Open access peer-reviewed chapter
Abstract
Celiac disease can involve any organ system, leading to various non-classical or atypical manifestations. These atypical signs and symptoms have been seen increasingly in the last few decades, both in children and adults, which may or may not involve the gastrointestinal system. This transition from a malabsorptive disorder causing GI symptoms and malnutrition to a more subtle condition causing a variety of extraintestinal manifestations led to newer nomenclature of gastrointestinal and extraintestinal signs and symptoms. Infancy and early childhood onset celiac disease may have a predominance of gastrointestinal manifestations leading to protein energy malnutrition and failure to thrive. The late presentation may have subtle manifestations, and extraintestinal signs and symptoms may be commoner. Short stature, delayed puberty, osteopenia, neuropsychiatric manifestations, iron-deficiency anemia, and elevated liver enzymes are common extraintestinal symptoms. The pathogenesis of extraintestinal manifestations may be due to malabsorption or associated with a systemic autoimmune response. These atypical presentations, especially in the absence of gastrointestinal symptoms and family history, may be missed, leading to a delay in diagnosis and management. A suitable case-finding strategy and liberal use of serological tests may improve the detection rate of CD.
Keywords
- celiac disease
- gluten-free diet
- wheat allergy
- atypical celiac
- asymptomatic celiac
1. Introduction
Celiac disease (CD) is common in all ages and has various signs and symptoms. These symptoms could be classified as classical (chronic diarrhea and weight loss, etc.) or non-classical (anemia, osteoporosis, neurological disturbances, etc.). Due to atypical manifestations, many CD cases currently escape diagnosis and are exposed to the risk of long-term complications. Infancy and early childhood-onset celiac disease may have a predominance of gastrointestinal manifestations leading to protein energy malnutrition and failure to thrive. Late presentation may have subtle manifestations, and extraintestinal signs and symptoms may be commoner.
Non-classical or atypical symptoms have been increasingly recognized in the last few decades and have become commoner than classical presentation. Due to increasing awareness and serological screening of at-risk groups, non-classical forms are being recognized more yet awareness is lacking [1, 2, 3]. Even though this term, typical or atypical, is discouraged but remains in common use, the European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) working group recommends the following nomenclature: gastrointestinal and extraintestinal symptoms and signs [4].
Gastrointestinal manifestations may include nonspecific recurrent abdominal pain, irritable bowel-like symptoms (e.g., recurrent diarrhea), and recurrent aphthous stomatitis. The most frequent extraintestinal presentations include (a) iron deficiency which may or may not be associated with anemia; (b)isolated elevation of liver transaminases (celiac hepatitis) characterized by non-progressive inflammation of liver parenchyma; (c) short stature and delayed puberty. CD is one of the commonest causes of short stature and is characterized by delayed bone age, either normal or blunted growth hormone response to stimulatory tests and low levels of insulin-like growth factor-1 [5]; (d) chronic fatigue; (e) behavioral disturbances, such as irritability, and impaired school performance. Detailed list is mentioned in Table 1. Extraintestinal symptoms occur at similar rates in children and in adults: 60 and 62%, respectively [7]. However, clinical manifestations and rate of improvement differ in the two age groups. In children, short stature, fatigue, and headache appear to be the most common, while iron-deficiency anemia is the predominant manifestation in adults. Children respond faster to GFD in the resolution of symptoms than in adults [7, 8]. While some of the extraintestinal manifestations, such as weight loss, fatigue, short stature, and delayed puberty, can be attributed to nutritional deficiencies and their metabolic consequences, others follow different and often poorly understood pathways.
| Extraintestinal symptoms | Percentage of total no. children/adolescents with CD |
|---|---|
|
|
Table 1.
2. Diagnosis
It is crucial to diagnose CD not only in children with obvious gastrointestinal symptoms but also in children with a less clear clinical picture because the disease may have negative health consequences. Children with extraintestinal manifestations may present to a different speciality, which sometimes makes diagnosis difficult because of unfamiliarity with the disease. This undiagnosed proportion can be as high as 85–90% [9, 10]. Because atypical symptoms may be considerably more common than classic symptoms, the ESPGHAN working group decided to use the following nomenclature: gastrointestinal symptoms and signs (e.g., chronic diarrhea) and extraintestinal symptoms and signs (e.g., anemia, neuropathy, decreased bone density, increased risk of fractures) [4]. Based on this, they recommended CD testing in children and adolescents with the following otherwise unexplained symptoms and signs: chronic abdominal pain, cramping or distension, chronic or intermittent diarrhea, growth failure, iron-deficiency anemia, nausea or vomiting, chronic constipation not responding to usual treatment, weight loss, chronic fatigue, short stature, delayed puberty, amenorrhea, recurrent aphthous stomatitis (mouth ulcers), dermatitis herpetiformis-type rash, repetitive fractures/osteopenia/osteoporosis, and unexplained abnormal liver biochemistry [4, 6].
3. Underlying pathophysiology
Two mechanisms play crucial roles in the pathogenesis of extraintestinal manifestations: proximal bowel mucosal damage and the autoimmune response. However, many aspects of pathogenesis remain unclear. Many of the extraintestinal manifestations correlate with the extent of intestinal damage but may not be true for all. Anemia, stunted growth, and osteopenia are some examples correlating with the extent of damage and consequent malabsorption. Autoimmune phenomenon plays a role in some extraintestinal manifestations, but correlation or justification may not be straightforward. Tissue transglutaminase 2 (TG2) is the main, but not the only autoantigen involved in CD. IgA deposits co-localize with TG2 in the liver, lymph nodes, muscle, thyroid, bone, and brain indicating that the autoantibodies, probably originated in the gut, can access TG2 throughout the body and cause pathogenic effects. Other autoantibodies which can have possible roles in the pathogenesis of extraintestinal manifestations in CD are tissue transglutaminase 3 (TG3) and tissue transglutaminase 6 (TG6). The TG3 is mainly expressed in the epidermis, and its presence is used as a diagnostic test for DH. They are also present in areas away from the skin lesions, suggesting that other factors might have a role. The TG6 is mainly expressed in the neurons, and an association between neurological symptoms and the presence of anti-TG6 antibodies has been postulated. Again, their presence in asymptomatic patients may suggest other unknown mechanisms may have a role. Specificity of these autoantibodies and the gluten-dependence of their production have not been definitely proven [11]. Antibodies to gangliosides have been reported in immune-mediated peripheral neuropathies and in patients with neurological symptoms, their titers reduced on GFD [12] (Table 2).
| Extraintestinal symptoms | Possible underlying pathogenic mechanism |
|---|---|
| Delayed puberty and amenorrhea | Malnutrition, hypothalamic-pituitary dysfunction, and immune dysfunction |
| Weight loss, failure-to-thrive, stunted growth/short stature | Malnutrition, hypothalamic-pituitary dysfunction, and vitamin deficiency |
| Chronic iron-deficiency anemia | Iron, folate, vitamin B12, or pyridoxine deficiency |
| Dermatitis herpetiformis-type rash | Epidermal (type 3) TG autoimmunity |
| Irritability and chronic fatigue | Generalized muscle atrophy, hypokalemia |
| Abnormal liver biochemistry | Celiac hepatitis, autoimmune hepatitis |
| Neuropathy | Deficiencies of vitamin B12 and thiamine; immune-based neurologic dysfunction |
| Idiopathic seizures | unknown |
| Neuro-psychiatric manifestation | Immune-based neurologic dysfunction Cerebellar and posterior column damage |
| Recurrent aphthous stomatitis | Unknown |
| Decreased bone mineralization (osteopenia/osteoporosis) and repetitive fractures | Malabsorption of calcium and vitamin D, secondary hyperparathyroidism, and chronic inflammation |
| Dental enamel defects | Vitamin D and calcium malabsorption |
Table 2.
Extraintestinal manifestations and their underlying pathophysiology [13].
4. Extraintestinal manifestations
4.1 Weight loss, failure-to-thrive, and stunted growth/short stature
Short stature can be an isolated initial presentation, it is one of the commonest extraintestinal manifestations of CD in children, and 10 to 40% will have short stature at the time of diagnosis [7]. Severe growth failure, along with severe disease onset, has been commonly seen in younger children [14]. CD can be found in up to 10% of children undergoing evaluation for short stature [15], which is between 19 and 59% of all non-endocrinological causes [16, 17]. Recently, a meta-analysis found one in 14 patients with all-cause short stature and one in nine patients with idiopathic short stature to have a biopsy-confirmed CD [18]. Such children respond well and show catch-up growth to GFD if the diagnosis has been made well before puberty [7].
4.2 Delayed puberty and amenorrhea
The prevalence of delayed puberty is seen in up to 20% of children with celiac disease [19]. This could be because of hypogonadism or hormonal resistance [20]. Hormonal resistance can develop due to antibodies against hormones, their receptors, or endocrine organs. Nutrition may also play a role. These patients respond very well to GFD, and puberty occurs within 6–8 months.
4.3 Chronic iron-deficiency anemia
Iron-deficiency anemia (IDA) is adults’ most common extraintestinal manifestation. Delay in diagnosis in adults could be one of the reasons for higher prevalence. Prevalence in children has been found to be around 15% [7, 8]. It can be the sole manifestation or presenting feature of CD, especially in older children and adolescents. Iron deficiency may or may not be associated with anemia. In the ProCeDE study, the cohort of children diagnosed based on symptoms, iron-deficiency anemia was reported in 17% [21]. A large pediatric population-based study in Germany found no significant differences between TGA-IgA positive children compared with negatives. Still, serum ferritin was significantly lower in the seropositive group, indicating lower iron stores [22]. A different study from the same region found CD in 6 (4.4%) IDA patients without gastrointestinal symptoms, but they found zero cases in 223 healthy asymptomatic children without anemia [23].
Anemia, most commonly IDA, in CD children can result from several different, and sometimes combined, causes [24]. IDA severity co-relates with the disease severity (histological and serological) and could be a manifestation of malabsorption due to damage in the proximal small bowel [25, 26]. However, even when asymptomatic, CD can lead to IDA [27]. Iron absorption occurs in the proximal small bowel, the area most commonly involved in CD, which explains the IDA. Vit B12 and folate deficiency can also contribute to the pathogenesis of anemia. But anemia in potential celiac, in the absence of histopathological changes, suggests the role of some other mechanism as well. Majority of (up to 84%) children with CD presenting with mild anemia on strict GFD and iron supplementation replenish their iron stores by 12–24 months [7, 25].
4.4 Joint and musculoskeletal disorders
Though rare, joint involvement has been reported in children and adults with CD [28]. It can be in the form of arthralgia, arthritis (non-erosive), and myopathy, which may be silent in the initial stages of the disease. Joint and musculoskeletal involvement may be because of other associated underlying autoimmune conditions, which are relatively common in children with CD and should be ruled out first before attributing it to CD. Pathophysiology of musculoskeletal involvement in CD is not very well understood, and even response to GFD is not consistent [29]. Patients with unexplained arthralgia/arthritis should be tested for underlying CD once other autoimmune musculoskeletal conditions have been ruled out [30].
4.5 Decreased bone mineralization (osteopenia/osteoporosis), repetitive fractures
Approximately 75% of pediatric patients have osteopenia (low bone mineral density), and 10–30% have osteoporosis (bone brittleness) [31]. Decreased bone mineralization can be due to a combination of intestinal malabsorption (the majority of calcium and vitamin D gets absorbed from the proximal small intestine, which is damaged in a patient with CD) and chronic inflammation. Low level of vitamin D can lead to a high level of parathyroid, which is a common finding in such patients. Hyperparathyroidism and other intermediate metabolites lead to higher bone turnover, causing osteopenia and osteoporosis. Higher serum OPG, telopeptide, and lower serum pro-peptide have been found in these patients, pointing again toward an increased bone turnover [32]. Growing trabecular bones are commonly involved. Osteopenia can even be found in the early stages of CD hence the emphasis on early detection and treatment. Osteopenia in children with CD responds very well to the GFD. Even adult patients too can improve their bone mineral density after some years on GFD, but the response is not as robust [33]. Vitamin D and calcium supplementation can hasten the recovery in such children; hence, adequate supplementation should be ensured in newly diagnosed CD children.
4.6 Oral manifestations and recurrent aphthous stomatitis
Geographical tongue and aphthous ulcers are common oral manifestations in children with CD. Lichen planus, cheilosis, atrophic glossitis, and glossodinia are other common manifestations which may or may not be specific to CD. Children with geographical tongue have more prevalence of CD in comparison with the general population [34]. Aphthous ulcers are a non-specific occurrence in CD and can be found in other autoimmune or medical conditions like IBD and Behcet’s disease. The underlying pathogenic mechanism is not very clear and may have some relation with malabsorption, and changes in the normal oral flora and ecosystem may be contributory. Such lesions respond very well to GFD, and they remit completely on GFD.
In a case-control study, 50 CD cases and 50 controls were assessed, and the prevalence of aphthous ulcers was 62% and 13%, respectively [35]. In the same study, delayed dental eruption was observed in 38% and 11% and specific enamel defects in 48% and 0%, respectively [35]. An Iranian study among teenagers and adults reported a prevalence of CD in 2.8% of children with recurrent aphthae and was significantly higher than the general population [36].
4.7 Dermatitis herpetiformis-type rash
DH affects primarily older children and adults. In contrast to CD, the annual incidence of DH has been decreasing probably because of the diagnosis of even silent and asymptomatic patients. It may suggest that subclinical CD may predispose to DH. Gastrointestinal symptoms are rare in patients with DH, but enteropathy can be documented in up to 72% of the patients [37]. DH manifests as bilateral, symmetrical blisters with pruritus affecting extensor surfaces followed by shoulders, buttocks, sacral region, and face. These lesions may be preceded by itching and burning sensation followed by erosions, excoriations, and hyperpigmentation. DH is considered the skin manifestation typical of celiac disease as similar antibodies are at play, which leads to intestinal changes [38]. Epidermal transglutaminase (TG3) acts as an autoantigen against which patient develops an antibody which gets deposited in the skin layer. Characteristic granular IgA deposits can be demonstrated by direct immunofluorescence microscopy in the biopsy of the adjacent unaffected skin at the dermo-epidermal junction [39]. Strict GFD is very effective with 100% resolution, but in the initial phase, dapsone or other drugs can be used.
4.8 Dental enamel defects
Dental enamel hypoplasia is a common occurrence in children, and prevalence ranges between 10% and 97% in various studies. Still, prevalence has been decreasing in recent studies suggesting a less severe presentation of the disease nowadays [40]. Nutritional deficiency due to malabsorption during the period of enamel formation (<7 years), and immunological disturbances lead to the defect. Deciduous teeth (incisors and molars) are more frequently involved in a symmetrical way. The enamel defects manifest as pitting or grooving on the surface or sometimes with complete loss of enamel. They can also include discoloration and structural changes on the surface. These changes improve once nutritional and immunological disturbances are restored. Improvement will occur in primary teeth, but the same may not be valid for permanent teeth, even on strict GFD. These enamel defects, like other extraintestinal manifestations, may or may not have other symptoms and hence can be a useful clinical screening tool [41].
4.9 Elevation of transaminases
Liver enzymes may be deranged in children with CD, a most common hepatic manifestation of CD, which could be related to the disease itself (idiopathic or known as celiac hepatitis) or due to associated autoimmune hepatitis. Celiac hepatitis is seen in about one-third of children with CD [42]. On the contrary, CD may be found in 12% of children with mild unexplained elevated transaminases [42]. Extent of involvement usually correlates with overall disease severity (histopathological and serological). Duodenal damage may expose the liver to hepatotoxins because of the increased permeability, and autoimmune factors may also play a role suggested by the deposition of CD antibodies in the liver [43, 44]. Liver involvement is usually mild and reversible and rarely causes liver failure [45]. When a child presents with deranged liver function and coagulopathy, underlying malabsorption needs to be considered and treated with supplementing Vitamin K. Good compliance with GFD leads to normalization of the liver transaminases levels in up to 95% within 1–2 years [46]. The same is not true if the liver involvement is because of another concomitant autoimmune liver disease.
4.10 Alopecia areata
Alopecia areata is characterized by a patchy hair loss on the scalp, a common form of hair loss in children. It is believed to be an autoimmune condition and is common in CD children [47]. It can occur in the absence of GI signs and symptoms but, once diagnosed, shows an excellent response to the GFD.
4.11 Headache, migraine, idiopathic seizures, depression, and psychiatric disorders
Neurological symptoms are more common in children with CD than controls [48]. Headache is the most common neurological symptom (in 18%) and responds well to the exclusion of gluten from the diet [49, 50]. Other neurological symptoms are peripheral neuropathy and seizures, which also tend to improve with GFD [48, 51]. Anti-ganglioside antibodies, along with nutritional deficiencies, like Vitamin B12, E, and D, may play a role in neuropathy. These manifestations may be present in children in the absence of enteropathy, suggesting that other mechanisms like a cross-reaction between anti-gliadin antibodies and synapsin might be responsible. Epilepsy’s prevalence is higher, though some studies did not find a significant difference in the prevalence, in CD children, and the difference remains uncertain. The seizures are generalized tonic-clonic, but partial and occasionally absence seizures are also seen [52]. GFD helps control frequency of seizure episodes, especially those poorly controlled despite antileptic medications. Epilepsy associated with occipital calcification has been reported in children with CD [53]. A patient with epilepsy disorder without a clear etiology should be considered for CD screening as their seizure control will be better on GFD. Ataxia, a neurological manifestation of CD, tends to manifest predominantly in adult patients. The presence of anti-TG6 antibodies against the cerebellar cells might play a pathogenic role. These autoantibodies can also be found in children without neurological disorders, suggesting some other unknown mechanism. Psychiatric issues like anxiety, hallucinations, and depression are common in adolescents and may persist into adult life, and interestingly, they respond to GFD [54, 55]. An increased suicide tendency in CD patients has also been observed [56].
4.12 Vitamin deficiency
Vitamin D deficiency is the most common deficiency seen in children with CD, and its testing is recommended at diagnosis so that adequate supplementation can be given. Vitamin D deficiency can lead to hyperparathyroidism and subsequent osteopenia. Other vitamin levels can also be diminished in CD due to malabsorption and manifest in different ways, as discussed in other sections.
5. Peri-natal and post-natal manifestations
Over the last three decades, several reports, mostly retrospective, have examined the potential impact of undiagnosed celiac disease on pregnancy and fetal outcomes. Asymptomatic and undiagnosed celiac disease has been associated with various gynecological, obstetric, and fetal complications with conflicting results, particularly unexplained infertility, miscarriages, fetal growth restriction, low birth weight, and preterm birth [57, 58, 59, 60].
The association between untreated maternal celiac disease and intrauterine growth restriction (IUGR) and small for gestational age (SGA) has been highly significant in most scientific reports. The odds ratio from a large population-based Danish cohort study was 1.31 (CI 1.06–1.63) and OR 1.62 (CI 1.22–2.15) in a similar Swedish study [61]. Evidence in favor of the normalization of most of these complications with a gluten-free diet appears reassuring, though the literature is limited [7, 59, 61, 62]. There are some reports concerning the effect of paternal celiac disease on preterm birth and birth weight. However, further research is needed to confirm the findings [63, 64]. We could not find data on the impact of undiagnosed maternal disease on neonates and infants.
6. Treatment
GFD is the only effective therapy available; none of the pharmacological alternatives is effective and can replace GFD [65]. Recovery from GFD is faster in children and can lead to complete remission of extraintestinal manifestations [7]. Starting GFD as soon as possible is essential and will have a good prognosis. This is especially true for bone diseases or short stature.
Nevertheless, sometimes more than the diet is needed, vitamins and minerals need supplementation. Anemia may need iron supplementation, vitamin D deficiency needs supplementation with Vitamin D and calcium, and DH may require medical therapy in the initial days. Compliance is an issue, especially in adolescents, affected with the highest prevalence of extraintestinal manifestations and complications [59]. Compliance needs to be ascertained, especially if there is no improvement in the symptoms. If there is no improvement despite compliance, other diagnoses or pathogenic mechanisms should be investigated, for instance, growth hormone deficiency in children with short stature and hematological disorders in children with anemia.
7. Conclusion
Extraintestinal manifestations are more common in CD in children and often get overlooked because of a lack of awareness. These atypical manifestations make diagnosis difficult, which leads to delay in diagnosis. With easily available efficient screening serological tools, diagnosis can be straightforward, but awareness over the multispecialty levels (hematologists, neurologists, rheumatologists, and endocrinologists) needs to be increased. An early diagnosis is vital to prevent long-term complications, especially those that are no more correctable after a certain age (e.g., osteopenia and short stature).
Appendices and nomenclature
| CD | celiac disease |
| TG | transglutaminase |
| DH | dermatitis herpetiformis |
| GFD | gluten-free diet |
| TGA IgA | transglutaminase antibody IgA |
| IDA | iron-deficiency anemia |
| ESPGHAN | European society of pediatric gastroenterology hepatology and nutrition |
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