Celiac Disease

Background

Celiac disease (CD) is a multifactorial, autoimmune disorder that occurs in genetically susceptible individuals. It is triggered by a well-identified environmental factor (gluten and related prolamins), and the autoantigen is also well known (ie, the ubiquitous enzyme tissue transglutaminase). The disease primarily affects the small intestine, where it progressively leads to flattening of the small intestinal mucosa. 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). Three cereals contain gluten and are toxic for patients with celiac disease: wheat, rye, and barley.

The genetic susceptibility to celiac disease is conferred by well-identified haplotypes in the human leukocyte antigen (HLA) class II region (ie, DR3 or DR5/DR7 or HLA DR4). Such haplotypes are expressed on the antigen-presenting cells of the mucosa (mostly dendritic cells); approximately 90% of patients express the DQ2 heterodimer, and approximately 7% of patients express the DQ8 heterodimer. The remaining 3% of patients possess only half of the DQ2 heterodimer.

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

The morbidity rate of celiac disease can be high. Its complications range from osteopenia, osteoporosis, or both 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, the overall mortality in patients with untreated celiac disease is increased.

Evidence also suggests that the risk of mortality is increased in proportion to the diagnostic delay and clearly depends on the diet; subjects who do not follow a gluten-free diet have an increased risk of mortality, as high as 6 times that of the general population. The increased death rates are most commonly due to intestinal malignancies that occur within 3 years of diagnosis. Some indirect epidemiological evidence suggests that intestinal malignancies can be a cause of death in patients with undiagnosed celiac disease.

Race

In some ethnicities, such as in the Saharawi population, celiac disease has been found in as many as 5% of the population. As mentioned, celiac disease is considered extremely rare or nonexistent in people of African, Chinese, or Japanese descent.

Sex

Most studies indicate a prevalence for the female sex, ranging from 1.5:1 to 3:1.

Age

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

Clinical Presentations

Currently, 4 possible presentations of celiac disease are recognized, as follows:

• Typical presentation: This presentation is primarily characterized by GI signs and symptoms.
• Atypical presentation: GI signs and symptoms are minimal or absent, and various extraintestinal manifestations are present.
• Silent presentation: The small intestinal mucosa is damaged, and celiac disease autoimmunity can be detected with serology; however, no symptoms are present.
• Potential presentation: Patients are symptomatic, and the mucosa morphology is normal. These individuals have genetic compatibility with celiac disease and may also show positive autoimmune serology. Full-blown celiac disease may develop at a later stage in some of these individuals

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.