Abstract

Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms of Celiac disease are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen); often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years.

Disease Name and Synonyms

Celiac disease (CD) in children and celiac sprue in adults are probably the same disorder with the same pathogenesis. The synonyms are: Coeliac disease (British spelling) – Celiac sprue – Nontropical sprue-Gluten-sensitive enteropathy – Idiopathic steatorrhea

Definition

Celiac disease is a chronic intestinal disease mostly associated with malabsorption caused by intolerance to gluten. It is characterized by immune-mediated enteropathy (villous flattening), resulting in maldigestion and malabsorption. Clinical and histological improvement can be obtained after withdrawal of dietary gluten.

Celiac disease is characterized by malabsorption and villous atrophy. However, diseases other than Celiac Disease can cause marked villous flattening and increased intraepithelial lymphocytes (IEL) [1]. Differential diagnosis is of special importance for subjects in whom Celiac Disease is suspected and who have negative serology. The following diseases, which can have similar features, must be ruled out [1-4]:

• Tropical sprue
• Collagenous colitis
• Whipple's disease
• Giardiasis
• Viral enteritis
• AIDS
• Crohn's disease of the small intestine
• Small intestinal lymphoma
• Carbohydrate intolerance, cow's milk intolerance
• Autoimmune enteropathy
• Graft-vs-host disease
• Radiation damage

Prevalence of clinically overt celiac disease varies from 1/270 in Finland to 1/5,000 in North America. However, since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. In epidemiological studies aimed to assess Celiac Disease prevalence, large cohorts in North America and Europe were screened for highly-sensitive endomysium or tissue transglutaminase antibodies. Besides, they underwent subsequent small intestinal biopsies when antibody testing was positive. The Celiac Disease prevalence was found to be much higher than expected. Approximately 1/100 to 1/500 were found positive for antibodies and had villous atrophy of the small intestine [5-10]. Thus, up to 1% of a western population tests positive for celiac disease. There are approximately 7–10 undiagnosed subjects for each known Celiac Disease patient. Furthermore, approximately 10% of the first-degree relatives also have Celiac Disease [11,12].

Celiac disease is diagnosed typically in early childhood around age of 2 years. A second peak is found around age of 40 years [3]. Most symptoms are due to malabsorption of nutrients and vitamins [13,14]. However, the clinical manifestations differ greatly, depending on each case and ranging from asymptomatic (silent) [15] to full blown (symptomatic, clinically overt) celiac disease [16]. The severity of symptoms is not necessarily proportional to the severity of the mucosal lesions and patients with total villous atrophy can be asymptomatic or present with subclinical symptoms such as iron deficiency or muscle cramps. Nowadays, more subjects present with asymptomatic or mild celiac disease than with the classical symptoms of severe malabsorption [4,17].

The term "atypical" celiac disease is used for patients who present with extraintestinal symptoms like Immunoglobulin A (IgA)-nephropathy, hemosiderosis of the lungs and a variety of neurological diseases. Antibodies and typical small intestinal changes can be found. Early diagnosis is desirable since many of these symptoms can disappear after the initiation of a gluten-free diet.

The term "latent" celiac disease refers to subjects who will develop the disease later in life but who do not have a flat mucosa despite a gluten-containing diet [17-20]. Increased intraepithelial lymphocytes (IEL) and positive endomysium antibody (EMA) or positive tissue transglutaminase (tTG) antibody tests are sometimes found in these subjects [21-23]. What triggers the onset of the disease in these subjects remains unknown.

Ferguson et al. introduced the term "potential" celiac disease in 1993 to characterize in details patients with latent Celiac Disease [24]. The authors suggested "potential" Celiac Disease to be used for the subjects who have markers of latent Celiac Disease (elevated IEL, positive for tTG) without ever developing overt Celiac Disease, with "latent" Celiac Disease being used for patients who will develop a flat mucosa in the future. However, this discrimination is very artificial and not shared by other specialists in the field [25]. The terms "latent" and "potential" celiac disease are not used by all authors in the same way, which can further confuse matters. Patients with latent or potential celiac disease may develop symptoms that respond to a gluten-free diet [26]. For the definition of the different states of celiac disease, see table 1.

Table 1. Definition of Different States of Celiac Disease.

Celiac disease is also associated with several extraintestinal diseases and autoimmune diseases, which can not be linked to nutrient deficiencies [27-33]. For example, up to 8% of patients with type 1 diabetes were reported to test positive for Celiac Disease [4]. Celiac Disease patients are also at higher risk of developing malignancies. Holmes et al. reported an increased risk especially of intestinal lymphoma in subjects with untreated celiac disease compared to patients on a gluten-free diet [34]. However, more recent data indicate that this risk may be lower than previously anticipated [35,36].

The following extraintestinal symptoms are secondary to malabsorption [2,3]

• Peripheral neuropathy (vitamin B12 and B1 deficiency)
• Anemia (iron, vitamin B12 and folate deficiency)
• Growth failure in children
• Bone pain (osteoporosis and osteopenia, vitamin D and calcium deficiency)
• Muscle cramps (magnesium and calcium deficiency)
• Night blindness (vitamin A deficiency)
• Weight loss (impaired absorption of most nutrients)
• Edema (protein and albumin loss)
• Weakness (hypokalemia and electrolyte depletion)
• Bleeding and hematoma (vitamin K deficiency)

The following extraintestinal symptoms/manifestations are probably not secondary to malabsorption (atypical CD) [27]

The following diseases/conditions are associated with celiac disease [29-31]

• Autoimmune diseases such as type 1 diabetes, Sjögren syndrome, thyroid diseases (Hashimoto's thyroiditis and Graves's disease), autoimmune hepatitis and primary biliary cirrhosis
• Selective IgA deficiency
• Turner's syndrome