AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Celiac sprue, also known as celiac disease or gluten-sensitive enteropathy, is a chronic disease of the digestive tract that interferes with the digestion and absorption of food nutrients. People with celiac sprue cannot tolerate gliadin, the alcohol-soluble fraction of gluten. Gluten is a protein commonly found in wheat, rye, and barley. Most patients with celiac disease tolerate oats, but they should be monitored closely. When people with celiac sprue ingest gliadin, the mucosa of their intestines is damaged by an immunologically mediated inflammatory response, resulting in maldigestion and malabsorption. Patients with celiac disease can present with failure to thrive and diarrhea (the classical form). However, some patients have only subtle symptoms (atypical celiac disease) or are asymptomatic (silent celiac disease).

Pathophysiology

Celiac sprue has a strong hereditary component. The prevalence of the condition in first-degree relatives is approximately 10%.

A strong association exists between celiac sprue and two human leukocyte antigen (HLA) haplotypes (DQ2 and DQ8). Damage to the intestinal mucosa is seen with the presentation of gluten-derived peptide gliadin, consisting of 33 amino acids, by the HLA molecules to helper T cells. Helper T cells mediate the inflammatory response. Endogenous tissue transglutaminase deamidates gliadin into a negatively charged protein, increasing its immunogenicity. Absence of intestinal villi and lengthening of intestinal crypts characterize mucosal lesions in untreated celiac sprue. More lymphocytes infiltrate the epithelium (intraepithelial lymphocytes). Destruction of the absorptive surface of the intestine leads to a maldigestive and malabsorption syndrome.

Frequency

United States

The frequency of celiac sprue in the United States is relatively low, about 1 case in 3000 persons. Estimates suggest that approximately 1% of the population is affected. Celiac disease is underdiagnosed in most affected people.

International

Approximately 3 million people in Europe and another 3 million people in the United States are estimated to be affected by celiac sprue. Celiac sprue is prevalent in European countries with temperate climates. The highest prevalence of celiac sprue is in Ireland and Finland and in places to which Europeans emigrated, notably North America and Australia. In these populations, celiac sprue affects approximately 1 in 100 individuals. The incidence of celiac sprue is increasing among certain populations in Africa (Saharawui population), Asia (India), and the Middle East. 

Mortality/Morbidity

Although rarely lethal, celiac sprue is a significant and often debilitating maldigestive and malabsorption syndrome affecting multiple organ systems.

• Patients with celiac sprue are at increased risk for complications, such as lymphomas and adenocarcinomas of the intestinal tract.
• Untreated pregnant women are at risk of miscarriage and at risk of having a baby with a congenital malformation.
• Short stature often results when celiac sprue prevents nutrient absorption during the childhood years when nutrition is critical to growth and development.
• Symptoms of celiac sprue malabsorption can include one or more of the following (see History):
  • Chronic diarrhea
  • Steatorrhea
  • Abdominal bloating or cramps
  • Flatulence
  • Weight loss
  • Fatigue
  • Anemia
  • Bleeding diathesis
  • Osteopenia
  • Seizure disorders
  • Stunted growth

Race

Celiac sprue is most prevalent in Western Europe and the United States. The incidence is increasing in Africa and Asia.

Sex

Incidence of celiac sprue is slightly higher in females than in males.

Age

The age distribution of patients with celiac disease is bimodal, the first at 8-12 months and the second in the third to fourth decades. The mean age at diagnosis is 8.4 years (range, 1-17 y).

• Celiac disease might become apparent in infants when gluten ingestion begins. Symptoms of celiac disease might persist throughout childhood if untreated but usually diminish in adolescence. Symptoms often reappear in early adulthood, between the third and fourth decades of life.
• Approximately 20% of patients with celiac disease are older than 60 years.
• Adolescents with celiac sprue frequently present with extraintestinal manifestations, including short stature, behavioral problems, fatigue, and skin problems. The diagnosis of celiac sprue is often not established until middle age or old age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The manifestations of untreated celiac sprue can be divided into gastrointestinal symptoms and extraintestinal symptoms.

• Gastrointestinal symptoms  
• • Diarrhea is the most common symptom in untreated celiac sprue and present in 45-85% of all patients. Diarrhea caused by celiac sprue is due to maldigestion and malabsorption of nutrients. The stools might be watery or semiformed, light tan or gray, and oily or frothy. The stools have a characteristic foul odor. In infants and young children, extensive diarrhea can lead to severe dehydration, electrolyte depletion, and metabolic acidosis.
  • Malabsorption of ingested fat (steatorrhea) results in the delivery of excessive dietary fat to the large bowel. This results in the production of hydroxy fatty acids by bacteria, which causes secretion of fluids into the intestine.
  • Flatulence (28% of patients) and borborygmus (35-72% of patients) results from the release of intestinal gas by the bacterial florae feasting on undigested and unabsorbed food materials and often becomes excessive or even explosive.
  • Weight loss (present in 45% of all patients) is variable because some patients might compensate for the malabsorption by increasing dietary intake. In infants and young children with untreated celiac sprue, failure to thrive and growth retardation are common.
  • Weakness and fatigue (prevalence 78-80%) are usually related to general poor nutrition. In some patients, severe anemia can contribute to fatigue. Occasionally, severe hypokalemia due to the loss of potassium in the stool can cause muscle weakness.
  • Severe abdominal pain (prevalence 34-64%) is unusual in patients with uncomplicated celiac sprue. However, abdominal bloating or cramps with excessive malodorous flatus is a common complaint.
• Extraintestinal symptoms  
• • Anemia (10-15% of patients) is usually due to impaired absorption of iron or folate from the proximal small intestine. In severe celiac disease with ileal involvement, absorption of vitamin B-12 might be impaired.
  • A bleeding diathesis is usually caused by prothrombin deficiency due to impaired absorption of fat-soluble vitamin K.
  • Osteopenia and osteoporosis (prevalence 1-34%) might cause bone pain for several reasons, including defective calcium transport by the diseased small intestine, vitamin D deficiency, and binding of luminal calcium and magnesium to unabsorbed dietary fatty acids.
  • Neurologic symptoms (frequency 8-14%) that result from hypocalcemia include motor weakness, paresthesias with sensory loss, and ataxia. Seizures might develop because of cerebral calcifications.
  • Skin disorders, including dermatitis herpetiformis (a pruritic papulovesicular skin lesion involving the extensor surfaces of the extremities, trunk, buttocks, scalp, and neck), is associated in 10-20% of patients with celiac disease.
  • Hormonal disorders, such as amenorrhea, delayed menarche, and infertility in women and impotence and infertility in men, have been described.

Physical

• Abdominal examination shows a protuberant and tympanic abdomen due to distention of intestinal loops with fluids and gas. Ascites occasionally can be detected in patients with severe hypoproteinemia.
• Evidence of weight loss, including muscle wasting or loose skin folds
• Orthostatic hypotension
• Peripheral edema
• Ecchymoses
• Hyperkeratosis or dermatitis herpetiformis
• Cheilosis and glossitis
• Evidence of peripheral neuropathy
• Chvostek sign or Trousseau sign

Causes

Celiac sprue results from a combination of immunological responses to an environmental factor (gliadin) and genetic factors.

• Immune mechanisms  
• • The interaction of alcohol-soluble gliadin in wheat, barley, and rye products with the mucosa of the small intestine is crucial to the pathogenesis of celiac sprue. Endogenous tissue transglutaminase deamidates glutamine in gliadin, converting it from a neutral to a negatively charged protein. Negatively charged gliadin has been shown to induce interleukin 15 in enteric epithelial cells, stimulating proliferation of natural killer cells and intraepithelial lymphocytes to express NK-G2D, a marker for natural killer T lymphocytes.
  • Gliadin (a complex mixture of proline- and glutamine-rich polypeptides obtained by alcohol extraction of wheat gluten) can produce symptoms and histological changes in the small intestine when administered to patients with asymptomatic celiac sprue. Antigliadin antibodies can frequently be identified in untreated patients.
  • Immunoglobulin A (IgA) antibodies to smooth muscle endomysium and tissue transglutaminase (the most commonly used test) are used for serological diagnosis. However, 3-5% of all patients with celiac disease are IgA deficient. Therefore, determining total IgA prior to antibody testing is appropriate in patients with celiac disease.
  • Cell-mediated immune responses are also important for the pathogenesis of celiac sprue, as demonstrated by the presence of large numbers of CD8+ T lymphocytes in the intestinal epithelium.
• Genetic factors 
• • Genetics play an important role in celiac sprue. The incidence of celiac disease in relatives of patients with celiac sprue is significantly higher than in the general population. The prevalence in first-degree relatives of patients with celiac sprue is approximately 10%. Concordance for the disease in monozygotic twins approaches 75% and is approximately 30% for first-degree relatives.
  • Gliadin binds to HLA-DQ2 heterodimers or HLA-DQ8 heterodimers found in 90-95% and 5-10% of patients with celiac disease, respectively. HLA-DQ2 and HLA-DQ8 are present on the surface of antigen-presenting cells in the lamina propria, and binding of gliadin leads to expression of the proinflammatory cytokine interferon gamma and activation of CD4+ T lymphocytes.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Jejunoileitis
Enteropathy-type T-cell lymphoma
Non-Hodgkin lymphoma

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Patients with diabetes mellitus type 1, Down syndrome, or Turner syndrome have an increased incidence of celiac disease.
• Electrolytes and chemistries
• • Electrolyte imbalances, such as hypokalemia, hypocalcemia, hypomagnesemia, and metabolic acidosis, can develop.
  • Evidence of malnutrition, such as hypoalbuminemia, hypoproteinemia, hypocholesterolemia, and a low serum carotene level, might be present.
• Hematologic tests  
• • Anemia due to deficiency in iron, folate, and, rarely, vitamin B-12 might be present.
  • A low serum iron level is common.
  • The prothrombin time (PT) might be prolonged because of malabsorption of vitamin K.
• Stool examination  
• • The typical bulky, greasy appearance and rancid odor of stools often suggest malabsorption of fat.
  • Findings from a Sudan stain of the stool might reveal fat droplets.
  • For a more quantitative measurement of fat absorption, a 72-hour fecal fat collection is frequently helpful in documenting steatorrhea.
• Oral tolerance tests  
• • Excretion of breath hydrogen, a product of bacterial fermentation of unabsorbed lactose, is often elevated in celiac sprue.
  • The oral D-xylose tolerance test can reveal carbohydrate malabsorption. D-xylose is absorbed preferentially in the proximal small intestine and excreted unmetabolized in the urine. In untreated celiac sprue, urinary D-xylose excretion and peak blood xylose levels are depressed.
  • Lactose tolerance is another oral tolerance test.
• Serology 
• • The most sensitive and specific antibodies for the confirmation of celiac disease are tissue transglutaminase IgA, endomysial IgA, and reticulin IgA and correlate with the degree of mucosal damage. As the incidence of selective IgA deficiency is higher among patients with celiac disease, total IgA serum concentrations should be determined. If the patient is IgA deficient, tissue transglutaminase IgG can be measured.
  • The presence of serum IgA antibody to endomysium in untreated celiac sprue has higher sensitivity and higher specificity than antigliadin antibodies. However, serum IgA antiendomysial antibody often becomes undetectable after 6-12 months of gluten withdrawal. Persistently elevated IgA endomysial and tissue transglutaminase antibodies for 12 months usually indicate poor compliance with a gliadin-free diet.
  • Seronegative celiac disease has been reported in 6.4-9.1% of patients with normal IgA serum concentrations; however, these patients either were elderly or had severe disease.

Imaging Studies

• Small bowel barium studies
• • Radiographic evaluation of the small bowel after barium ingestion is helpful in making a diagnosis of untreated celiac sprue.
  • Abnormal radiographic findings can include dilatation of the small intestine, a coarsening or obliteration of the normally delicate mucosal pattern, and fragmentation or flocculation of the barium in the gut lumen.

Procedures

• Upper endoscopy with at least 6 duodenal biopsies is considered the criterion standard to help establish a diagnosis of celiac disease. Serology and endoscopy should be considered, especially in patients presenting with classical symptoms, evidence of malabsorption, and endoscopic findings, including mucosal fold scalloping, reduced mucosal folds, and mosaic pattern.

Histologic Findings

Celiac sprue primarily involves the mucosa of the small intestine. The submucosa, muscularis, and serosa are usually not involved. The villi are atrophic or absent with a decreased villous-to-crypt ratio (normal ratio, 4-5:1) and crypts are hyperplastic. The cellularity of the lamina propria is increased with a proliferation of plasma cells and lymphocytes. The number of intraepithelial lymphocytes per unit length of absorptive epithelium is increased (normal intraepithelial lymphocyte to epithelial cell ratio, 1:10).

Staging

Histologically, duodenal biopsies can be graded into the following 5 stages:

• Stage 0 - Normal
• Stage 1 - Increased percentage of intraepithelial lymphocytes (>30%)
• Stage 2 - Characterized by an increased presence of inflammatory cells and crypt cell proliferation with preserved villous architecture
• Stage 3 - Mild (A), moderate (B), and subtotal to total (C) villous atrophy
• Stage 4 - Total mucosal hypoplasia

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• The primary treatment of celiac sprue is dietary.
• • Removal of gluten from the diet is essential. Complete avoidance of gluten-containing grain products is relatively difficult for patients to achieve and maintain because certain products, such as wheat flour, are virtually ubiquitous in the American diet.
  • Careful and extensive indoctrination of the patient by the physician and the dietitian is often necessary to achieve full compliance.
• Corticosteroids
• • A small percentage of patients with celiac sprue fail to respond to a gluten-free diet. In some patients who are refractory, corticosteroids might be helpful.
  • In patients who fail to respond to corticosteroids, other comorbid conditions, such as lymphomas of the small intestine, have to be ruled out.

Consultations

• Dietitian
• Nutritionist

Diet

Complete elimination of gluten-containing grain products, which include wheat, rye, and barley, is essential to treatment. After an initial period of avoidance, oats might be reintroduced into the diet of patients with celiac disease. These patients should be monitored carefully for recurrent symptoms.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Corticosteroids might be indicated in patients with refractory celiac sprue.

Drug Category: Corticosteroids

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• The risk for malignant disease is increased in patients with celiac disease.
• • These malignancies include adenocarcinoma of the oropharynx, esophagus, pancreas, small and large bowel, and hepatobiliary tract.
  • Other malignancies with an increased incidence in patients with celiac disease are enteropathy-associated T-cell lymphoma with a poor prognosis and T- and B-cell non-Hodgkin lymphoma. 
• Refractory celiac disease occurs in approximately 5% of patients despite strict adherence to a gliadin-free diet.
• • Refractory celiac disease is characterized by symptoms of malabsorption, weight loss, diarrhea, abdominal distention, and anemia.
  • Refractory celiac disease is subdivided into two types: type 1 is characterized by a normal intraepithelial lymphocyte phenotype, and type 2 is characterized with an increased number of intraepithelial lymphocytes, possibly due to an increase in epithelial interleukin 15 expression.

Prognosis

• The prognosis for patients with correctly diagnosed and treated celiac sprue is excellent.
• The prognosis for patients with celiac sprue who are not responding to gluten withdrawal and corticosteroid treatment is generally poor.

Patient Education

• For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center and Teeth and Mouth Center. Also, see eMedicine's patient education articles Celiac Sprue, Anatomy of the Digestive System, and Canker Sores.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Patients with celiac sprue are at increased risk for complications, such as lymphomas and adenocarcinomas of the intestinal tract. A small percentage of patients with celiac sprue fail to respond to a gluten-free diet, and, in some patients with refractory disease, corticosteroids might be helpful. In patients who fail to respond to corticosteroids, other comorbid conditions, such as lymphomas of the small intestine, should be considered.
• Removal of gluten from the diet is essential to successful treatment of patients with celiac sprue. However, complete avoidance of gluten-containing grain products is relatively difficult to achieve and maintain because certain products, such as wheat flour, are virtually ubiquitous in the American diet. Careful and extensive indoctrination of the patient by the physician and the dietitian is often necessary to achieve full compliance.
• • Compliance is important for pregnant women because, if untreated, pregnant women are at risk of miscarriage and at risk of having a baby with a congenital malformation.
  • Compliance is important for infants and young children because, with untreated celiac sprue, failure to gain weight and growth retardation are common in this population.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Sategna-Guidetti C, Pulitanó R, Grosso S, et al. Serum IgA antiendomysium antibody titers as a marker of intestinal involvement and diet compliance in adult celiac sprue. J Clin Gastroenterol. Sep 1993;17(2):123-7. [Medline].
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Article Last Updated: Aug 14, 2008