Dig Dis 2008;26:121–127 DOI: 10.1159/000116769
Celiac Disease: What’s New about It? Giovanni Gasbarrini a Noemi Malandrino a Valentina Giorgio b Carlo Fundarò b Giovanni Cammarota a Giuseppe Merra a Davide Roccarina a Antonio Gasbarrini a Esmeralda Capristo a Departments of a Internal Medicine and b Pediatrics, Catholic University of Rome, Rome, Italy
Key Words Celiac disease ⴢ Malabsorption ⴢ Villous atrophy ⴢ Extraintestinal manifestations ⴢ Autoimmune disorders ⴢ Gluten-free diet
Abstract In the present review we will try to summarize the clinical and diagnostic features of celiac disease (CD) as well as the new findings on extraintestinal manifestation. CD is an immune-mediated enteropathy caused by a permanent gluten intolerance. In the last years, the diagnosis is becoming more and more frequent because of the recognition of ‘new’ symptoms and associated extraintestinal manifestations. Classical CD is dominated by symptoms and sequelae of gastrointestinal malabsorption. In the ‘atypical forms’, the extraintestinal features usually predominate, with few or no gastrointestinal symptoms. Silent CD refers to asymptomatic patients with a positive serologic test and villous atrophy on biopsy. This form is detected by screening of highrisk individuals, or villous atrophy occasionally may be detected by endoscopy and biopsy conducted for another reason. The potential form is diagnosed in groups at risk including relatives of celiac patients, Down syndrome and autoimmune diseases. Latent CD is defined by positive serological tests but not histological changes on biopsy. These individuals are asymptomatic, but later may develop symptoms and/or histological alterations. Recognition of atypical
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manifestations of CD is very important because many cases can remain undiagnosed with an increased risk of long-term complications. Copyright © 2008 S. Karger AG, Basel
Introduction
Celiac disease (CD) is an immune-mediated enteropathy caused by a permanent gluten intolerance. The ingestion of this protein, present in wheat, barley, and rye, determines a chronic inflammation of the small intestinal mucosa that may result in partial or total atrophy of intestinal villi and malabsorption.
Prevalence and Pathogenesis of CD
CD affects genetically susceptible subjects, with a higher prevalence in females (F/M = 2.5/1). Epidemiological studies have shown that the prevalence of CD is in a range between 1/100 and 1/150 in both Europe and the USA. The prevalence of CD is increased in first-degree relatives of individuals with biopsy-proven CD (4–12%) [1] (table 1). The histological hallmarks of CD are villous subtotal or total atrophy, crypt hyperplasia and lymphoplasmacellular infiltrate in the intestinal lamina propria, with an Giovanni Gasbarrini, MD Institute of Internal Medicine, Catholic University of Rome, Gemelli Hospital Largo A. Gemelli, 8 IT–00168 Rome (Italy) Tel. +39 06 3015 4334, Fax +39 06 3550 2775, E-Mail
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Table 1. Prevalence of CD in low-risk populations
Country
Year
Prevalence
USA Germany Sweden Spain Netherlands Italy United Kingdom Hungary
2003 2002 1999 2000 1999 1996 2003 1999
1:133 1:500 1:492 1:390 1:330 1:210 1:100 1:85
Table 2. Gastrointestinal manifestations of CD
Diarrhea Weight loss Abdominal distension Flatulence Recurrent aphthous stomatitis, glossitis, angular chelosis Steatorrhea Anorexia, nausea and vomiting
histopathologic and serologic alterations, the association with specific genetic markers (HLA-DQ2 and HLADQ8), the improvement of intestinal damage after steroid therapy, and the association of CD with other immunemediated diseases [4]. CD is characterized by an immunological reaction to peptides of the gliadin molecule: their high glutamine and proline content render them resistant to digestion by intestinal enzymes [5–7]. Because of a dysregulation of the zonulin system that causes the opening of tight junctions [3], gliadin peptides cross the intestinal barrier to the lamina propria and are deamidated by tissue transglutaminase. The deamidated gliadin subsequently binds to either DQ2 or DQ8 molecules on antigenpresenting cells, causing MyD88-dependent release of both zonulin and cytokines. Gliadin peptides are also presented to T lymphocytes, initiating an aberrant humoral and cell-mediated immune response, ultimately responsible for the autoimmune process resulting in villous injury [4].
Clinical Presentation Table 3. Clinical presentation of CD (>2,000 Italian patients >30 years)
Symptoms
1971–1980 1981–1990 1991–2000
Diarrhea Weight loss Constipation Vomiting Abdominal pain Abdominal distension Weakness Edema Muscle cramps/tetany Bone pain/osteoporosis Aphthous stomatitis Menstrual irregularities Finger clubbing Short stature
89.4 82.5 2.6 34.2 63.1 47.3 65.7 39.4 18.4 36.8 7.8 13.1 10.5 2.6
70.8 63.8 2.0 29.8 56.2 70.8 63.8 31.9 19.4 19.4 18.0 18.7 38.8 11.1
30.9 30.9 1.3 7.9 22.1 23.8 32.3 11.9 8.8 11.9 5.3 not assessed not assessed not assessed
increased production of IgM, IgG and IgA [2]. Moreover, changes in intestinal permeability are related to alterations of tight junctions [3]. The mechanisms on the basis of the gluten-related damage of small intestinal mucosa and malabsorption are not still clarified. The immunological hypothesis is the most credited; it is supported by the characteristic 122
Dig Dis 2008;26:121–127
CD clinical symptoms can present at any age, starting from weaning and the consequent introduction of gluten in the diet, to the elderly, with an increased prevalence in the fourth decade. The initial clinical appearance of CD is more severe in childhood than in adulthood. It is characterized by chronic or recurrent diarrhea, with loose, not formed and smelly feces and steatorrhea. Vomiting could also appear, in particular in early childhood, causing dehydration and electrolyte imbalance. Moreover, children present with apathy, pallor, muscle wasting and hypotonia associated with abdominal distention, poor appetite, hemorrhagic manifestations, edema and anemia. Impaired growth, altered bone metabolism and pubertal delay represent other characteristic pediatric symptoms [8]. In adults, the clinical presentation of CD is more insidious than in pediatrics. In particular, clinical manifestations range from severe malabsorption with diarrhea, steatorrhea, weight loss and nutritional deficiencies, to asymptomatic forms, detected by screening (fig. 1, 2). This high variability is at least in part conditioned by the extension and severity of intestinal mucosal damage. In the last years, CD diagnosis is becoming more and more frequent because of the recognition of ‘new’ symptoms and CD-associated extraintestinal manifestations. Gasbarrini et al.
Classical CD is dominated by symptoms and sequelae of gastrointestinal malabsorption (chronic diarrhea, steatorrhea, weight loss, abdominal distension) (tables 2, 3). The ‘atypical forms’ of the disease are characterized by few or no gastrointestinal symptoms, e.g. altered bowel habits (diarrhea and/or constipation), abdominal pain and bloating; moreover, the extraintestinal features usually predominate, as chronic iron deficiency anemia, osteoporosis, short stature, pubertal delay, infertility and recurrent spontaneous abortions [9–11] (table 4). Recognition of atypical manifestations of CD is very important because many cases can remain undiagnosed with an increased risk of long-term complications [12]. Silent CD refers to patients who are asymptomatic but have a positive serologic test and villous atrophy on biopsy. This form is detected by screening of individuals at high risk, or villous atrophy occasionally may be detected by endoscopy and biopsy conducted for another reason. A potential form of CD is diagnosed in groups at risk including relatives of those with diagnosed CD [13], Down syndrome [14, 15], type 1 diabetes and other autoimmune diseases [16–19]. Latent CD is defined by positive serological tests but not histological changes on biopsy. These individuals are asymptomatic, but later may develop symptoms and/or histological alterations [20].
kC Fran
D
Ol i CD g o sy m
Silent CD pto m
Classical CD
ati c
tC ten La
D
Potential CD
Fig. 1. Clinical types of CD.
Classical celiac disease (Gastrointestinal manifestation)
Subclinical celiac disease (extraintestinal manifestation)
Potential celiac disease
Silent celiac disease (asymptomatic)
Latent celiac disease
Fig. 2. The ‘celiac iceberg’.
Symptomatology Table 4. Atypical presentations of CD
Diarrhea represents the main symptom in the classical form of CD. Several factors contribute to the appearance of the diarrhea in CD patients: (i) the malabsorption induces an increased intraluminal osmotic content with consequent increased stool volume. The increased stool volume is metabolized by bacteria present in the colon, especially when a high percentage of lipids is present. The consequence is the production of fat acids with an important cathartic effect; (ii) altered intercellular junctions cause a further transport of water and solutes by the intestinal mucosa; (iii) proteic and lipidic maldigestion due to the altered secretion of cholecystokinin and secretin cause steatorrhea. Weight loss represents a typical symptom in CD patients, although CD diagnosis should not rule out in patients with a normal weight or obesity. The weight loss can get worse if anorexia is also present. On the other hand, several factors can hide the weight loss including the possible increased food intake and the hypoalbuminemia-related peripheral edema. Celiac Disease: What’s New about It?
Lethargy, chronic fatigue Bruising Anemia Abnormal liver function tests Osteoporosis Short stature Dental defects Hair loss Constipation Infertility, recurrent miscarriages Late puberty, early menopause Unsteady gait, muscle weakness Depression
Asthenia is one of the most common CD symptoms although often neglected by both patients and physicians and difficult to quantify. Asthenia can be independent from the presence of diarrhea and/or anemia, while it can be associated with hypotension. Muscular fatigue is more Dig Dis 2008;26:121–127
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Table 5. Extraintestinal manifestations of CD
Laboratory abnormalities Iron and folate deficiency anemia Hypocalcemia Prolonged PT Hypertransaminasemia Skin Dermatitis herpetiformis Follicular keratosis Alopecia Hematological Splenic atrophy, thrombocytosis Psychiatric/psychological Irritability, poor school performance, anxiety, depression Musculoskeletal Osteopenia, osteoporosis, fractures Dental enamel hypoplasia Arthritis, myopathy, cramps, tetany Neurological Peripheral neuropathy Ataxia Epilepsy (8 cerebral calcification) Migraine Night blindness Reproduction Female and male infertility Recurrent abortion Intrauterine fetal growth retardation
often related to hydroelectrolytic alterations, as in particular hypokalemia. Abdominal pain is usually not constant and with a light intensity. It is typically a colic pain due to the intestinal handles distension by large volumes of gas generated by colic bacteria fermentation. On the other hand, a severe subocclusive pain should induce physicians to suspect an intestinal lymphoproliferative disease, in particular if it is associated with other serious symptoms, fever and lymphadenopathies. Nausea and vomiting are less frequent gastrointestinal symptoms. In CD patients these symptoms can be related to the presence of complications such as intestinal ulceration and lymphoma. Malabsorption and nutritional deficiencies can cause systemic (so-called ‘extraintestinal’) signs and symptoms that are of great interest since these symptoms can appear before or without the classical intestinal ones [21, 22] (table 5). Dimorphic anemia represents a typical systemic manifestation in about 50% of CD patients without glutenfree diet (GFD) treatment. Sideropenic anemia is due to the malabsorption and/or to presence of blood in stool. 124
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Consequently, sideropenic anemia is not reversible after oral iron supplementation. In CD patients, anemia can present as hypochromic and microcytic. However, hypofolatemia is often on the basis of a normocytic anemia with a dimorphism on the peripheral smear. On the contrary, B12 vitamin deficit represents a rare condition since it is adsorbed selectively in the ileum that is involved only in the late and/or untreated clinical phases of CD. K vitamin deficit represents another less common condition with consequent coagulation alterations and clinical manifestations such as purpura and occult blood in stool, urine and oral and nasal mucosa. The most frequent clinical manifestations of the CDassociated osteopathy include bone pain, osteoporosis, bone deformities, and fractures. Factors influencing the clinical manifestations of osteopathy in CD patients include calcium malabsorption with the consequent secondary hyperparathyroidism and D vitamin malabsorption. Calcium malabsorption can also induce muscular cramps, tetany and paresthesia, especially if a magnesium malabsorption coexists. D vitamin deficit is also on the basis of a characteristic myopathy of the proximal (scapular and pelvic) muscles. Recurrent aphthous ulceration is the presenting symptom of CD in 10–40% of patients with untreated CD. Other oral lesions can also occur including the geographic atrophic glossitis due to B vitamin deficits and the dental enamel hypoplasia related to a deficit in the dentin synthesis. Approximately 10% of CD patients show neurological symptoms, most often peripheral neuropathy with paresthesia, tremors and fatigue due to vitamin deficits (especially group B vitamins). Other less common neurological manifestations include various forms of epilepsy with occipital calcifications, idiopathic cerebellar ataxia, multifocal leukoencephalopathy, dementia, chorea and migraine. The malabsorption of A vitamin can also cause nocturnal blindness and hemeralopia [23]. A recent study has also shown a possible association between CD and sensorineural hearing loss [24]. Among psychiatric symptoms, CD patients can present schizophrenic symptoms, major depression as well as affective disorders such as the state-reactive form of anxiety and current depression. The last ones could be related to a cerebral regional hypoperfusion [25]. Moreover, while state anxiety disappears after GFD, depression seems to be steady in treated patients [26]; on this point, a recent study showed that psychological support counseling is able to improve both depression and GFD adherence [27]. GFD adherence represents the main aim Gasbarrini et al.
Fig. 3. High-resolution/magnification (!2) videoendoscopic im-
age of normal, finger-shaped duodenal villi.
in the treatment of CD patients since the possible both malignant and non-malignant complications related to gluten chronic exposure [28, 29]. Both males and females can also present disorders related to the reproductive apparatus. In particular, female CD patients can present delayed menarche, amenorrhea, and infertility with recurrent abortion [30]. In male CD patients the presence of infertility, impotence and altered spermatic motility has been described. In childhood, other than the above-mentioned symptoms, the delayed growth should also induce the suspect of a malabsorption. Physical examination can also relieve different and sometimes aspecific signs. Severe malabsorption can cause reduction of cutaneous elasticity, cutaneous and appendage dystrophy (including the rare condition called hypertrichosis lanuginosa), peripheral edema and muscular mass reduction. Other symptoms also include skin hyperpigmentation, anemia-related paleness, A-vitaminrelated follicular hyperkeratosis, clubbing and onychodystrophy. Several skin manifestations can be associated with CD [31]. Among them, Duhring dermatitis herpetiformis represents the most common cutaneous manifestation, also for the similar serological features. Psoriatic lesions can also occur in CD patients and seem to disappear after GFD [32]. Finally, physical examination of CD patients can also include a tympanic abdomen, a feature related to meteorism, splenic area reduction, cutaneous hypoesthesia, and osteotendinous hyporeflexia.
Celiac Disease: What’s New about It?
Fig. 4. High-resolution/magnification (!2) videoendoscopic image showing absence of duodenal villi in patient with CD.
Autoimmune Diseases Associated with CD
Several CD-associated autoimmune disorders have been described and reported, including Hashimoto’s thyroiditis, type 1 diabetes mellitus, autoimmune hepatitis and cholangitis, primary biliary cirrhosis, Sjögren syndrome, Addison’s disease, peripheral neuropathy, psoriasis, idiopathic dilated cardiomyopathy and autoimmune myocarditis. This association is thought to be secondary to HLA alleles shared by both CD and autoimmune diseases. Duration of gluten exposure seems to be an important factor in the risk to develop associated autoimmune disorders. An earlier diagnosis may prevent the development of the autoimmune diseases in CD patients [33].
Complications of CD
Untreated CD is associated with several complications classified into two groups: (1) complications due to delayed diagnosis and/or no adherence to GFD: splenic hypotrophy and atrophy, ulcerative jejunitis, enteropathyassociated T-cell lymphoma, increased risk for MALT lymphoma, esophageal and oropharyngeal carcinomas and small bowel adenocarcinoma [34–36], and (2) complications not related to delayed diagnosis and/or no adherence to GFD: refractory CD, referring to persistence of symptoms and intestinal inflammation despite a GFD, minimal or microscopic colitis (collagenous colitis and lymphocytic colitis). Dig Dis 2008;26:121–127
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Diagnosis
Endoscopic evaluation and small bowel biopsy are the gold standard for CD diagnosis, and should always be performed if the clinical suspicion for CD is strong. Multiple biopsies either from the second portion of the duodenum or the proximal jejunum should be obtained because the histological alterations may be focal [37, 38]. Recently, a new endoscopic technology with additional magnification [39–41] has raised high expectations for a substantive improvement in endoscopic recognition of villous atrophy (fig. 3, 4). Serologic tests are important to identify subjects eligible for biopsy. IgA anti-tissue transglutaminase or endomysial antibody have a high sensitivity and specificity (190%) [42, 43]. In patients with selective IgA deficiency, known to be at high risk for CD, IgG class antibodies (for tissue transglutaminase or endomysial antibody) should be determined instead of IgA antibodies [44]. Other hematologic, biochemical and imaging abnormalities may lead to the suspicion and eventually to the diagnosis of CD, such as the following ones: (1) steatorrhea in the stool examination; (2) hematologic abnormalities such as the presence of Howell-Jolly bodies and target cells in the peripheral smear, reflecting hypersplenism associated with CD; (3) anemia, thrombocytopenia, leukopenia, and hypoprothrombinemia [45]; (4) decreased levels of serum iron, calcium, folate, D vitamin and albuminemia, and abnormal liver enzymes as the
aminotransferases; (5) radiographic changes associated with CD including dilatation of the small intestine and loss of the mucosal folds [46], and (6) the computerized bone mineralometry can show a diffuse demineralized and decreased bone mineral density.
Treatment of CD Patients
The treatment of CD patients consists in a lifelong strict adherence to a GFD, eventually associated with supplemental therapy (iron, calcium, zinc, magnesium, various vitamins, especially of the B complex). Some CD patients may require steroid therapy to obtain clinical and histological improvement. Immunosuppressive therapy, such as azathioprine, may be used to decrease steroid dosage [3]. The prognosis of CD is usually favorable since GFD determines a clinical and histological recovery. However, 30% of CD patients do not present a clinical and histological improvement after a GFD. This group of patients is considered affected by ‘refractory sprue’. This condition is rare and its most common cause is the failure to adhere to a strict GFD. Refractory sprue is associated with uncommon complications of CD, such as intestinal ulceration, mesenteric lymph node cavitation, T-cell lymphomas, and collagenous sprue [47–49], with unfavorable prognosis and splenic atrophy, with a consequent increased risk for infections and/or thromboembolic complications [50].
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