Recently, new oral iron formulations, sucrosomial iron, has been proposed for patients who are intolerant to iron sulfate. Hypertransaminasemia has been reported as the most frequent hepatic manifestation in CD patients. Most times the liver damage is not severe and reversible, but in rare cases it can lead to liver failure The grade of hypertransaminasemia is correlated to the duodenal mucosal damage, malabsorption, and serum levels of anti-endomysial and anti-tissue transglutaminase2 TG2 antibodies.
It has been hypothesized that the altered gut permeability can determine an increased exposure to hepatotoxins in the portal circulation leading to inflammation and liver damage 19 , 44 , Nevertheless, in line with the other extra-intestinal manifestations, also in this case autoimmune factors may play a role, as indicated by the presence of anti-TG2 antibodies deposits in the liver An early diagnosis of CD may prevent future hepatic problems and a strict compliance of GFD can make unnecessary a routine control of liver function A link between thyroid and liver disease has been reported, also based on the observation that usually CD patients with elevated ALT had also a higher TSH.
The liver, in fact, performs a central role in the transport, metabolism, and deiodination of thyroid hormones Bone manifestations in CD patients are mainly osteopenia, defined as low bone mineral density BMD , and osteoporosis, defined as low bone density leading to brittleness of the bones. The trabecular bone is usually the most involved, since it is the most metabolically active. Evaluation of the BMD is important in short-statured CD children, also in relation with height, gender, and age in order not to misinterpret BMD values.
However, there is no demonstration of increased risk of fractures during childhood and youth in CD patients. It is possible to have osteopenia also in the very early phases of the disease. These values returned to the normal range after GFD was started, and that occurred already in the first year of GFD, emphasizing the importance of an early diagnosis 52 , Osteopenia may be further worsened by inadequate calcium intake, hence the need to supplement the GFD with Calcium-fortified foods and vitamin D metabolites 54 , The most common joint and musculoskeletal disorders in CD include myopathy, arthralgia and non-erosive arthritis that can be silent in the early stages of disease Ultrasonography is important for the diagnosis, particularly in those patients whose symptoms are mild.
The pathogenesis of the rheumatological manifestations remains obscure 56 and similarly their response to the GFD. It is important to remember that CD can be associated with autoimmune diseases involving joints and muscles such as Sjogren's syndrome, juvenile idiopathic arthritis, rheumatoid arthritis and systemic lupus erythematosus LES. A two-fold risk of LES has been recently reported in the pediatric celiac population Several neurological manifestations are significantly associated with CD in the pediatric population.
The most common being headache, that is present in up to one-fifth of the cases. Rarer conditions in the pediatric population are ataxia and neuropathy, ranging from 0. A prevalence of 0.
Thus, the link between epilepsy and CD remains still uncertain. The most common seizures patterns are the complex partial, followed by tonic-clonic seizures. A particular type of epilepsy characterized by the presence of occipital calcifications has been specifically reported in association to CD 63 , 64 — Figure 1. Cerebellar ataxia is more common in adults, with a median age of onset around 20 years.
Chronic, symmetric distal neuropathy is the most common form of neuropathy described in CD patients, but its precise prevalence is unclear. A possible pathogenetic mechanism behind the neuropathy involves the anti-ganglioside antibodies, but nutritional deficiencies may also have a role.
Particularly, some neurological manifestations are correlated with the deficit of vitamins such as E, B12 and D, or micronutrients like magnesium. Nevertheless, these manifestations may be present even in children with no enteropathy, excluding a role for malabsorption and suggesting that other mechanism might be responsible, for example a cross reaction between anti-gliadin antibodies and synapsin has been postulated. The pathogenesis of gluten ataxia can be related to the presence of anti-TG6 antibodies that might be directed against the cerebellar cells. However, their pathogenic role remains unclear since these autoantibodies can also be present in celiac children who are not affected by neurological disorders.
An association between CD and psychiatric disorders, including attention deficit and hyperactive disorder ADHD , autism spectrum disorders ASD , mood disorders, anxiety, eating disorders and depression, has been reported In a large cohort of CD children, an increased risk of psychiatric disorders development 1. There is evidence supporting an association of CD with depression and, although to a less extent, with eating disorders For panic disorder, autism and ADHD there are few reports indicating an association but further studies are necessary.
Finally, the association between CD and schizophrenia or other anxiety disorders is still debated. As far as pathogenic mechanisms involved, a direct effect of CD, perhaps based on inflammation and immunological dysregulation has been proposed 69 , but another possible concomitant cause could be the psychosocial discomfort associated with a chronic condition for CD children. The exact prevalence of enamel defects in CD is not known.
However, in a recent meta-analysis it was observed that CD patients had significantly higher prevalence of enamel defects compared to controls The enamel defects are characterized by pitting and sometimes by complete loss of enamel; they include discoloration and structural changes. Aine described enamel defects as detectable in all quadrants of the dentition, involving deciduous teeth incisors and molars are the more frequently involved teeth and most importantly symmetrical, the latter feature being more specific for CD He proposed a grading, detailed in Table 1.ogilifitof.tk
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Usually defects in dental enamel occur when CD affects children during dental development before 7 years of age. When the defect affects permanent teeth, there is no improvement upon GFD. Table 1. Classification of systemic and chronologic enamel defects [modified from Aine 74 ]. The defect of amelogenesis, malnutrition, in particular hypocalcemia, and immunological disturbances have been proposed as causes of enamel defects in CD.
However, some reports deny a correlation between the degree of enamel defects and the severity of small bowel mucosal damage Patients with HLA-DR3 genotype have been reported to have a higher risk of enamel lesions, pointing to a genetic contribution 76 Figure 2. Figure 2. Model of enamel defects in celiac pediatric patient; these lesions have a symmetrical distribution. Other oral disorders have been related to CD including delayed teeth eruption, lichen planus, cheilosis, atrophic glossitis, glossodinia.
Aphthous stomatitis is an inflammatory ulcerative condition characterized by multiple recurrent small, round or ovoid ulcers with circumscribed margins appearing in the oral cavity. It usually manifests in the non-keratinized oral mucosa and can cause considerable pain. The mechanisms underlying this manifestation remain still obscure.
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It is unclear if there is any relation with malabsorption. Disturbances of the oral ecosystem saliva, leukocytes, microbioma have been hypothesized. Usually patients remit completely on GFD Depending on the extension of the lesion it is possible to distinguish alopecia areata, totalis, and universalis.
Autoimmune mechanisms are thought to be involved in its pathogenesis, nevertheless GFD can lead to the total regrowth of hair by 12—24 months in half of the cases Dermatitis herpetiformis DH is considered an extraintestinal manifestation of CD. It is particularly interesting to note that, in contrast to CD, the annual incidence rate is decreasing. It has been hypothesized that subclinical CD may predispose to DH, but what renders some individuals more prone to the development of skin lesions is unknown. The disease starts in the gut and evolves with the deposition in the papillary dermis of immune complexes of TG3 and high avidity anti-TG3 IgA antibodies From a clinical standpoint it presents with itchy papules and small blisters, often crusted because of the intense itch and consequent scratching, located on the extensor surfaces of elbows, knees and on the buttocks.
Upper back, abdomen, scalp, and face may also be affected. The diagnosis is made on a biopsy of unaffected skin showing by direct immunofluorescence pathognomonic granular IgA deposits at the dermo-epidermal junction. Some patients may need additional medical therapy with dapsone, but with time the lesions are well-controlled by a GFD alone.
In children the long-term prognosis on exclusion diet is excellent. The pathogenesis of extra-intestinal manifestations in many respects is still unclear. There are two main mechanisms probably involved, one related to the mucosal damage and the consequent malabsorption, the second sustained by the autoimmune response. In line with the first, some extra-intestinal manifestations are clearly correlated with the severity of intestinal damage.
Indeed, patients with extra-intestinal manifestations at diagnosis have a more severe grade of intestinal mucosal atrophy as compared to patients presenting only with gastrointestinal symptoms Anemia is associated with malabsorption of iron, vitamin B12, and folate Stunted growth is likely caused by nutrients malabsorption 25 , Finally, osteopenia may be due to malabsorption of calcium and vitamin D, leading to secondary hyperparathyroidism and subsequently a high bone turnover Extra-intestinal manifestations may also be the consequence of autoimmune phenomena, although in many cases this hypothesis needs to be supported by more evidences.
Tissue-transglutaminase 2 TG2 is the main, but not the only autoantigen involved in CD.
Whether anti-TG2 autoantibodies play a role in CD pathogenesis has not been definitely proven. They bind to several epitopes including the enzymatic core and can then interfere with bioactivity of TG2 The presence of IgA deposits co-localizing with TG2 in liver, lymphnodes, muscle, thyroid, bone and brain 86 indicate that the autoantibodies, probably originated in the gut, can access to TG2 throughout the body and cause pathogenic effects. Consistently with this hypothesis, data in mice showed that the injection of anti-TG2 antibodies in the lateral ventricle of the brain caused deficits in motor coordination Other members of transglutaminase family possibly involved in the pathogenesis of extra-intestinal manifestations in CD are TG6 and TG3.
The latter is mainly expressed in the cornified layer of epidermis and for this reason also defined epidermal TG. They are present also in areas located far away from the skin lesions, suggesting that other factors, besides the mere presence of the antibodies, are necessary to provoke the lesions. The TG6 is mainly expressed in neurons, playing an important role in neurogenesis An association between neurological manifestation in CD and the presence of anti-TG6 has been suggested. In fact, anti-TG6 is elevated in the serum of patients with gluten neuropathy Furthermore, TG6 is the target autoantigen in gluten ataxia However, both specificity of these autoantibodies and gluten-dependence of their production have not been definitely proven As said, tissue transglutaminase is not the only autoantigen in CD.
Antibodies to gangliosides have been reported in immune mediated peripheral neuropathies 93 , 94 ; in particular, they have been described in CD patients in conjunction with neurological symptoms 95 , their titers responding to the exclusion of gluten from the diet Neutralizing autoantibodies against osteoprotegerin have also been detected in CD patients 97 , but their role in development of osteoporosis is still uncertain Table 2. Possible pathogenetic mechanisms for each extra-intestinal manifestations in celiac disease.
None of the pharmacological alternatives nowadays available or under investigation seems to be capable to replace the GFD In children GFD can lead to a complete recovery and a faster remission of extra-intestinal manifestations as compared to adults The prognosis in children is very good, if adequately treated with GFD. However, timing of diagnosis is crucial. It is important to start the GFD as soon as possible. That means that an early diagnosis is decisive for a good prognosis.
That is particularly true for bone diseases or for short stature. Patients diagnosed early during childhood did not have an increased risk of later development of osteoporotic fractures and showed a very satisfactory catch up growth with a good final height Nevertheless, sometimes the diet alone is not sufficient. This is the case of severe anemia, when it is advised to complement the dietary regimen with iron supplementation, or of severe DH, when adding a medical therapy with dapsone could be necessary in some cases , or even of severe osteopenia, when supplement the diet with calcium and vitamin D is important 54 , Problems arise when the GFD is not properly followed.
This occurs mostly in adolescents , the pediatric population affected also by the highest prevalence of extra-intestinal manifestations and complications. When extra-intestinal manifestations show no improvement despite the GFD, patients' compliance to the dietary regimen should be questioned.
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In recent years a non-invasive, specific and novel approach to assess compliance with GFD has been reported, based on the detection of gluten immunogenic peptides GIP in the stools or in the urine by ELISA In case of no clinical improvement despite a strict GFD, additional diagnosis or pathogenic mechanism should be investigated. For instance, CD children presenting with short stature, but failing to show a satisfactory catch-up growth despite a verified compliance to the GFD, should be investigated for other co-existing conditions e.
With extra-intestinal manifestations dominating the clinical presentation of over half of the patients, also in children CD may be considered a systemic disease. These proteiform clinical features may complicate the diagnosis. With still too many cases being undetected, education becomes very important.
Given the availability of very efficient non-invasive diagnostic tools, such as measurement of serum anti-TG2 antibodies, it is necessary to increase the awareness among general pediatricians, but also other specialists hematologists, neurologists, rheumatologists, endocrinologists. A more careful case finding strategy, together with a more liberal use of CD-specific serological tests, will improve the detection rate. Furthermore, an early diagnosis is particularly important for a faster remission of symptoms, better prognosis as well as to prevent long-term complications, especially those that are no more correctable after a certain age e.
Finally, extra-intestinal manifestations may help understanding the pathogenic mechanisms of CD, in particular the role played by autoimmunity in the different clinical presentations. SN: first draft of the manuscript, manuscript revision, final approval of the version to be published, and agreement to be accountable for all aspects of the work. RT: corresponding author, primary responsibility for communication with the journal during the manuscript submission, drafting the work, manuscript revision, final approval of the version to be published, agreement to be accountable for all aspects of the work.
RA and VD: critical revision of the article, final approval of the version to be published, agreement to be accountable for all aspects of the work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.