Celiac sprue

Celiac sprue (CS), also known as gluten-sensitive enteropathy and celiac disease, is an autoimmune disease in which ingestion of gluten-containing products causes a histologic change in the mucosal lining of the small intestine.1-4 Once thought of only as a childhood illness and relatively rare-approximately 1 in 10,000-it is becoming clear that CS occurs in people of all ages and affects anywhere from 1 in 1,504 to as many as 1 in 133 people.5 The clinical presentation of CS can mimic many other diseases and can range from asymptomatic to severe complications resulting from malnutrition.3,6

However, even those with silent (asymptomatic/subclinical) CS may have reduced bone density, iron and folate deficiencies, and autoimmune diseases. Many patients spend years seeking help for nonspecific complaints before they are finally diagnosed with celiac disease.7 Early diagnosis and treatment can prevent long-term sequelae such as intestinal lymphoma, osteoporosis, and infertility, and a complete histologic recovery occurs in the majority of patients 3 to 6 months after treatment has begun.1-3,8

* Pathophysiology

The development of CS depends on the interaction of three factors: genetic predisposition, gluten ingestion, and immune mediated responses.1,2,8 The genetic susceptibility to the disease is associated with the presence of human leukocyte antigen (HLA) alleles HLA-DQ2 (DQA1*0501/DQB1*0201) or HLA-DQ8 (DQA1*0301/DQB1*0302) and HLA-DQ2 is expressed in 90% of persons with celiac disease.9 Even though it is necessary to have either HLA-DQ2 or HLA-DQ8, it is not sufficient in order to develop the disease.9

Celiac sprue has an estimated 10% prevalence in first-degree relatives of those diagnosed with the disease2 and a 70% concordance rate with identical twins,9 indicating that other factors are involved. There have been numerous studies that correlate CS with other autoimmune disorders such as Addison's disease, dermatitis herpetiformis, type 1 diabetes mellitus, autoimmune thyroiditis, Sjogren's syndrome, infertility, and miscarriage.1,6,8-11

It is the ingestion of gluten by individuals with these alleles that causes a T-cell mediated immune response and chronic inflammation.2,9 Once ingested, the gliadin fraction of gluten is released into the intestinal lumen and absorbed into the lamina propria of the small intestine.2,8,10,11 Gliadin containing neutral glutamine molecules binds with both alpha and beta receptors found on the T-cell.2 Tissue transglutaminase then converts the neutral glutamines to a glutamic acid residue. In response to the presence of the glutamic acid residue, antibodies are produced.2,8 The antibodies then activate the leukocytes and the cytokines that release interferon (IFN), interleukin-4, and tumor necrosis factor (TNF). The release of the cytokines directly destroys the microvilli and brush border of the intestinal mucosal cells. Malabsorption is the result of the eventual disappearance of the microvilli as well as the loss of the brush border digestive enzymes.1,2,8 The destruction of the absorptive tissues of the small bowel begins a cascade of secondary malabsorption syndromes. With the continued ingestion of gluten, this pathologic process continues, affecting numerous areas of the small bowel.1,3,8,11 Included in the pathologic lesion is increased epithelial cell proliferation with crypt hyperplasia as well as reduced enterocyte differentiation. All of these increase the risk of developing lymphoma4 and this increase may be as much as 6-fold in patients who remain untreated.12

* Clinical Findings

Due to the complex interactions between genetics, environment, and immunity, the presenting signs and symptoms of celiac disease are varied. Because CS has long been thought of as a childhood disease, the classic clinical presentation occurs in infants, usually between 6 to 18 months of age and includes anorexia, abdominal distention, diarrhea, failure to thrive, foul-smelling and sometimes watery stools, and muscle wasting.6,8,9 The symptoms in infancy are closely related to the time in which cereal grains are introduced into the diet.1,2,8 Older children often present with nongastrointestinal manifestations such as short stature, anemia, and neurological symptoms.9

Most adults present with signs and symptoms unrelated to the gastrointestinal tract, which include rheumatoid arthritis, chronic hepatitis, dermatitis herpetiformis, dental enamel hypoplasia, iron deficiency anemia, neurologic dysfunction, osteoporosis, short stature, and reproductive problems.1,2,8,11,13 Diarrhea is present in less than 50% of cases.9 Even though it has been known since the 1970s that diarrhea is not always present in patients with CS, the diagnosis of sprue is not usually considered unless diarrhea is present.9 In fact, rheumatoid arthritis may be present in up to 1.5% to 7.5% of those diagnosed with CS including adolescents, and resolves with a gluten-free diet.8 In one study, chronic hepatitis and hypertransaminasemia were the only symptoms in at least three children with complete resolution of the abnormalities after treatment for CS.8 Dermatitis herpetiformis (skin celiac disease) presents with vesicular lesions typically found on the scalp, trunk, elbows, knees, extensor surfaces of the arms and legs, and buttocks.2,8 The vesicles contain granular deposits of IgA and intestinal enteropathy is found in almost 100% of cases with dermatitis herpetiform.8 There is also an apparent link between celiac disease and psoriasis. In one study, researchers tested patients with psoriasis for CS and found that 4.34% had previously undetected celiac disease.14

Iron deficiency anemia has been reported in many studies as the most predominant sign in celiac sprue patients.1,2,8,11,13,15 Dental enamel hypoplasia, osteoporosis, and short stature are found in 10% to 30% of patients due to growth and bone turnover impairment secondary to the malabsorption of calcium and Vitamin D.1,2,8 Reproductive problems found in patients diagnosed with CS include delayed puberty, infertility, and spontaneous abortion.8

* Differential Diagnosis

As stated previously, the clinical manifestations of CS may range from severe gastrointestinal complaints with malnutrition to an asymptomatic presentation.4,6 Therefore, the list of differential diagnoses for this disease can be lengthy. When the patient presents with diarrhea, celiac disease is not the first thought of the primary care practitioner (PCP). However, since the incidence is as high as 1 in 133, CS should be suspected, especially when other causes of diarrhea are ruled out, such as Crohn's disease and infectious diarrhea. The gastrointestinal symptoms of irritable bowel syndrome (IBS) and those of CS are remarkably similar. Some authors suggest that patients are diagnosed with IBS when in fact they have CS, and conclude that routine serological testing for CS should be done when patients meet the clinical criteria for IBS.16-18

Since the majority of persons with CS do not have diarrhea, the practitioner should be familiar with the different modes of presentation and suspect CS in these cases, especially when other causes of the symptoms are eliminated. For example, a patient should be screened for CS when a bone mineral density indicates osteopenia or osteoporosis, particularly in younger individuals.19 The diagnosis of CS should also be considered in patients with anemia when other causes such as bleeding and bone marrow suppression have been ruled out. Since there is a relatively high correlation between psoriasis, dermatitis herpetiformis, and other autoimmune diseases, the diagnosis of CS should be considered in these cases as well. The neuologic symptoms associated with both classic celiac disease and subclinical CS are headache (particularly migraine and mixed type) and peripheral neuropathies, such as weakness, paresthesias, reduced vibratory sense, hyporeflexia, and muscle cramps.20,21 When these symptoms are found and other neurologic disorders are eliminated, CS should be suspected. Early diagnosis of CS is important because the length of time a person has had the disease has been linked proportionally to the risk of other autoimmune diseases as well as intestinal lymphomas (see Figure: "Diagnosis and Treatment of Celiac Sprue").8

* Diagnostic Tests

The PCP is at the forefront of diagnosing CS since it can have manifestations in many body systems and mimic a host of other disorders. Historically, the gold standard and conformational diagnostic test for CS relied on clinical presentation and histologic examination of a biopsy sample taken from the duodenum and proximal small intestine.11,28 Recently, scientific breakthroughs in serologic analysis have introduced laboratory tests for CS that, when used in combination, are both sensitive and specific.2,8,11,15,22

The first of these tests is an assay for the antigliadin antibody (AGA), and has shown a sensitivity of 60% to 100% and a specificity of 65% to 100%.2,8,11,15,22 Next is an assay for antiendomysium antibody (AEA). The AEA test has shown a sensitivity of 75% to 98% and specificity of 96% to 100%.2,8,11,15,22 The third test is an assay for tissue transglutaminase (tTG), which has a sensitivity of 98.5% and a specificity of 98%.2,8,11,15,22

Combined serologic testing is both specific and sensitive for diagnosing CS and should be considered in patients that exhibit subclincial signs or classic symptoms of celiac disease. It is recommended that serologic testing for sprue be done in patients with a diagnosis of IBS.16,17 Histologic evaluation of a biopsied sample remains the gold standard for diagnosis at this time. The mucosa appears flattened with a noticeable absence of villi, indicating a degree of atrophy (see Figure: "Damaged Mucosa").2,8,11,15,22

* Treatment

At the present time, scientific advances have not been developed that allow alteration in a person's genetic susceptibility and immune response to the gluten ingestion. Therefore, the only treatment is a total gluten-free diet.1-3,6,8,10-13 Gluten is found in wheat, barley, and rye grains.1-3,6,8,10-13,23 Studies have reported that oats are both beneficial and detrimental to patients with CS. Oats in pure form contain no harmful gluten; however, most oat products are contaminated in the milling process by machines that also process wheat, rye, and barley without being cleaned in between.24-26 Gluten is also found in many food and medicine sources as additives, preservatives, and stabilizers.1,3,23

With the introduction of a gluten-free diet, mucosal recovery usually occurs within 3 to 6 months.1-3 In some cases of CS, the disease does not respond to the absence of gluten. These cases are called refractory sprue and treatment involves the combination of a gluten-free diet and the use of glucocorticosteroids.1-3,8

When a gluten-free diet is not followed, mucosal destruction will recur. It is therefore important for the practitioner to help the patient adhere to this rather restrictive eating plan. Diet teaching and counseling should be part of each follow-up visit as well as a frank discussion of the possible complications of CS if a gluten-free diet is not followed. These include other autoimmune diseases, infertility, and T-cell lymphoma.1-3,8

Most patients have difficulty maintaining a gluten-free diet when eating out and traveling.27 Quality of life is impacted negatively by a gluten-free diet while health is improved.27,28 The practitioner needs to be aware that adherence to a gluten-free diet may be difficult and require purchasing special foods. Wheat-free/gluten-free products are widely available in health food stores, but usually cost more than their wheat-containing counterparts. Patients may need outside sources of support and there are numerous support groups and Web sites available.

* Conclusion

Celiac sprue is a disease that combines genetic, environmental, and immunologic factors to decrease the functionality of the mucosal tissue in the small intestine. Due to the variability in the individual's genetic susceptibility, consumption of gluten-containing products, and immune response, each person's clinical presentation can be different.1,2,8 What was once thought of as a disease diagnosed in infancy and early childhood with predictable symptom presentation has shown to present with quite different symptoms in adults.1-3 Although the gold standard for definitive diagnosis remains the use of histologie examination of the small intestine tissue, these samples are most commonly taken from patients presenting with gastrointestinal symptoms. The use of serologic testing for AEA, AGA, and tTG is quickly becoming acceptable and definitive for diagnosis of CS subclinical patients.2,8,9,11,15,22

The only treatment option available at the present time is the life-long elimination of gluten from the diet. The practitioner needs to be aware of the asymptomatic presentation of this disease, allowing for increased and earlier detection. Earlier detection can decrease the patient's risks of further malnutrition complications as well as development of T-cell lymphoma.1,3,8 The continued research and development of quicker and more accurate serologic tests will assist in the practitioner's ability to detect a greater number of asymptomatic or silent cases of CS. The practitioner must also be aware of the psychosocial issues of adhering to a life-long gluten-free diet. Patients with CS may need referral to a nutritionist as well as a celiac disease support group.

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Linda S. Young, MS, APRN

Debera Jane Thomas, DNS, APRN

ABOUT THE AUTHORS

Linda S. Young is a Geriatric Psychiatric Consultant at GeriCare, Providence, R.I. Debera Jane Thomas is an Associate Professor at Florida Atlantic University, Boca Raton.

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