for gluten auto-antibodies, was related to the presence of high levels of antipituitary autoantibodies Citation[18]. This evidence suggests the association between CD and autoimmune hypophysitis, detectable with the evaluation of antipituitary and antihypothalamus autoantibodies Citation[19]. The occurrence of an autoimmune mechanism as the cause of GH impairment in some CD patients is, in our opinion, a considerable novelty in this domain, and claims to look for antipituitary and antihypothalamus antibodies in all patients with GH deficency associated to CD. In following these patients, we are trying to confirm the effect of GH-replacement therapy in association with a GFD, as recently demonstrated by other studies Citation[20].
In conclusion, CD is no longer only considered to be a gastroenterological disease, but a multiorgan disease, especially affecting endocrine organs. Therefore, a multidisciplinary approach to this disease is mandatory to avoid late diagnosis and inaccurate treatment.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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