INTRODUCTION	Section 2 of 11
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Background: Sprue (ie, celiac disease) is a permanent intolerance to certain storage proteins (gliadins) found in some cereals (wheat, rye, barley) that occurs in genetically susceptible individuals. Sprue is triggered by an immune-mediated mechanism. In 1888, Samuel Gee first described the classic clinical picture. In the typical presentation of celiac disease in the young child, a combination of a potbelly and thin buttocks are observed, with proximal arm and thigh muscle wasting as a result of nutrient malabsorption.

About 1950, understanding of the disease improved when the Dutch pediatrician W. K. Dicke cleverly observed an association between wheat consumption and incidence of celiac disease. During World War II, wheat was unavailable; therefore, grain products were scarce in Holland. People with sprue had a surprising improvement in their symptoms, which ended when wheat and other grains became available again.

Since then, research has uncovered the pathophysiology of this disease, which has enabled medical understanding and treatment. In 1968, adult nontropical sprue and childhood celiac disease were discovered to be the same affliction.

Sprue can occur at any stage in life; a diagnosis is not unusual in people older than 60 years.

Pathophysiology:

Pathogenesis

Celiac disease is an autoimmune disease, and tissue transglutaminase (tTG) has been discovered to be the autoantigen against which the abnormal immune response is directed. Gluten is the single major environmental factor that triggers celiac disease, which has a narrow and highly specific association with class II haplotypes of human leukocyte antigen (HLA) DR17-DQ2 and, to a lesser extent, DR4-DQ8. However, despite an enormous increase in scientific knowledge in the past few years, the intimate mechanisms leading to the intestinal damage are incompletely understood. Most studies on the pathogenetic mechanisms have been directed toward elucidating the role and function of T cells and related cytokines.

The initial event in the pathogenesis of the celiac lesion is thought to be an abnormal permeability, which allows the entry of gliadin peptides not entirely degraded by the intraluminal and brush border–bound peptidases. Under normal physiologic conditions, the intestinal epithelium bars the passage of macromolecules, such as gluten. Only trace amounts of high-molecular-weight peptides cross this barrier. However, in celiac disease, permeability to macromolecules is increased. This alteration is secondary to a loosening of the intestinal tight junctions, which is possibly a prerequisite for the further development of the immune events to follow.

The epithelial barrier may also be disrupted in the course of a viral infection. This event is believed to be a possible contributing factor to the onset of celiac disease in predisposed individuals.

The early changes induced by exposure to gluten in celiac disease are mediated by the innate branch of immunity, and attention is currently being given to the early events that occur in response to gluten exposure, as they seem pivotal in setting up the subsequent involvement of the adaptive branch of immunity mediated by T cells. The involvement of T cells leads to the celiac disease and its full-blown mucosal changes.

Approximately 95% of all patients express the DQ2 heterodimer, which is encoded by DQA10501/DQB10201, whereas the remaining 5% have DR4 with the DQ8 heterodimer encoded by DQA10301/DQB10302. This strong association implies that the adaptive branch of the immune system (CD4⁺ T lymphocytes in particular) must play a crucial role in the pathogenesis. In fact, DQ2 and DQ8 molecules are located on the surface of antigen-presenting cells (mostly dendritic cells) and bind peptides to be presented to CD4⁺ T lymphocytes. tTG, the major target of autoantibodies in celiac disease, selectively can convert glutamine residues within gluten to glutamic acid. Such deamidation strongly enhances DQ binding and T-cell recognition.

Relevant anatomy

Sprue primarily affects the small intestine. This organ is divided into 3 areas: the duodenum (which begins at the pylorus located at the end of the stomach), the jejunum, and the ileum (ending at the ileocecal junction, the beginning of the large intestine). These 3 parts share similar tissue architecture and are responsible for most of the body's nutrient absorption. The intestinal wall has 4 layers, which (from the lumen inward) are termed the mucosa, submucosa, muscularis, and serosa. The 2 main functions of the mucosa are to accomplish all digestive-absorptive processes for nutrients and electrolytes and to provide a barrier function by excluding foreign antigens and toxins.

Sprue primarily affects the mucosal layer, which is where an inflammatory state, caused by a cascade of immune events, is activated in predisposed individuals by the exposure to gliadins. The condition causes a deepening and hyperplasia of the crypts and a concomitant flattening of the villi (fingerlike projections of the mucosa with the primary function of increasing its absorptive surface). These changes are more evident proximally and fade distally. These typical changes may occur with a patchy distribution, though the duodenal bulb (the first part of the duodenum) appears to be always involved. When gluten is excluded from the diet, the diseased mucosa returns to normal. The process of normalization is a highly variable one and may occur as soon as a few weeks or as late as 1-2 years. Typically, the mucosa completely heals within 3-4 months.

Microanatomy

At the microanatomic level, the mucosa consists of simple columnar epithelium with goblet cells, underlain by a lamina propria. A thin layer of muscularis mucosa separates the mucosal layer from the submucosa. The small intestine mucosa is composed of 2 main areas (created by the villi) and 6 specialized cell types: enterocytes, goblet cells, M cells, Paneth cells, enteroendocrine cells, and undifferentiated cells.

Villi are epithelium-covered fingerlike projections into the lumen. The expanded surface area they create enable the small intestine to serve its main function, ie, nutrient absorption. Villi are more than just cells; each has a core of lamina propria that forms its loose connective tissue and surrounds a lymphatic capillary (ie, lacteal) and a blood capillary into which absorbed nutrients flow.

At the base of the villi are the crypts of Lieberkühn. They are the valleys around the villi and consist of simple tubular glands coiled below the bases of the villi, extending into the lamina propria. All the following types of cells are found in these crypts, which is the perfect environment to perform their tasks.

Enterocytes are the predominant cells in the small intestine. Enterocytes cover the villi and are present in the crypts in lesser amounts. These tall, columnar cells laterally adhere to each other to create tight junctional complexes at the luminal side and loose junctions on the basal side. Enterocytes also have a microvilli-covered luminal wall, which is termed the striated layer because of the thin lines that can be perceived when all the microvilli are swaying at the luminal border. Disaccharidases and dipeptidases are secreted into the striated border (spaces between the microvilli) and break down sugars and proteins into their most elemental form for absorption by the microvilli into the enterocyte.

The secretory endoplasmic reticulum in the cytoplasm of the enterocyte is responsible for processing monoglycerides and fatty acids into chylomicrons to be packaged by the Golgi apparatus for absorption into the lacteals. Several mechanisms for absorbing complex nutrients into the enterocyte also exist.

Goblet cells are mucus-producing cells that produce glycoprotein and that secrete lubrication for the intestinal wall. Goblet cells are not indigenous to the small intestine, but here they gradually increase in population from the duodenum to the ileum. Goblet cells are more populous in the large intestine than in the small intestine.

M, or microfold, cells are flat cells overlying lymphoid nodules and Peyer patches. M cells have folds rather than microvilli in the luminal side. These cells signal immune responses to the underlying lymphoid tissue.

Paneth cells lie at the bases of the crypts and synthesize a protein-polysaccharide complex (lysozyme), which helps control intestinal flora.

Enteroendocrine cells are also found in the crypts. They produce hormones to regulate intestinal function.

Undifferentiated cells are located at the bases of the crypts. Undifferentiated cells make renewal of the intestinal wall possible by replacing all the sloughed components of the intestinal wall.

Effects on cells

When intestinal lesions caused by sprue are observed under a microscope, the villi (which greatly increase the surface area available for absorption) are flattened, and the remaining epithelial cells have lost their cylindrical shape. Numerous immune cells, particularly T cells, can be seen in these patches. T cells also infiltrate the epithelium. In the lamina propria of the mucosa, an intense mononuclear infiltrate, which includes plasma cells, is present.

The flattening of the villi is accompanied by a markedly increased turnover by young enterocytes produced in the crypts; this is another histologic sign, ie, an increase in mitotic figures. The ability to signal the need for particular types of cells is obviously not lost because the disease is wholly reversible; however, in the presence of gluten and gliadin, the injury seems to overwhelm the cells' ability to catch up.

Frequency:

• In the US: Celiac disease is thought to be one of the most common life-long disorders affecting whites. In a number of epidemiologic investigations, its prevalence in many Western countries, particularly those in Europe, has been estimated to be 1 case per 80-340 population. It was long believed that prevalence in the United States was far less. A large epidemiologic investigation reported in 2003 showed that the prevalence in the United States is the same as that in Europe (1 case per 133 population). As such, the rate is slightly higher than that of Crohn disease, ulcerative colitis, and cystic fibrosis together. Celiac disease was probably underestimated in the United States because it is more common in its asymptomatic than in its symptomatic form.

• Internationally: The disease is rare or nonexistent in Far East Asia and in blacks because of the paucity of individuals positive for HLA-DQ2 or HLA-DQ8.

Mortality/Morbidity: The morbidity rate of sprue can be high. Its complications range from osteopenia and/or osteoporosis to infertility in women, short stature, delayed puberty, anemia, and even malignancies (mostly related to the GI tract, eg, intestinal T-cell lymphoma). As a result, mortality is increased by up to 6-fold in untreated celiac disease.

Race: As mentioned, the disease is common in whites but probably rare in Asians and blacks.

Sex: Most studies indicate a slight prevalence for the female sex.

Age: Sprue can occur at any stage in life; a diagnosis is not unusual in people older than 60 years.

• Classic GI pediatric cases usually appear in children aged 9-18 months.

• Sprue may also occur in adults and is usually precipitated by an infectious diarrheal episode or other intestinal disease.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History:

• The classic presentation of a child with celiac sprue (mostly in those aged 6-24 mo) is progressive irritability and anorexia, chronic diarrhea, failure to thrive, potbelly, and notable muscle wasting (particularly in the gluteal area). GI symptoms include constipation and vomiting or recurrent abdominal cramping.

• Atypical presentations that are now becoming more frequent include growth failure without diarrhea, anemia (typically iron deficient), osteopenia or osteoporosis, bleeding disorders, chronic hepatitis, dental enamel hypoplasia, epilepsy with cerebral calcifications, delayed puberty, and short stature. The atypical presentations are more common in the older child and in the adult.

• Strong evidence suggests that celiac disease occurs more often in family members than in others. Sprue affects approximately 10% of first-degree relatives (and possibly up to 5% of other relatives) of a known patient. However, lack of a family history for other dietary allergies, including allergy to wheat, should not influence clinical suspicion for celiac disease.

• Early studies of identical twins failed to prove the disease in all instances. However, studies performed after serologic test became available and after subtle changes in duodenal morphology were appreciated as causes have shown that, given the same genetic and environmental factors, concordance is nearly 100%.

• Disease associations: Celiac disease is associated with a number of autoimmune conditions and genetic syndromes.

• Autoimmune conditions
  • Type 1 diabetes (celiac disease prevalence: 8%)
    
  • Hashimoto thyroiditis (celiac disease prevalence: 3%)
    
  • Juvenile rheumatoid arthritis (celiac disease prevalence: 3%)
    

• Genetic syndromes
  • Down syndrome (celiac disease prevalence: 10%)
    
  • Turner syndrome (celiac disease prevalence: 5%)
    
  • Williams syndrome (celiac disease prevalence: 3%)
    

Physical: Examination findings depend on extent of the disease.

• Pale conjunctiva characterizes the child with anemia.

• Dry mucosal membranes with vomiting or diarrhea indicate the degree of dehydration.

• Oral aphthae are more frequent than in normal population.

• Dental enamel hypoplasia is a highly specific but relatively uncommon finding.

• Bloating of the abdomen is a relatively common finding.

• Muscle wasting is an obvious but uncommon finding.