Celiac sprue is a frequently unrecognized diagnosis in the adult population. Although this disease is referred to by other descriptions such as adult celiac disease, nontropical sprue, and gluten-sensitive enteropathy; several key features must be present. Classically, these include evidence of malabsorption, pathological damage of the small intestine, and response to a gluten-free diet.¹⁷ Although the first descriptions of celiac sprue date back to the first or second century, A.D., detailed clinical aspects of the disease were not described until the late 1800’s and early 1900’s. This included work by Gee on children and Thompson on adults.² Then in the 1940’s, Dr. W.K. Dicke, a Dutch pediatrician, noted that dietary grains were the causative factor. He observed during World War II that the symptoms of his celiac sprue patients improved during the time that food (grain) was scarce. After the war, when food was more plentiful, their symptoms returned.¹⁴ It wasn’t until the 1950’s that biopsies were discovered to be helpful in diagnosing the disease. At approximately the same time the peroral suction biopsy was perfected, thus allowing biopsies to be safely conducted on the general population. Now the prevalence of celiac sprue in the United States is thought to be 1 in every 3,000 - 10,000 adults. This is believed to be a gross underestimation as many are asymptomatic or only have vague symptoms. The disorder is more common in the Western European population with as many as 1 in 300 adults being affected in Western Ireland. The disease is rare in those of Oriental or African ancestry.¹⁹

The pathogenesis of celiac sprue has still not been clearly defined. The debate currently focuses on environmental factors, genetics, and immunology all having an influence. One hypothesis that has now been discarded is the idea that the peptidase activity of the small intestine is deficient, however this normalizes with a gluten-free diet. Also gliadin carbohydrate side chains or gluten lectinlike properties (cytotoxic against epithelial cells) do not seem to be important. Finally, the intestinal mucosa permeability defect does not appear to be a major cause as it, as well, resolves with a gluten-free diet. Below are listed the major theories that seem to contribute to the development of celiac sprue.¹⁰

It is now known that the cereal grains of wheat, rye, barley and oats (small amounts may be tolerated in some) disturb the small intestinal mucosa in celiac sprue patients. The further removed grains of rice, corn, sorghum, and millet are well tolerated. Prolamins (gliadins, secalins, and hordeins) are the alcohol-soluble proteins of gluten in these grains that are toxic to the small intestine (Figure 1¹⁰). Originally it was thought that only one fraction of the prolamins was toxic, but now it appears that many fractions cause the typical mucosal changes. There also appears to be other environmental factors playing a role as monozygotic twins susceptible to the disorder do not always manifest the classical changes. It was discovered that a certain fraction of gluten (A-gliadin) had a 12 amino acid segment similar to the E1b protein of human adenovirus serotype 12.¹⁰ Kagnoff showed that 89% of untreated celiac sprue patients versus 17% of control subjects had evidence of prior infection with the virus. Two other similar viruses were also studied, however these demonstrated no correlation with celiac sprue. It was then proposed that this adenovirus via molecular mimicry may be the catalyst necessary for developing the disease in some who are already predisposed.¹¹

It is felt that celiac sprue patients have a genetic predisposition. Studies have confirmed that the prevalence among first-degree relatives is as high as 10%. HLA identical siblings have a concordance rate of approximately 28-40% and monozygotic twins have a concordance rate of 70-75%.¹⁸ The fact that this study did not show all identical twins to be concordant supports the hypothesis that environmental factors other than gluten ingestion are influencing disease expression. Of note, not all sets of twins in the study that demonstrated a 75% concordance were proven to be identical.¹⁰

Celiac sprue is also associated with several HLA halotypes. It has been demonstrated that as many as 90% of affected individuals have HLA-B8, HLA-DR3 or HLA-DQw2 halotypes. When sampling the general population, 25-30% of individuals also possess this halotype and are disease free. Therefore it is estimated that only 0.1% of persons with the HLA susceptible halotypes eventually develop the disorder thus making genetic typing a poor screening test. In addition, the fact that concordance rates between HLA identical siblings and monozygotic twins are not analogous supports the claim that genes other than the HLA loci may be necessary for expression of the disease.⁹

Immunologic Factors

There are several humoral and cell-mediated mechanisms that may be responsible for the pathological changes seen in celiac sprue patients. These include antigliadin antibody triggering the complement cascade or invoking cytotoxic cell-mediated actions causing mucosal damage. These antibodies are also found in normal individuals so their role still has not been proven. Intraepithelial lymphocytes seen in the lamina propria of absorptive cells are known to increase greatly in affected patients. There is debate currently whether or not lymphokines produced by these cells are involved in mucosal injury.¹⁰

Celiac sprue primarily affects the mucosa of the small intestine in a proximal to distal manner with changes beginning in the duodenum. The ileum is usually spared as the damaging glutens are often digested or absorbed prior to contacting this mucosa. The pathological changes are continuous with the length of small intestine involved correlating with the severity of the symptoms. The classical changes that occur include villous atrophy and crypt hyperplasia thus decreasing the villous:crypt ratio (causing flattening of the absorptive surface). However, the thickness of the mucosa remains fairly constant (Figure 2²). The individual cells are noted to change from their typical columnar shape to a more cuboidal or squamous shape. Microvilli on the surface of the cells are also noted to decrease. The tight junctions between cells are also disturbed making them more permeable. Within the individual cells, mitotic activity is increased possibly contributing to the fact that these patients are at greater risk for lymphoma and other carcinomas. Intraepithelial lymphocytes, plasma cells, mast cells, and eosinophils are also increased in number.¹⁰

The entire realm of pathological changes need not be present for a patient to be diagnosed with celiac sprue. Research now is considering the changes seen to form a continuum between minimal changes seen in asymptomatic patients to severe changes seen in the worst cases. The mucosa injury can be seen just hours after ingestion of glutens. Resolution of the damage, however, takes weeks to months or may never occur. Finally, the pathological changes are not pathognomonic for celiac sprue and can be seen in other diseases. These include soy or milk protein allergy, tropical sprue, giardiasis, viral or eosinophilic gastroenteritis, malnutrition, intestinal bacterial overgrowth, common variable immunodeficiency, Zollinger-Ellison syndrome, and diffuse intestinal lymphoma.¹⁵

Celiac sprue may present at almost any age, but most frequently it develops in early childhood or early adulthood. With the initiation of cereal grains into the diet, children usually between the ages of one and five first start to demonstrate the clinical manifestations. Most commonly these symptoms include failure to thrive; abdominal distention; anorexia; apathy or irritability; and soft, frequent, bulky, foul-smelling stools. Breast feeding may delay the onset of celiac sprue, however, the disease still occurs when glutens are introduced. Symptoms tend to remit during adolescence although the underlying disease may progress.¹⁴

The recurrence of celiac sprue in adulthood appears to peak in women in the third and fourth decades and slightly later in men. The most common presenting symptoms in adults include diarrhea, abdominal distention, flatulence, weakness, lassitude, and progressive weight loss.¹⁴ The diarrhea typically occurs three to four times a day (usually not exceeding ten) with most episodes occurring in the morning hours. The stools characteristically are bulky, loose, pale, floating secondary to the fat content, and foul-smelling.² The diarrhea is thought to be a result of malabsorption of fats, carbohydrates, proteins, water and electrolytes. In addition, there may be a decrease in intraluminal digestion of nutrients secondary to fewer pancreatic secretions. The inability to reabsorb conjugated bile salts is also thought to contribute to the frequent stools. As a result of the severe diarrhea, most patients tend to demonstrate progressive weight loss. This symptom may be offset by some patients increasing their dietary intake and thus overcoming their malabsorption. Nonetheless, celiac sprue patients commonly exhibit abdominal distention and flatulence which more often occurs in the evenings. Abdominal pain is uncommon, and in advanced celiac sprue may be the first sign of an underlying cancer necessitating prompt evaluation.¹⁷

Extraintestinal Symptoms

In addition to the gastrointestinal symptoms of celiac sprue, patients may exhibit a vast array of other symptoms mainly due to malabsorption of vitamins and elements in the diet. Anemia has been estimated to occur in 40-90% of adults with advanced disease. Anemia, as the only presenting symptom, may even occur in up to 20% of patients. Studies have shown that approximately 75% of patients are iron deficient and as many as 95% are folate deficient. Both factors contribute to the patient’s anemia and consequently their weakness. Historically, it was believed that that the iron deficiency was due to poor absorption of iron and sloughing of epithelial cells containing iron.⁵ Research by Fine now has demonstrated that 57% of celiac sprue patients with diarrhea concurrently have heme-positive stools. The mechanism appears to involve both microerosions secondary to chronic inflammation, as well as weakness in the epithelial surface from sloughing, allowing red blood cells into the intestinal lumen.³ Vitamin B₁₂ deficiency has also been a recognized contributor to anemia, however this is less likely as the distal ileum (where absorption occurs) is involved in only the most severe cases. Vitamin K deficiency, thrombocytosis, and hyposplenism have also been described in patients.

Osteopenia is also observed in the celiac sprue population. Factors that predispose a patient to this manifestation include decreased calcium absorption, decreased vitamin D absorption, and binding of calcium in the lumen of the intestine thus preventing further absorption. Nearly one third of affected individuals may experience bone pain, but fortunately few develop pathological fractures. Muscle cramps and tetany are also seen with low serum calcium levels. In the most severe forms, hypocalcemia may result in secondary hyperparathyroidism. In addition to these electrolyte abnormalities patients may concurrently have hypokalemia and hypomagnesemia.²

Neurological deficits are fairly common in celiac sprue patients. Paresthesias, sensory deficits, ataxia, and peripheral neuropathy are well described. Hypokalemia and vitamin B₁₂ deficiency may be causative factors. Less frequently occurring but important neurological symptoms include spinal cord demyelination and cerebellar atrophy. Night blindness has also been observed secondary to vitamin A deficiency. Depression and anxiety have been diagnosed in others.¹⁷

The reproductive system is also susceptible to abnormalities in association with celiac sprue. Women may experience amenorrhea, delayed menarche, and infertility while men are prone to developing impotence and infertility. Pregnancy may even cause an exacerbation in symptoms.⁸

Physical Findings

The extent of the physical findings varies among celiac sprue patients usually correlating with the severity of small intestine involvement. Some patients may have no physical findings while others have numerous abnormalities on physical exam. General exam may reveal pallor secondary to anemia. Malabsorption tends to produce the characteristic weight loss, wasting, loose skin folds and even hypotension if the disease is advanced. Head and neck exam may exhibit cheilosis, glossitis, aphthous ulcers or dental enamel hypoplasia secondary to vitamin deficiencies. The tongue may be become red, sore, ulcerated and in extreme cases restrict swallowing ability. The abdominal exam in these patients is described as doughy, protuberant, or tympanic consistent with distended bowel loops filled with fluid and gas. Ascites occurs if hypoproteinemia becomes critical. Peripheral edema is also a manifestation of hypoproteinemia. The dermatologic exam may be significant for ecchymoses secondary to vitamin K deficiency, or hyperkeratosis follicularis secondary to vitamin A deficiency. Finally, neurological abnormalities include decreased deep tendon reflexes and decreased sensation as a consequence of peripheral neuropathy. Hypocalcemia may be demonstrated with a positive Chvostek or Trousseau sign. Lymphadenopathy is uncommon with typical celiac sprue, but if present should precipitate a work-up for lymphoma, a well-recognized complication.²

Malabsorption studies were the mainstay for diagnosing celiac sprue prior to being replaced by small bowel biopsies and serological tests. Malabsorption tests are very nonspecific and would not be helpful in the diagnosis of gastrointestinally asymptomatic patients. The D-xylose test, which requires a normal intestinal mucosa for absorption, has historically been used. Xylose, of which 60% is absorbed in the jejunum, would be abnormally low in both the serum and the urine after oral challenge. The sensitivity of this test approaches 95%, however, its specificity is quite low. The lactose intolerance test (with an inappropriately low glucose level after challenge), as well as the breath hydrogen test (with an inappropriately high hydrogen concentration in expired air) after lactose challenge both demonstrate malabsorption but again are nonspecific.¹⁵

Upper gastrointestinal barium studies with small bowel follow through have little value in the initial diagnosis of celiac sprue as they as well are nonspecific. Barium studies do demonstrate dilation of small bowel loops in addition to coarsening and obliteration of the normal mucosal folds (Figure 3²). These findings are most likely to be seen in the proximal small intestine, although with serious disease radiographic changes can be seen throughout the ileum. Barium studies may be of most use in aiding in the diagnosis of the complications of celiac disease. Irregularly narrowed segments of the small intestine may be consistent with lymphoma while rigidity may be consistent with collagenous sprue. Of note, plain films demonstrating osteopenia or pathological fractures can possibly be seen as part of the destruction of this multisystem disease.¹⁵

Various serological studies are now being developed and used to help in screening, diagnosing, and monitoring response to treatment of celiac sprue. None of these immunological markers have yet to replace small bowel biopsy as the diagnostic method of choice. Antigliadin (AGA), antireticulin (ARA), and antiendomysial (AEA) antibodies have all been studied to determine their usefulness. A summary of sensitivities, specificities, positive predictive values and negative predictive values appears below.¹⁵

Table 1

Celiac Sprue Antibodies¹⁵