Only a few years ago, researchers believed the prevalence of celiac disease (CD) in the United States to be approximately 1 in 6,000 people—much lower than in Europe, where it was 1 in 300.1 However, the most recent data show that this number is sorely underestimated, largely because screening is uncommon in the United States and CD is difficult to recognize, especially in adults. Newer serologic tests have improved the diagnostic process worldwide and, as a result, the disease is being diagnosed more and more often in adults. Currently, an estimated 1 in 120 to 300 people in North America and Europe have CD (also called celiac sprue). Unfortunately, primary care providers diagnose only 6% of cases.2
History
Although accounts of CD date back to the first century, no one linked the symptoms to gluten ingestion until the 1940s. At that time, Willem Karel Dicke, a Dutch pediatrician, observed that the condition of children with CD improved during the food shortages of World War II, only to relapse after cereal supplies were restored.1 Most 
primary care providers still regard CD as a disease of malnutrition and chronic diarrhea, although these manifestations are rare with modern diets. CD exists in people of all ages, can involve practically any organ system, and manifests with signs and symptoms ranging from severe to mild to none at all.
Testing is crucial
Testing adults for CD should be done in a primary care setting because patients who go untreated are at risk for various complications, including malabsorption, vitamin or mineral deficiency, infertility, osteoporosis, autoimmune diseases, and small bowel lymphoma.3 A delay of more than 10 years in diagnosis and treatment can increase mortality nearly fourfold compared to that in age-matched controls.4 If PAs begin to consider CD in their differential diagnoses, they can improve quality of life and decrease mortality in their patients with CD (see Table 1).
CD is a genetic autoimmune enteropathy that causes malabsorption. Affected persons are sensitive to gluten, the protein that gives wheat, rye, and barley their elastic substance. Since a wide variety of beverages, medicines, and foods—including potato chips, cookies, soups, and breads—contain gluten in some form, avoiding it is a challenge. CD is caused by a delayed-type cellular hypersensitivity to the proteins in these grains, specifically the gliadin portion of wheat protein. This causes a CD4+ cell response that results in inflammation of the small bowel.4 These physiologic effects tend to improve dramatically when gluten is removed from the diet.
Genetics
The concordance rate for CD in monozygotic twins is estimated to be 75%, and approximately 10% to 15% of 
first-degree relatives of persons with CD also have the disease.4 Eighty percent of affected persons express the human leukocyte antigen (HLA) alleles DQ2 and DQ8 (compared to 20% of the general population), though for reasons not yet understood, not all HLA-DQ2/8-positive persons develop CD.5 CD is more common in people of Celtic descent and uncommon in those of African or Asian descent.
Clinical presentation
Age CD has a bimodal distribution, manifesting both in young children and in adults in the fourth or fifth decades. Symptoms can occur early in life, subside for many years, and then reappear in adulthood. Researchers do not know what causes discernible disease to develop in adulthood after existing subclinically for years, although studies suggest that signs and symptoms may become noticeable after physically or emotionally stressful events. In the United States, CD is most often diagnosed in adults, which is probably a result of the lack of a specific screening protocol in children and the limited knowledge of CD and underestimation of its prevalence among clinicians.6
Signs and symptoms Clinical manifestations of CD vary noticeably with the duration and extent of the disease and the age of the patient (see Table 2). Most patients receive a diagnosis after presenting with symptomatic CD, which may include a diarrheal syndrome, malabsorption, or other GI symptoms such as indigestion, constipation, abdominal pain, and reflux.7
Some studies show that the most common presenting signs and symptoms of CD in adults are abdominal pain, fatigue, bloating or gas, and iron deficiency anemia. In one study, 32% of affected adults were underweight, and 50% complained of frequent diarrhea and weight loss.6 In another study, 17% of patients with CD fulfilled the Rome II criteria for irritable bowel syndrome (IBS) (12 or more weeks of abdominal discomfort or pain that has two of the following three features: it is relieved by defecation, onset is associated with a change in the frequency of stool, and onset is associated with a change in the appearance of stool). Thirty-seven percent of these respondents reported an initial diagnosis of IBS. Other frequent diagnoses were anxiety, depression, stress, and fibromyalgia.8
Women, who comprise 75% of all patients with CD, often present differently than do men and at a younger age. Their symptoms are more diverse, severe, and rapid, whereas men are more likely to present with low body mass index and weight loss.9
Patients with CD also commonly present with hematologic abnormalities, such as iron or folate deficiency and, very rarely, vitamin B12 deficiency. Blood chemistry results, including decreased levels of serum albumin, carotene, and HDL and LDL cholesterol, provide clues to more advanced CD. Depletion of minerals and ions, such as zinc, magnesium, and potassium, may occur as well (see Table 3).9
Endocrine-related problems, including osteomalacia, osteoporosis, vitamin D insufficiency, secondary hyperparathyroidism, autoimmune thyroiditis, hypocalcemia, and hypocalciuria are also important features of CD. Furthermore, because of decreased intestinal absorption of levothyroxine, CD may manifest with excessive levothyroxine requirements in hypothyroid patients.3