Gluten-induced enteropathy includes sprue and celiac disease (childhood nontropical sprue), both diseases that affect the small intestine (predominantly the duodenum and jejunum). Both conditions are caused by immune reaction mediated by T-lymphocytes against gluten, a mixture of proteins found in wheat, rye, barley, and possibly oats. Celiac disease is found predominantly in Europeans, uncommonly in African Americans, and rarely in Asians. It is about 10 to 15 times more common in IgA-deficient persons and to a lesser extent (1%-3%) in patients with type I (insulin-dependent) diabetes mellitus. There is also an association with GI tract T-cell lymphoma and juvenile rheumatoid arthritis. There is increased incidence of the class II histocompatibility complex antigens (HLAs) HLA-DRw3 (about 80%-90% of Northern European-descent patients) and HLA-B8 to a lesser extent. HLA-DR7 is often seen in Southern Europeans. Some feel that HLA-DRw2 is even more important in all affected Europeans. Adults tend to have overt diarrhea more often than children with celiac disease; children are more likely to have anemia, nonspecific chronic illness, or short stature. A substantial number of patients have subclinical or mild disease. In those who are symptomatic there is often some degree of carbohydrate and fat malabsorption that may be accompanied by vitamin B12 and folic acid malabsorption if the ileum is affected.

Small intestinal mucosa typically first shows blunting (mild widening and shortening) of the mucosal villi and then flattening and loss of the villi with infiltration by lymphocytes. Mucosal biopsy (particularly the proximal jejunum) is still considered the gold standard for diagnosis. About 30%-50% of adult patients (not children) with nontropical sprue are reported to have some evidence of splenic atrophy, which may be seen as RBC Howell-Jolly bodies and thrombocytosis. Gliadin is the toxic protein component of gluten. Antigliadin antibodies (AGA) are found in 95% or more of patients with nontropical sprue or celiac disease. AGA-IgG are present in about 96%-97% (range, 91%-100%) of untreated patients, but only about 80% (range, 58%-95%) have celiac disease. In contrast, AGA-IgA is found in about 75% of patients (range, 42%-100%) but is about 95% specific for celiac disease (range, 80%-100%). One or both AGA are elevated in about 45%-85% of patients with dermatitis herpetiformis, which is a bullous skin disease also triggered by gluten sensitivity. False positive results in either AGA-IgA or IgA are most commonly due to ulcerative colitis or Crohn’s disease.

Antireticulum antibodies are reported to be elevated in about 50%-60% (range, 28%-97%) of patients, but specificity is said to be about 98% (range, 97%-100%). Endomysial antibodies (EMyA, reacting against the endomysial component of smooth muscle) for unknown reasons is elevated in 90%-95% of celiac disease patients (range, 85%-100%), with specificity of nearly 100%. However, both antireticulum and antiendomysial antibodies have been introduced relatively recently and have been evaluated less frequently than antigliaden antibodies. All of these antibody evaluations have been performed using homemade antibodies, which always differ somewhat and therefore make interpretation of reference laboratory results more difficult. In general, investigators seem to be currently screening patients using AGA-IgG, with ARA or EMyA either concurrently or as confirmation.

D-xylose absorption testing is said to be positive in about 80% (range, 43%-92%) of cases, but specificity for celiac disease is only about 50%. Another nonspecific absorption test recently advocated for screening purposes is the “differential sugar test,” based on poor absorption of smaller nonmetabolized carbohydrate molecules relative to larger molecules in patients with malabsorption due to small intestine mucosal dysfunction. Although several nonmetabolized sugars have been used, the most current ones are mannitol (small molecule) and lactulose (large molecule). A lactulose/mannitol urine excretion ratio greater than 0.10 was considered abnormal. Sensitivity in celiac disease was said to be 89% with specificity for celiac disease of 54%-100% (depending on the control group).

Workup for possible malabsorption

This section has considered certain tests for intestinal malabsorption. In the opinion of many gastroenterologists, the most useful tests in initial screening for malabsorption syndromes are the D-xylose, plasma carotene, and qualitative fecal fat. If the results of all these tests are normal, the chances of demonstrating significant degrees of steatorrhea by other means are low. If one or more results are abnormal and confirmation is desirable, it may be necessary to perform a 72-hour fecal fat study.

Once steatorrhea is strongly suspected or established, many investigators proceed to a D-xylose test. If the test is abnormal, many will attempt a small intestine mucosal biopsy, both to confirm a diagnosis of sprue and to rule out certain other conditions such as Whipple’s disease. Some prefer a trial period of oral antibiotics to eliminate the possibility of bacterial overgrowth syndrome and then repeat the D-xylose test before proceeding to biopsy. In some centers a biopsy is done without a D-xylose test. If gluten-induced enteropathy is suspected, antigliadin (or possibly antiendomysial) antibody assay could be useful as a screening procedure. If results of the small intestine biopsy are normal, possibilities other than sprue are investigated, such as pancreatic enzyme deficiency and bile salt abnormalities. A trial of pancreatic extract or an endoscopic retrograde cholangiopancreatography examination to investigate pancreatic or common bile duct status might be considered in these patients. Small intestine x-ray series may demonstrate some of the secondary causes of steatorrhea, such as lymphoma, diverticula, blind loops, and regional enteritis. However, barium may interfere with certain tests, such as stool collection for Giardia lamblia.

If small intestine biopsy is not available, a therapeutic trial of a gluten-free diet could be attempted. However, this requires considerable time and patient cooperation, and adults with nontropical sprue may respond slowly.

If pernicious anemia is suspected, a Schilling test is the best diagnostic procedure. Bone marrow aspiration could be performed prior to the Schilling test to demonstrate megaloblastic changes, which, in turn, would be useful mainly to suggest folate deficiency if the Schilling test result is normal. It may also reveal coexistent iron deficiency. More widely used than bone marrow aspiration are serum B12 and folic acid (folate) assay.