In celiac disease (gluten-induced or gluten-sensitive enteropathy) the mucosa of the small intestine is damaged by gluten-containing foods (i.e., those containing wheat, rye, barley and possibly oats). This causes a characteristic though nonspecific lesion and subsequent malabsorption of most nutrients. The precise mechanism of gluten toxicity is unknown. Fractionation of cereal proteins reveals that the component that is toxic to the intestinal mucosa is a portion of the gluten molecule called gliadin. Although gliadin can be inactivated in a test tube by enzymatic degradation, digestion to smaller peptides by pepsin and trypsin does not alter its toxicity in humans. In susceptible people, symptoms and pathologic changes occur within 12 hours of gluten intake. The immune system is also involved. The small intestine in patients with untreated celiac disease shows an increase in lamina propria lymphocytes, plasma cells and intraepithelial lymphocytes. Immunocytochemical studies indicate that cells producing IgA, IgG and particularly IgM are increased. Increased levels of serum IgA and decreased levels of serum IgM have also been reported and appear to revert toward normal with treatment.

Genetic studies indicate that about 10% of the patient's first-order relatives have asymptomatic disease. HLA-B8 and HLA-DW3, generally associated through linkage disequilibrium, are present in 80% of patients (compared to 20% of the general population). In addition, a specific antigen is present on the surface of B lymphocytes in approximately 80% of celiac disease patients (compared to 10-15% of controls). It is found in all parents of affected individuals, which suggests that this antigen is inherited by an autosomal recessive method. Celiac disease is also present in about 2% of insulin-dependent diabetics.

13.1.1 CHILDHOOD PRESENTATION

In children, onset of symptoms suggestive of celiac disease is gradual with failure to thrive after the introduction of cereals in the diet (Table 15). The affected infant is irritable, anorexic, pale and wasted. Physical examination discloses generalized hypotonia and abdominal distention. The stools are soft, bulky, clay-colored and offensive. In the slightly older child, abdominal pain may be the presenting complaint. It may be sufficiently severe to simulate an intestinal obstruction. Older children may also present with anemia, rickets and failure to grow normally. Quite often, adolescents have a clinical quiescence of the disease. Even if relatively asymptomatic in childhood, affected people often do not attain their normal growth potential, being shorter than their sibs.

Celiac disease can present at any age, even after 70 years, but in adults it usually occurs between 20 and 60 years. In adult and adolescent patients, presentations with classical features of diarrhea, weight loss and malnutrition, or bone pain (osteomalacia) have become much less common. Mild and subclinical forms are frequent, occurring in more than 50% of patients. The sole presentation may be an otherwise unexplained hematologic abnormality (iron deficiency with or without anemia, folate deficiency, macrocytosis), constitutional symptoms or fatigue with minimal weight loss and no intestinal symptoms, or mild abdominal or digestive complaints. The entity is most common in those of Irish and Scottish background or those who have a family history.

Diarrhea is common but many patients experience normal bowel habits, alternating diarrhea and constipation, and even constipation. The diarrhea is usually mild, with fewer than three bowel movements per day in most. Floating stools, also common in healthy subjects excreting high amounts of stool gas, are often not reported. Indeed, stools suggesting steatorrhea (i.e., unformed, bulky and hard to flush, greasy, sticky, pale and foul-smelling) are quite uncommon. Flatulence, abdominal distention, abdominal cramps and borborygmi are common complaints. Fatigue is the most frequent symptom at presentation. Weight loss is usually moderate (averaging 10 kg) and may be absent in mild cases. Clinically overt metabolic (tetany) and bone (osteomalacia) diseases have become uncommon with our generous Western diets, but these situations are hallmarks of celiac disease. A clue to the diagnosis of celiac disease is the development of lactose intolerance in person whose heritage is northern European.

Patients with dermatitis herpetiformis have gluten enteropathy but often without clinical impact. Overall, mucosal involvement in celiac disease progresses from duodenum to jejunoileum and is most severe proximally; the length of bowel involved determines to a great extent the clinical picture of the disease.

Laboratory findings, as clinical signs and symptoms, vary widely. The definitive diagnosis of celiac disease requires the demonstration of small bowel mucosal villous atrophy that improves upon gluten withdrawal. In practice, several tests can be used to strengthen the suspicion of celiac disease and/or evaluate the possible biochemical consequences.

Anemia is present in less than 50% of adult patients and may be secondary to iron, folate or (very rarely) vitamin B₁₂ deficiency. Since celiac disease involves the proximal small bowel (i.e., the duodenum, where iron absorption occurs) most severely, iron deficiency is the most common laboratory abnormality. Folate deficiency also occurs, providing two laboratory screening tests for celiac disease. Decreased absorption of B₁₂ and malabsorption of vitamin K (with prolonged prothrombin time) are uncommon.

Steatorrhea can be confirmed by a 72-hour fecal fat study. It is usually mild (10-20 g/24 hours) and may be absent in some patients. Its severity correlates with the extent of the intestinal lesion, so that patients whose disease is limited to the proximal small intestine often have normal stool fat excretion.

Depletion of minerals (zinc, magnesium) and ions (potassium) occurs only with severe disease. Plasma proteins are often within normal limits but this protein-losing enteropathy (leakage of serum protein into gut lumen) and possible malnutrition may result in decreased serum albumin. A low serum carotene (and sometimes cholesterol) level may be a clue to the presence of the disease.

Approximately two-thirds of patients with celiac disease exhibit an abnormal D-xylose test. D-xylose is an aldopentose that is absorbed in the upper small intestine and is excreted in the urine almost completely within the first five hours after ingestion. Abnormal D-xylose absorption is best evaluated by the serum concentration after ingestion and points specifically to small bowel disease or luminal bacterial overgrowth. Similarly, the absorptive cell lesion also results in secondary lactase deficiency; thus, the H₂-lactose breath test may be abnormal in celiac disease.

Barium studies of the small bowel may show dilation of the bowel and slight thickening of the mucosal folds. Intraluminal signs of malabsorption with flocculation, segmentation and clumping of the barium (features due to excess amount of fluid present within the lumen) are variable and not common. (The new barium suspensions now used have made this a rare finding.) Radiographic findings in celiac disease are not specific for this syndrome of malabsorption.

The intestine of patients with celiac disease may be "leaky" and allow passage from the lumen into the blood and then into the urine of sugars such as mannitol or lactulose. The finding of increased amounts of these sugars in the urine after an oral dose suggests an abnormal intestinal permeability barrier. Such a finding of increased permeability may suggest the presence of celiac disease or other small intestinal disorders.

The demonstration of antibodies in the serum to gliadin, reticulin or endomysium suggests the presence of celiac disease. Anti-endomysial IgA antibody measurement has proved to be a sensitive test for celiac disease, even in screening studies of asymptomatic children.

Small intestinal biopsies can be obtained endoscopically from the distal duodenum (at least four forceps biopsies). Rarely, when diagnostic uncer- tainty persists, a larger mucosal specimen may be needed and obtained from the duodenojejunal area using the peroral Rubin tube or the Crosby capsule.

A flat mucosal biopsy from a white adult in the Western world is almost certain to indicate celiac disease, although other disorders can be associated with similar changes (e.g., tropical sprue, diffuse lymphoma of small bowel, immunoglobulin deficiency syndromes and the Zollinger-Ellison syndrome with gastric hypersecretion). In infants, soy protein intolerance, cow's milk protein intolerance and viral gastroenteritis produce a similar appearance. Therefore, to establish unequivocally the diagnosis of celiac disease, clinical improvement with a gluten-free diet is needed. Proving this improvement with a second biopsy is usually not necessary in adults. Mucosal small bowel atrophy improves similarly, although reversion of histology toward normal requires months or even years of gluten withdrawal and often is not complete in the duodenum.

Microscopically the characteristic "flat" lesion of celiac disease will demonstrate absence of villi, an abnormal cuboidal surface epithelium, markedly lengthened crypts and increased numbers of plasma cells and lymphocytes in the lamina propria. The lesion may be very subtle and include increased intraepithelial lymphocytes and a change in the normal position of the nuclei in the enterocyte (Figure 19). In a subtle lesion with shortened villi, proper orientation of the specimen is important in order to correctly estimate the height of the villi. The proximal small bowel is most severely involved, while the lesion decreases in severity toward the distal small intestine. The lesion may be patchy. Celiac disease will not spare the proximal small intestine while involving the distal small intestine, however. Sometimes the gross appearance of the mucosa observed at the time of an upper endoscopy may alert the physician to the possibility of celiac disease and direct her/him to obtain a duodenal biopsy.