case study celiac disease quizlet

• Celiac Disease

Definition and Clinical Manifestations

• Pathogenesis
• Epidemiology
• Special Issues (FAQs)
• Associated Disorder

Gluten is the term for a protein component of wheat and similar proteins found in rye and barley. In people with celiac disease, the body mounts an immune reaction to gluten. The immune system goes on high alert. It attacks and damages the small intestine. The nature of this immune response is not an allergic reaction but a delayed type immune response.

A Quick Tour of The Small Intestine

Normal small intestine

In digesting the foods we eat, it’s the small intestine that does the “heavy lifting.” This organ performs the major work of breaking the food (nutrients) down into smaller fragments or components in a process that is called digestion. These components are then absorbed by the small intestine. They include protein, carbohydrate, fats, minerals and vitamins. They are then released into the bloodstream which carries them to all the tissues and cells of the body. This process of digestion, absorption and release into the circulation involves the normal functioning of the stomach, small intestine, pancreas and liver.

Critical to this process are tiny filaments called villi, which line the small intestine. These microscopic finger-like projections greatly expand the intestine’s surface area, maximizing the effective absorption of nutrients into the bloodstream. When the immune system of an individual with celiac disease goes into overdrive, it attacks and destroys intestinal villi (atrophy). Nutrients cannot be fully absorbed. This results in the term malabsorption. In celiac disease, all the components of the diet (carbohydrate, fats, minerals and vitamins) may be malabsorbed, or only a single nutrient such as a mineral (calcium or iron) or a single vitamin such as folic acid. The ability to take full nourishment from food is compromised.

The immune response in the intestine as well as causing atrophy of villi results in a marked inflammatory response and the generation of antibodies to food components (anti-gliadin antibodies and auto antibodies) tissue transglutaminase and endomysial antibodies. These antibodies while not causing any damage reflect the autoimmune nature of celiac disease and are used as diagnostic tests. This marked inflammatory response may be manifested as generalized systemic symptoms while the autoantibodies may be responsible or contribute to other organ damage and symptoms. In celiac disease, this systemic inflammatory response and multiple other organ involvement marks celiac disease as a multisystem disease. In fact, celiac disease more resembles a multisystem disorder with the possibility of every organ in the body being affected. Patients therefore may present with symptoms related to inflammation and malabsorption (diarrhea, abdominal pain and weight loss). Patients may present with manifestations of malabsorption of nutrients such as anemia due to iron deficiency or osteoporosis due to calcium and vitamin D malabsorption. Whereas the skin problem, dermatitis herpetiformis (DH), reflects a systemic antibody response to tissue transglutaminase generated in the intestine but manifested in the skin by these antibodies reacting with tissue transglutaminase present in the skin. Other organ involvement may be the result of nutritional deficiency, antibody directed inflammation as part as an autoimmune response.

And once in attack mode, the immune system doesn’t always stop with the small intestine, but may also damage other organs.

Modes of Presentation of Celiac Disease

The classification of the main modes of presentation of adults with celiac disease into “classical” – diarrhea predominant and “silent” is widely accepted. The silent group includes atypical presentations and those presenting with complications of celiac disease as well as truly asymptomatic individuals picked up through screening high risk groups.

Presentation in Children

Children with untreated celiac disease are at special risk. Malnutrition during this period can have significant effects on growth and development. Failure to thrive in infants, learning difficulties in school-age children, irritability and behavioral difficulties, delayed puberty, and short stature as well as recurrent abdominal pain and constipation are all common symptoms of celiac disease.

Presentation in Adults

In order to assess the clinical spectrum of celiac disease in the United States, we obtained data on 1138 people with biopsy proven celiac disease. Our results demonstrated that the majority of individuals were diagnosed in their 4th to 6th decades. Females predominated (2.9:1); however the female predominance was less marked in the elderly. Diarrhea was the main mode of presentation, occurring in 85%. Most strikingly, symptoms were present a mean of 11 years prior to diagnosis.

In order to assess whether the presentation had changed over time we analyzed the mode of presentation for a series of patients seen in the Celiac Center at Columbia University in New York.4 There were 227 patients with biopsy proven celiac disease. We noted that females again predominated, in a ratio of 1.7 to 1. Mean age at diagnosis was 46.4 ± 1.0 years (range 16 to 82 years) and was similar in men and women. Females were younger and had a longer duration of symptoms compared to the males. Diarrhea was the main mode of presentation (in 62%) with the remainder classified as silent (38%). This later group included anemia or reduced bone density as presentations (15%), screening first-degree relatives (13%), and incidental diagnosis at endoscopy performed for such indications as reflux or dyspepsia (8%). We compared those diagnosed before and after 1993, (when serologic testing was first seen in patients), and noted a reduction in those presenting with diarrhea, 73% versus 43% (p=0.0001) and a reduction in the duration of symptoms, from 9.0 ± 1.1 years to 4.4 ± 0.6 years (p<0001). These results suggested that the use of serologic testing was responsible for more patients being detected with celiac disease having presented in non-classical ways, after a shorter duration of symptoms. Further analysis of the patients seen at the Celiac Disease Center at Columbia University has revealed that progressively fewer patients are presenting with diarrhea, less than 50% of those diagnosed in the last 10 years.

Many patients with celiac disease, 36% in our series and 29% of Canadians with celiac disease, have had a previous diagnosis of irritable bowel syndrome. In fact, screening of patients seen in irritable bowel referral clinics in England and Iran reveals celiac disease in a significant number of patients. The majority of patients with celiac disease, detected in a primary care screening study had symptoms attributable to an irritable bowel syndrome.

Iron Deficiency Anemia

Iron deficiency anemia was the mode of presentation in 8% of the individuals seen by us, 4 and was reported as a prior diagnosis in 40% of Canadians with celiac disease. In a study from the Mayo Clinic, celiac disease was identified as the cause of iron deficiency in 15% of those undergoing endoscopic assessment for iron deficiency. While in a prospective study of adults, mean age in their 50’s, Karnum et al found 2.8% to have celiac disease. Anemia in celiac disease is typically due to iron deficiency, though vitamin B12 and folic acid deficiency may also be present and contribute to anemia.

Osteoporosis

A diagnosis of celiac disease may be made during the evaluation of reduced bone density (osteopenia or osteoporosis). In our study reduced bone density was more severe in men than women. Certainly men and premenopausal women with osteoporosis should be evaluated for celiac disease even if they lack evidence of calcium malabsorption, though the yield in menopausal women is low.

Incidental Recognition at Endoscopy for Reflux

An increasingly important mode of presentation is the recognition of endoscopic signs of villous atrophy in individuals who undergo endoscopy for symptoms not typically associated with celiac disease. These endoscopic signs include reduction in duodenal folds, scalloping of folds and the presence of mucosal fissures. The indications for upper gastrointestinal symptoms include dyspepsia, upper abdominal pain or gastroesophageal reflux. This presentation accounted for 10% of those who were diagnosed with celiac disease in our series. Interestingly symptoms of gastroesophageal reflux may resolve after starting a gluten-free diet. This is thought to be due to resolution of an accompanying motility disorder. These endoscopic abnormalities of the duodenal mucosa are not specific nor sensitive markers of celiac disease.

There is an argument for the routine biopsy of the duodenum in anyone undergoing upper gastrointestinal endoscopy to detect celiac disease, irrespective of the appearance of the duodenal mucosa.

Screening of high risk groups is, especially relatives of patients with celiac disease is a major mode of presentation. Studies reveal that 5% to 10% of first degree relatives of patients with celiac disease have serologic and biopsy evidence of the disease. A single testing of relatives does not suffice to detect all those with celiac disease. For those initially negative by screening antibodies, 3.5% will become positive a mean of 2 years after their initial testing. Other groups that are frequently screened for celiac disease include those with Type 1 diabetes, Down syndrome, and primary biliary cirrhosis.

Atypical Presentations

Among the atypical presentations that we have encountered are neurologic problems. We have found that 8% of those attending a peripheral neuropathy center, for evaluation of peripheral neuropathy, had celiac disease. The neuropathy is typically sensory in type, involving the limbs and sometimes the face. Nerve conduction studies are frequently normal; however skin biopsies reveal nerve damage in small fibers. We have also identified patients with severe ataxia. We have not identified patients with epilepsy, a neurologic manifestation that may be more common in childhood celiac disease.

Other, less common presentations, are abnormalities of blood chemistry determinations such as elevated serum amylase, secondary to macroamylasemia, hypoalbuminemia, hypocalcemia, vitamin deficiency states, and evidence of hyposplenism. We have seen patients referred because of dental enamel defects. Many females diagnosed with celiac disease have a history of infertility and there is a yield of screening infertile individuals for celiac disease.

Dermatitis Herpetiformis

Many people with gluten intolerance experience symptoms mainly as Dermatitis Herpetiformis (DH), a chronic disease of the skin. Patches of intensely itchy raised spots appear on the body, often symmetrically, on both elbows or both buttocks for example. However, it can occur anywhere on the body. It may occur on the face or in the hair, especially along the hairline. In this case, the immune system’s response consists of an immune reaction of anti tissue transglutaminase antibodies with a special form of tissue transglutaminase found in the skin. The lesions will typically form little blisters resembling herpes, hence its name, dermatitis herpetiformis.

Everyone with DH is considered to have a gluten sensitivity (celiac disease). While the majority of people will have an abnormal intestinal biopsy that demonstrates the characteristic changes of celiac disease, in 20% the biopsy can be normal. The diagnosis of DH requires a biopsy of skin immediately adjacent to a blistering lesion. Special studies (immunofluorescence for IgA deposition) are required for diagnosis. The lesions are very sensitive to ingestion of small amounts of gluten. Some patients require therapy with Dapsone to suppress the lesions. This may be used intermittingly and is not needed when patients are adhering to a strict gluten-free diet. Withdrawl of iodine from the diet may be necessary for the gluten-free diet to have a beneficial effect.

Patients with DH are a risk for all the complications that those with celiac disease but not DH experience. These include osteoporosis, iron deficiency anemia and vitamin and mineral deficiencies. Patients should be assessed regularly for these complications and treated accordingly. DH similar to celiac disease is associated with an increased risk of lymphoma. The gluten-free diet will protect against the development of lymphoma whereas Dapsone does not. A common problem is that patients will use Dapsone to control the lesions and not adhere to a gluten-free diet.

Autoimmune damage, the first manifestation of celiac disease, carries with it an array of potential symptoms. But as happens so often in life, one thing leads to another. When the immune system compromises the ability of the small intestine to absorb and transmit nutrients, malnutrition may result. And malnutrition carries its own array of potential disease symptoms. 250 different celiac disease symptoms and related conditions have so far been identified, among them. However the spectrum of the disease is very great with some people obese rather than malnourished.

Celiac Disease –multiple manifestations

Patients often have a vast array of symptoms and complications, not justone symptom. Here is a list which is not exhaustive. Patients with thesesymptoms warrant screening for celiac disease.

Gastrointestinal

• Recurring abdominal pain
• Chronic diarrhea
• Constipation
• Persistent anemia
• Chronic fatigue
• Weight loss
• Osteopenia, osteoporosis and fractures
• Infertility
• Muscle cramps
• Discoloration and loss of tooth enamel

Autoimmune Associations

• Dermatitis herpetiformis (DH)
• Aphthous stomatitis/ulcers
• Peripheral neuropathy, ataxia and epilepsy
• Thyroid disease
• Sjogren’s syndrome
• Chronic active hepatitis, primary biliary cirrhosis, sclerosing
• Cholangitis

Malignancies

• Non-Hodgkin lymphoma (intestinal and extra-intestinal, T- and B-cell types)
• Small intestinal adenocarcinoma
• Esophageal carcinoma
• Papillary thyroid cancer

The Biology Corner

Biology Teaching Resources

Case Study – Celiac Disease and Digestion

I designed this digestive system case study for my anatomy class and remote learners. The goal is for students to understand how digestion works and how an autoimmune disease (celiac) interferes with the process. I focused on specific details of the system, like villi and absorption of nutrients across the mucosa.

The case study on celiac disease can be completed independently or in small groups.

To start, this case introduces a person who was diagnosed with celiac disease and links to that person’s blog . I am fairly vague with the opening on this one, and the symptoms can describe anyone with celiac disease. After reading the introduction and symptoms, students answer questions from the text.

At this point, they will not need to look anything up unless they just need to refresh their memory on the sequence of structures in the alimentary canal. I assigned this activity after students learned about the digestive system and completed the digestive system labeling There are several challenging terms in this section, such as chronic disease, gastrointestinal, autoimmune, and malabsorption. I encourage students to use google to look up words they don’t understand.

Diagnosis and Treatment

Next, students examine photos from an endoscopy showing a normal duodenum and one from a person with celiac disease. Students learn that a blood test (serology) can detect the presence of antibodies in the blood that are known to attack tissues of the gut. They learn that a biopsy test can reveal microscopic changes in the lining of the gut. An image shows the progression of the disease and the presence of lymphocytes in the cells, as well as the changes in other cells. Over time, the villi flatten and lose their ability to absorb nutrients.

Each section is followed by questions to assess reading comprehension and understanding of the graphics. Students apply knowledge by analyzing data used to classify different types of celiac disease. On the final page, I tasked them with designing a daily meal plan that does not include gluten. Finally, students write a short summary to explain the basics of the disease to a fictional younger sister.

Shannan Muskopf

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Jane Han and Kara Mead

Celiac Disease Case Study

The following is a scenario of a 19 year-old female, Liz Gavin, who came into the Emergency Department by the ambulance in the morning with complaints of diarrhea and vomiting for a week, abdominal pain, weight loss of 15 pounds in one month, fatigue, dehydration, severe thirst, and paralysis of her lower extremities. She has a family history of Diabetes type 1, Celiac Disease, Rheumatoid Arthritis, and Psoriasis. She has a personal history of Celiac Disease, chronic constipation, weight loss, and abdominal pain associated with her Celiac Disease diagnosis. In the Emergency Department, her labs were taken and she had a hemoglobin of 9, a diagnosis. In the Emergency Department, her labs were taken and she had a hemoglobin of 9, a hematocrit of 32, a potassium of 2.8, a total protein f 5.0, a calcium of 8., a magnesium of 1.0, and metabolic acidosis. Her vitals in the emergency department were heart rate of 103, respiratory rate of 20, blood pressure of 85/50, oxygen saturation of 98%, temperature of 98.7 degrees fahrenheit, and stabbing pain of 8 in her abdomen. Liz was diagnosed with Celiac Crisis. Celiac Crisis is a life threatening form of Celiac Disease that starts with the classic gastrointestinal symptom of diarrhea that leads to dehydration and electrolyte imbalances (Hijaz, Bracken, & Chandratrem, 2014).

She was transferred to the ICU for care. In the ICU she was treated for her dehydration, fluid and electrolyte imbalances, hypotension, nausea/vomiting, and her overall Celiac Crisis. This was done with intravenous lactated ringers, supplements of potassium, magnesium, and calcium. She was also given norepinephrine to increase her blood pressure, Zofran for her nausea, dapsone for her skin rash, and prednisone to treat the overall Celiac Crisis. Upon assessment the primary nurse found that the cause of Liz’s Celiac Crisis was due to nonadherence to her dietary regimen. She is a freshman in college and though she was compliant to her gluten free diet previously, the pressures of fitting into a new school and environment led her to stop her diet. She was educated by the nurse on the signs of Celiac Crisis in the future in order to get help immediately. She was also referred to a dietician, case management, and tele psych in order to help her cope with her disease process and prevent complications in the future.

Discussion Questions

• What are some relevant nursing diagnosis to this patient?
• What are some relevant laboratory results for this patient?
• What is the appropriate treatment for this patient?

Question 1: Risk for imbalanced nutrition, risk of infection, ineffective coping, anxiety, fluid and electrolyte imbalances

Question 2: Potassium, PT and PTT, Hemoglobin and Hematocrit, Magnesium, Calcium, Protein

Question 3: Corticosteroids, gluten-free diet, fluids, support group, vitamins

Nursing Case Studies by and for Student Nurses Copyright © by jaimehannans is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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The only way to confirm a celiac disease diagnosis is to have an intestinal biopsy. A pathologist will assign a Modified Marsh Type to the biopsy findings. A Type of 3 indicates symptomatic celiac disease. However, Types 1 and 2 may also indicate celiac disease.

Why an Intestinal Biopsy?

An intestinal (duodenal) biopsy is considered the “gold standard” for diagnosis because it will tell you (1) if you have celiac disease, (2) if your symptoms improve on a gluten-free diet due to a placebo effect (you feel better because you think you should) or (3) if you have a different gastrointestinal disorder or sensitivity which responds to change in your diet.

If the results of the antibody or genetic screening tests are positive, your doctor may suggest an endoscopic biopsy of your small intestine. An endoscopy is a procedure that allows your physician to see what is going on inside your GI tract. A scope is inserted through the mouth and down the esophagus, stomach and small intestine, giving the physician a clear view and the option of taking a sample of the tissue.

This is usually an outpatient procedure. Samples of the lining of the small intestine will be studied under a microscope to look for damage and inflammation due to celiac disease. It is recommended that the doctor take at least 4-6 duodenal samples from the second part of duodenum and the duodenal bulb, in order to obtain an accurate diagnosis.

What Does the Intestinal Biopsy Show? (Give Me the Science)

• Density of intra-epithelial lymphocytes (IELs), which are white blood cells found in the immune system. More than 25 IELs per 100 epithelial cells is significant. Epithelial cells line your intestines and act as a barrier between the inside and the outside of your body.
• Crypt hyperplasia with a decreased villi/crypt ration. Crypts are grooves between the villi, which are the small fingerlike projections that line the small intestine and promote nutrient absorption. Crypt hyperplasia is when the grooves are elongated compared to a normal intestinal lining which has short crypts.
• Blunted or atrophic villi. This is a shrinking and flattening of the villi due to repeated gluten exposure.
• Mononuclear cell infiltration in the lamina propria. The lamina propria is a thin layer of loose connective tissue, which together with the epithelium forms the mucosa which stops pathogens from entering the body.
• Epithelial changes, including structural abnormalities in epithelial cells.

The endoscopy itself may show scalloping and/or flattening of dudodenal folds, fissuring over the folds, and a mosaic pattern of mucosa of folds.

Modified Marsh Classification of Histologic Findings in Celiac Disease

The World Gastroenterology Organization recommends pathologists use a modified Marsh classification for interpretation. Dr. Michael Marsh introduced the classification system in 1992 to describe the stages of damage in the small intestine as seen under a microscope, also known as histological changes. Originally the Marsh Types ranged from 0 to 4, with a type of 3 indicating celiac disease. It has since been simplified to allow for a greater degree of consistency and reproducibility between pathologists.

Modified Marsh Classification of histologic findings in celiac disease (Oberhuber)

View table data.

• Type 0: Intestinal lining is normal -celiac disease highly unlikely
• Type 1: Intestinal lining has been infiltrated with IELS – seen in patients on a gluten free diet (suggesting minimal amounts of gluten or gliadin are being ingested), patients with dermatitis herpetiformis and family members of celiac disease patients. This may also indicate gastroduodenits caused by H. pylori, hypersensitvity to food, infectons (viral, parasitc, bacterial), bacterial overgrowth, pharmacological drugs (mainly NSAIDs), IgA defcit, common variable immunodefciency or Crohn’s disease.
• Type 2: Very rare, seen occasionally in dermatitis herpetiformis.
• Type 3: Spectrum of changes seen in symptomatic celiac disease

Simplified systems may be more reproducible (Corazza, Roberts, Ensari)

• Seen in patients on gluten free diet (suggesting minimal amounts of gluten or gliadin are being ingested); patients with dermatitis herpetiformis; family members of celiac disease patients, not specific, may be seen in infections
• Spectrum of changes seen in symptomatic celiac disease

What to Expect During an Endoscopy

Once there, the physician will examine the duodenum (entryway into the small intestine) and take multiple tissue samples due to the “patchy” nature of villous atrophy. The tissue samples will then be examined by a pathologist under a microscope and assigned a  Marsh  classification.

Since there are no nerve endings in the lining of the intestine, the procedure is not painful – though some patients may experience a sore throat.

Patients who cannot or will not tolerate an endoscopy may be given the option to undergo  video capsule or “pill” endoscopy  where a capsule the size of a large vitamin pill is swallowed and takes thousands of pictures of the small intestine. However, there is no conclusive evidence that this can substitute for traditional endoscopy and biopsy.

For Individuals with Dermatitis Herpetiformis (DH)

A skin biopsy is sufficient for diagnosis of both DH and celiac disease.

This biopsy involves collecting a small piece of skin near the rash and testing it for the IgA antibody. It is not necessary to perform an endoscopic biopsy to establish the diagnosis of celiac disease in a patient with DH; the skin biopsy is definitive.

For Children

For children with symptoms and signs of malabsorption, a very high tTG-IgA titer (>10 time upper limit of normal), and a positive EMA (antiendomysial) in a second blood sample, some physicians may recommend avoiding endoscopic biopsy, and directly starting a gluten-free diet.

Others may recommend genetic testing for additional confirmation. Resolution of symptoms while on a gluten-free diet may be used to confirm the diagnosis.

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Celiac Disease: Common Questions and Answers

• PMID: 35839368

Celiac disease is an immune-mediated, multisystem disorder that affects genetically susceptible individuals who are exposed to gluten-containing grains such as wheat, barley, and rye. The condition can develop at any age. Celiac disease presents with a variety of manifestations such as diarrhea, weight loss, abdominal pain, bloating, malabsorption, and failure to thrive. Most adult patients will present with nonclassic symptoms, including less specific gastrointestinal symptoms or extraintestinal manifestations such as anemia, osteoporosis, transaminitis, and recurrent miscarriage. Immunoglobulin A tissue transglutaminase serologic testing is the recommended initial screening for all age groups. Esophagogastroduodenoscopy with small bowel biopsy is recommended to confirm the diagnosis in most patients, including those with a negative serologic test for whom clinical suspicion of celiac disease persists. Biopsies may be avoided in children with high immunoglobulin A tissue transglutaminase (i.e., 10 times the upper limit of normal or more) and a positive test for immunoglobulin A endomysial antibodies in a second serum sample. Genetic testing for human leukocyte antigen alleles DQ2 or DQ8 may be performed in select cases. A gluten-free diet for life is the primary treatment, and patients may benefit from support groups and education on common and hidden sources of gluten, gluten-free substitutes, food labeling, balanced meal planning, dining out, dining during travel, and avoiding cross-contamination. Patients with celiac disease who do not respond to a gluten-free diet should have the accuracy of the diagnosis confirmed, have their diet reassessed, and be evaluated for coexisting conditions. Patients with refractory celiac disease should be treated by a gastroenterologist.

• Autoantibodies
• Celiac Disease* / diagnosis
• Diet, Gluten-Free
• Immunoglobulin A
• Protein Glutamine gamma Glutamyltransferase 2

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• v.9; Jan-Dec 2021

The Progression of Celiac Disease, Diagnostic Modalities, and Treatment Options

Zahid ijaz tarar.

1 University of Missouri, Columbia, USA

Muhammad Usman Zafar

2 Lehigh Valley Health Network, Allentown, PA, USA

Umer Farooq

3 Loyola Medicine/MacNeal Hospital, Berwyn, IL, USA

Veysel Tahan

Ebubekir daglilar.

Celiac disease (CD) is an autoimmune disorder that affects genetically predisposed individuals who are sensitive to gluten and related proteins. It affects children and adults with increasing prevalence in the older age groups. Both adaptive and innate immune responses play role in CD pathogenesis which results in damage of lamina propria and deposition of intraepithelial lymphocytes. There are other proposed mechanisms of CD pathogenesis like gastrointestinal infections, intestinal microbiota, and early introduction of gluten. The diagnosis of CD is based on clinical symptoms and serological testing, though a majority of cases are asymptomatic, and small intestinal biopsies are required to confirm the diagnosis. Celiac disease is generally associated with other autoimmune diseases, and it is advisable to test these patients for diseases like type 1 diabetes mellitus, Addison’s disease, thyroid diseases, inflammatory bowel disease, and autoimmune hepatitis. The patient with a new diagnosis of CD requires close follow-up after starting treatment to see symptom improvement and check dietary compliance. A newly diagnosed patient is advised to follow with a dietitian to better understand the dietary restrictions as about 20% of patients stay symptomatic even after starting treatment due to noncompliance or poor understanding of diet restrictions. The most effective treatment for CD is a gluten-free diet, but work on non-dietary therapy is in process and few medications are in the clinical trial phase.

Introduction

Celiac disease (CD) is an immune-mediated disorder affecting small intestine in genetically predisposed individuals. It results from sensitivity to gluten and related proteins. 1 , 2 The global prevalence of CD is 1% 3 , 4 though it does not represent the actual number of CD cases due to the vast majority of cases are asymptomatic and undiagnosed as reported in different studies. One study done in Italy showed 7:1 ratio of asymptomatic to symptomatic cases, 5 which is further reinforced by studies in which antibody testing performed for screening purposes. 6 - 9 Celiac disease is more prevalent in first- and second-degree relatives and people with other autoimmune disorders. 8 , 10

Celiac disease results from an abnormal response to gluten which causes small intestinal injury and leads to malabsorption of nutrients. Celiac disease prevalence has increased 4 to 5 times in the last few decades, and the average age of diagnosis is the fifth decade of life in the United States. 11 , 12

CD has 2 peaks of onset, one in early childhood around age of 2 years and the second in second to third decade of life. 13 , 14 As per Oslo’s 2011 definition, CD can be classified as classic, non-classic, subclinical, silent, overt, potential, and refractory. 15 , 16 The other way of classifying CD is based on location and histological appearance. Based on location, it can be categorized as intestinal vs extraintestinal or a combination of both. 17

Histologically, CD was classified by Marsh and was later modified by Marsh-Oberhuber in 1999 ( Table 1 ). Corazza proposed another classification but not widely accepted. Modified Marsh classification is the recommended histological classification by the Gastroenterology association but still not used widely. 18 - 20

Modified Histological Classification of Celiac Disease.

Pathogenesis

Celiac disease is an autoimmune disease affecting the genetically predisposed individuals in the setting of environmental trigger. 21 It results from abnormal T-cell response to gluten, which is found in cereal grain wheat, rye, and barley. 21 , 22 In genetically predisposed individuals, exposure to gliadin peptide which is a component of gluten leads to an adaptive immune response that causes damage to lamina propria. 23 - 26 In addition to adaptive response, innate immune response is the other factor which plays an important part in CD pathogenesis which can be seen by the presence of intraepithelial lymphocytes. 26 , 27 Celiac disease is common in families which is evident by the presence of specific HLA types HLA-DQ2 and HLA-DQ8 in almost all cases. 28 , 29 The intestinal microbiota is also considered another factor in the pathogenesis of CD leading to an immune response in addition to gluten and other environmental factors and this is shown in few studies. 30 - 34 Other factors considered and discussed in literature about CD pathogenesis are a shorter duration of breastfeeding, infections, and early introduction of gluten, but these are not proven with studies 35 , 36 ; it is noted in one study that children who develop CD were consuming more gluten than those without CD. 37 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition’s current guideline is against high consumption of gluten in the first few weeks of life and it can be introduced after 4 months of age. 38

Clinical Subtypes of CD

Celiac disease is clinically defined as classic, non-classic, subclinical, potential, and refractory. 16 Classic CD, however, affects both pediatric and adult population but mainly diagnosed between 6 and 18 months of age and presents with typical symptoms of malabsorption including diarrhea, failure to thrive, and weight loss. The atypical or non-classic form mainly present as extraintestinal manifestation of CD such as osteoporosis, abnormal liver function, vitamin deficiencies, anemia, neuropathy, or infertility, but patients with atypical disease can have gastrointestinal symptoms like reflux, bloating, or abdominal pain. The atypical form is usually diagnosed in high-risk population on screening. Subclinical form of CD also falls under atypical disease. Latent or potential form of CD is defined as normal small bowel architecture but positive serology and presence of HLA-DQ2 and/or HLA-DQ8. Refractory CD is the presence of symptoms even after strict dietary restriction for 6 to 12 months. 39 , 40

Clinical Manifestations

Celiac disease is more common in females with F:M ratio of 2:1, and females are usually diagnosed at a young age with predominant symptoms of constipation and iron deficiency anemia. 13 , 15 , 41 Celiac disease diagnosis is challenging as the majority of patients are asymptomatic and the ones with symptoms vary significantly. 42 The symptomatic patients can have gastrointestinal symptoms in combination with extraintestinal manifestation or they can just present with extraintestinal symptoms. 17 Gastrointestinal symptoms like diarrhea, loss of appetite, malabsorption, failure to thrive, short stature, and delayed puberty are mainly seen in the pediatric population. 16 , 43 On the contrary, the adult populations rarely have the classic malabsorption symptoms, and they usually present with irritable bowel syndrome-like symptoms in association with nausea and vomiting, and the reason for their hospitalization is mainly electrolyte imbalance and cachexia. 44 - 46

Celiac disease in its classic form presents with gastrointestinal malabsorption symptoms, but we need to be careful in diagnosing as about 40% of patients with CD are obese at diagnosis and constipation can be presenting symptom in 20% of patients. 15 , 16 , 47 , 48 Another rare presentation is the celiac crisis which presents as diarrhea and shows severe electrolyte disturbances. 48 In the past, majority of diagnosed cases were of symptomatic disease but now the non-classic and subclinical forms are increasingly diagnosed but the classic form is still the most common presenting type and makes about half of the diagnosed cases. 15 , 45

Celiac disease is now seen more frequently in adults and older population, and the reason for this is better diagnosis tools and understanding of the disease, although in most cases the disease is mild in this age group and the main presenting symptoms are nutrient deficiencies and iron deficiency anemia. 15 , 49

Celiac disease is a multi-organ system disease, and few studies showed extraintestinal symptoms as the most common presentation. 15 , 45 Extraintestinal symptoms are seen in both children and adults and osteoporosis is the most common with a frequency of about 70% due to changes in calcium and vitamin D absorption. 44 , 45 , 50 Patients with severe osteoporosis and bone loss especially if they are young males should be worked up for CD even in the absence of gastrointestinal symptoms. 51 Bone disease is the main cause of morbidity in patients with CD and increases the fracture risk significantly as compared with the general population. 51 , 52 The second most common presentation is iron deficiency anemia which is seen in about 40% of cases secondary to inflammation and malabsorption of iron and commonly seen in newly diagnosed patients. 53 , 54 The other common manifestations are neurological symptoms such as headache, paresthesia, cerebellar ataxia, myoclonic syndrome, epilepsy with cerebral calcifications, anxiety, and depression, and it is associated with elevated levels of anti-gliadin antibodies. 45 , 55 - 57 Celiac disease affects the reproductive system in both males and females, so patients can present with unexplained infertility, recurrent abortions, miscarriages, early menopause, late menarche, or abnormality of sperms, and these changes are reversible with a gluten-free diet, so these cases need high suspicion and need a workup for CD even in the absence of malabsorption symptoms. 43 , 58 - 62 Undiagnosed pregnant cases of CD can lead to premature and small for gestational age babies. 61 , 63

Other common extraintestinal manifestations of CD are abnormal liver tests known as celiac liver, 64 , 65 hyposplenism, 66 dermatitis herpetiformis, 45 , 67 , 68 aphthous ulcer, 45 , 69 dental enamel hypoplasia, 70 and acute and chronic pancreatitis. 71

The mainstay of CD diagnosis is based on clinical features in combination with serology testing and histological findings. Antibodies used for CD diagnosis are anti-tissue trans-glutaminase (anti-tTG), anti-endomysium, and deamidated gliadin peptide (DGP). The preferred single test is anti-tTG antibodies with a sensitivity of 93% and specificity of 94%. Although the anti-endomysial antibody test is most specific than all other serological tests, it is a qualitative test, operator dependent, and difficult to perform. 72 - 76 Studies done on DGP, in the beginning, were promising about its role in the diagnosis of CD, but over the course, data showed a decrease in its specificity, so now IgG-DGP is sometimes used for diagnosis in children aged <2 years but DGP-IgA lacks accuracy and not used in current practice. 72 , 77 , 78 To increase the sensitivity of serological testing, British society of Gastroenterology recommends sequential testing with tTG-IgA and DGP-IgG. 79 Even with the advancement in serology testing and easy availability still, none of these tests are 100% sensitive or specific which makes intestinal biopsy an important component for the diagnosis. 46 , 80

The best method to establish the diagnosis is based on the “4 out of 5 rule,” in which 4 out of these 5 criteria need to be present to diagnose someone with CD. These include classic signs and symptoms, antibody positivity, HLA-DQ2 and/or HLA-DQ8 positivity, intestinal damage, and clinical response to the gluten-free diet. 81 The current guidelines for the diagnosis of CD are based on case findings in which all populations with high risk need to be tested, but this is not proven beneficial and U.S Preventive service Task Force (USPSTF) has recommended against it. 75 , 79 , 82 , 83 In the pediatric population, intestinal biopsy can be avoided if a child has typical symptoms and signs of CD in combination with high titers of anti-tTG, detectable endomysial antibody, and HLA-DQ2/HLA DQ8 positivity, as recommended by the European Society for Pediatric Gastroenterology Hepatology and Nutrition, 84 , 85 but these criteria are not used worldwide, 85 so biopsy is still needed in the majority of the pediatric and almost all adult cases to establish the diagnosis.

Endoscopy with small intestinal biopsy is the gold standard test in adult patients and mandatory for establishing the diagnosis of CD. 86 Endoscopists need to be vigilant while taking duodenal biopsies as CD results in patchy mucosal changes, mainly involve the proximal intestine, with only 10% of cases will show changes in the duodenal bulb. So during endoscopy, at least 4 to 6 biopsies, out of which 2 from duodenal bulb and 4 from second part of the duodenum is needed for accurate diagnosis. 14 , 87 Celiac disease lesions can be differentiated into 5 stages based on histology as defined by Marsh and later modified by Oberhuber. 20 But studies have shown these systems are not used widely by pathologists due to disagreement on grading, so a more uniform grading system is needed. 88

There are certain conditions like enteric infection, congestive heart failure, and a chronic liver disease which can lead to false-positive results due to cross-reactivity of antibodies. 89 On the contrary, patients need to be on a gluten-containing diet “gluten challenge” (>3 g gluten/day for at least 2 weeks) before getting tested, otherwise, there are chances for false-negative results. 75 , 89 , 90 A patient with CD has a higher prevalence of IgA deficiency as compared to the general population which is another reason for false-negative results, so in IgA-deficient patient anti-DGP IgG antibodies or tTG-IgG antibodies should be performed. 75 , 91

There are cases in which serology is negative, but antigen haplotype DQ2 and or /DQ8 and histological changes like villous atrophy are present, this is called seronegative CD and it can result from strong antigen-antibody complexes deposition in mucosa which leads to decreased antibody entry into circulation. 91 - 93

HLA typing is a good way of ruling out CD, but it cannot be used for the diagnosis. 84 HLA typing is used for the diagnosis of seronegative CD as well a screening tool for seronegative first-degree relative of a patient with CD. 84 , 94

The presence of low hemoglobin, elevated transaminases, and bone-specific alkaline phosphatase on routine blood work can provide clues about CD diagnosis. Iron deficiency is one of the most common extraintestinal manifestations, though you can also see normocytic or macrocytic anemia due to malabsorption of vitamin B12 and folic acid in CD. 53 , 95 - 97

At present, the main and only effective treatment for CD is a gluten-free diet for life and strict avoidance of wheat, barley, and rye is needed. 46 , 98 , 99 Strict adherence to gluten-free diet results in resolution of symptoms within days to weeks, negative serology, and normalization of villous atrophy. 47 , 100 Although a gluten-free diet is very effective in treating CD, still it comes with many disadvantages, including high cost, nutrient and mineral deficiencies, psychological impact, constipation, and cardiovascular disease risk. 100 - 103 To avoid these negative effects of a gluten-free diet, it is recommended to have a regular follow-up with a trained dietitian who carries expertise in treating patients with CD. 104 , 105 One main reason for non-adherence to a gluten-free diet is wrong online information about gluten products, cross-contamination, presence of a small amount of gluten in medications, social pressure in adolescence, and for all these reasons close follow-up with dietitian and enrollment in a CD support group is recommended. 106 - 109

Nonresponsive and Refractory CD

There are about 20% of patients in which diarrhea, abdominal pain, and fatigue persist even after starting a gluten-free diet and in these cases either the initial diagnosis of CD was made wrong or the patient is non-compliant with a gluten-free diet or gluten contamination. 110 - 113 So in the cases of deliberate gluten ingestion or food contamination, a dietitian referral is recommended to get more information about the gluten-free diet and possible contamination. 111 Persistent symptoms after 12 months of treatment can be due to other conditions like microscopic colitis, irritable bowel syndrome, and lactose intolerance, so for that reason, duodenal biopsies and colon biopsies are recommended to find the actual cause of symptoms. 110 , 113 , 114 In few patients, even after strictly following the diet restriction for 12 months, symptoms and villous atrophy persist labeled as refractory CD. The refractory CD has 2 subtypes and duodenal biopsies are required to look for aberrant T-cell population found in type 2 which is severe form and associated with worse outcomes. 115 - 117 Refractory CD type 1 is treated with steroids or azathioprine in combination with steroids, open-capsule budesonide, and aggressive nutrition is commonly used as first-line therapy. There is no agreement on the treatment of refractory CD type 2, although steroids, cyclosporine, cladribine, and stem cell transplant are considered. 118 - 121 Patients with type 2 refractory CD are at increased risk to develop T-cell lymphoma. 120

New Treatments

It is a need of time to develop non-dietary therapies for CD as about 40% of patients are not satisfied with the only dietary treatment. 122 There are recent advances in dietary therapies and few drugs are in the clinical trial phase and the most promising ones are larazotide acetate and gluten-specific proteases ALV003 or latiglutenase. 123 - 125 Larazotide acetate is a zonulin antagonist, an oral peptide designed to tighten adhesions between intestinal cell linings and prevents gluten from crossing the epithelial barrier. It has shown effectiveness in relieving symptoms in patients who are on a gluten-free diet as compared to a placebo plus diet. 126 Latiglutenase, an oral mixture of recombinant gluten targeting proteases, targets gluten, breaks it into small fragments before reaching duodenum so in theory to prevent the pathological damage caused by gluten. In a large study done by Murray et al, there was no difference between latiglutenase and placebo in symptoms or histological improvement. 124 , 127 A monoclonal antibody against interleukin-15 and a vaccination called Nexvax2 are currently under investigation. 128

Patients diagnosed with CD need close and well-arranged follow-up. Strict adherence to gluten-free diet results in improvement of clinical symptoms in 4 weeks and more than half of the patients’ symptoms resolve completely within 6 months. In serological testing, there is a noticeable decrease in antibody titers after 6 months, so the first follow-up is advised to be scheduled after 6 months of the diagnosis, followed by every 12 to 24 months. 47 , 129 The histological changes take more time to correct, so it is advisable to repeat biopsy after 1 year of treatment and even better if done after 2 years to confirm complete healing. 130

Celiac disease is associated with conditions like autoimmune thyroid disease, type 1 diabetes, inflammatory bowel disease, autoimmune hepatitis, autoimmune gastritis, primary biliary sclerosis, and adrenal insufficiency, so physicians need to be vigilant and keep a close eye on these conditions and check anti-nuclear and other organ-specific antibodies during follow-up visits. In newly diagnosed cases, it is recommended to get the basic blood work including complete blood cell count, vitamin B12, folate, vitamin D, calcium level, liver function test, serum albumin, copper, zinc, and vitamin A and E. 45 , 75 , 79 , 131

Newly diagnosed adult patients are advised to undergo bone density testing as osteopenia and osteoporosis are very common. It is recommended by the British Society of gastroenterology to measure bone density after 1 year of a gluten-free diet in patients older than 55 years with other risk factors for osteoporosis. 75 The ones with osteopenia or osteoporosis need calcium and vitamin D replacement and repeat bone scan in 2 years. 132 , 133 Celiac disease can present as wide range of clinical symptoms and can be associated with multiple autoimmune conditions. A prompt diagnosis and initiation of treatment carry high importance to prevent associated complications.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Celiac Disease Autoimmunity

• Published: 25 August 2018
• Volume 66 , pages 423–430, ( 2018 )

Cite this article

• Miguel Ángel López Casado 1 ,
• Pedro Lorite 2 ,
• Candelaria Ponce de León 2 ,
• Teresa Palomeque 2 &
• Maria Isabel Torres   ORCID: orcid.org/0000-0002-9309-3837 2  

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Celiac disease is an autoimmune condition triggered by the ingestion of gluten, the protein fraction of wheat, barley and rye. It is not simply an intestinal disease; it is multifactorial caused by many different genetic factors acting together with non-genetic causes. Similar to other autoimmune diseases, celiac disease is a polygenic disorder for which the major histocompatibility complex locus is the most important genetic factor, and is the result of an immune response to self-antigens leading to tissue destruction and the autoantibodies production. Celiac disease exemplifies how an illness can have autoimmune-like features having to be driven by exogenous antigen and how can be reasonably considered as a model of organ-specific autoimmunity.

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Celiac Disease as an Autoimmune Disorder

Celiac disease (CD) is one of the best-understood immune-related diseases. CD is frequent, with a prevalence of approximately 1:100, and it occurs selectively in individuals expressing HLA-DQ2 or HLA-DQ8. The prevalence of CD is underestimated, as not all cases of CD are symptomatic and thus go undiagnosed (Catassi and Fasano 2008 ) Celiac disease has many features in common with autoimmune disease.

In CD, there is a massive, pro-inflammatory and pathogenic immune response towards certain parts of gluten and the intestinal tissue itself, resulting in structural changes. The pathogenesis of CD includes the potent and pathogenic CD4 + T-cell response towards post-translationally modified gluten and the highly disease-specific B-cell responses towards deamidated gluten and the self-protein transglutaminase 2 (TG2) (Fig.  1 ).

Re-drawn of Sollid and Jabri ( 2013 )

Schematic representation of celiac disease pathogenesis. Gluten peptides can be transported across the intestinal epithelium. Deamidation by TG2 leads to the production of deamidated gluten that are taken up and presented by antigen-presenting cells (APCs) of HLADQ2/HLA-DQ8 molecules. This presentation leads to activated gluten-reactive CD4 + Th1 cells that produce high levels of pro-inflammatory cytokines, with aTh1 cytokine pattern dominated by IFN-γ. Activated CD4 + T cells drive the activation and clonal expansion of B cells, which differentiate into plasma cells and produce anti-gliadin and anti-TG antibodies. Gluten peptides induce epithelial and APC cells to secrete IL-15, resulting in an increase in the number of IELs. IFN-γ production, and stimulating cytotoxic effects on epithelial cells (Torres et al. 2015 ).

It is important to consider how epithelial cell stress together with pro-inflammatory adaptive immunity causes cytotoxic T-cell-mediated tissue destruction in CD. The HLA-DQ molecules predispose to disease by preferential presentation of gluten antigens to CD4 + T cells (Bodd et al. 2012 ; Lundin et al. 1993 ; Torres et al. 2015 ). Although these predisposing HLA haplotypes are necessary for disease development, they are not sufficient, as they are highly prevalent in the general population.

The genetic predisposition to CD development has been studied by genome-wide association studies, which have found risk variants in the HLA region, especially HLA-DQ2.5, as well as HLA-DQ2.2 or HLA-DQ8 (Vader et al. 2003 ; Van Heel et al. 2007 ). Thirty-nine additional, non-HLA loci have been associated with CD (Hunt et al. 2008 ; Trynka et al. 2011 ). Of these genes, many are related to immunity, especially with T-cell and B-cell function. These non-HLA genes may be important determinants of disease susceptibility, as indirectly shown by the high disease concordance rate in monozygotic twins (70%) compared with only 30% in HLA-identical twins (Houlston and Ford 1996 ).

In general, the similarities between autoimmune diseases are multifaceted, with shared genetic, environmental and immunological factors that may explain the comorbidity. Novel theories have been put forth to explain the possible associations between autoimmune diseases, including the human gut microbiome’s influence on the gut-immune system axis, new shared immunological markers, the discovery of common genetic factors, and environmental factors (Wu and Wu 2012 ; Zhernakova et al. 2009 ).

CD is an excellent model for studying the contribution of genetic factors to immune-related disorders, because (1) the environmental triggering factor is known (gluten); (2) as in other autoimmune diseases, specific HLA types (HLA-DQA1 and HLA-DQB1) are critically involved; (3) there is involvement of non-HLA disease-susceptibility loci, many of which are shared with other autoimmune diseases; (4) there is an elevated incidence of other immune-related diseases both in family members and in CD individuals; and (5) both the innate and the adaptive immune responses play a role in CD (Kumar et al. 2012 ; Zhernakova et al. 2009 ).

Autoimmune Features of Celiac Disease

Celiac disease is a unique autoimmune disorder in that the key genetic components (HLA class II genes DQ2 and/or DQ8) are present in almost all patients, the autoantigen is known (tissue transglutaminase), and, most importantly, the environmental trigger is known (gluten) (Lundin et al. 1993 ).

Gluten is not a pathogen and should not be perceived as immunogenic. Some undigested gluten peptides from Triticum species, mainly the 33-mer (LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF, P57-P89, from α-2 gliadin) and the 25-mer (LGQQQPFPPQQPYPQPQPFPSQQPY, P31-P55 from α-gliadin), have cytotoxic activity or immune-mediated activity (Ciccocioppo et al. 2005 ). Human TG2 deamidates the 33-mer peptide, increasing its immunogenicity. This enzyme converts glutamine residues into glutamic acid, which results in higher affinity of the peptides to HLA-DQ2/DQ8 molecules and subsequent induction of gluten-specific CD4 + T-cell responses in the intestine of CD patients due to a complex interplay between innate and adaptative immune responses to ingested gluten (Barone et al. 2014 ; Jabri et al. 2005 ). The adaptative immune response to gluten appears to act in synergy with epithelial cell stress to allow intraepithelial T cells to induce villous atrophy in CD patients.

Gluten peptides, in contrast to other food peptides, are excellent substrates for TG2, and the gluten peptides with multiple B- and T-cell epitopes can be added onto the surface of multimeric complexes of TG2. CD4 + gluten-specific T cells provide help to activate B cells to produce anti-gluten and anti-TG2 antibodies in the plasma cells, which may serve as primary antigen-presenting cells (Lundin et al. 1993 ; Molberg et al. 1997 ). This could explain why hypersensitivity to gluten, but not to other food antigens, is established. It is important to understand how gluten-specific HLA-DQ-restricted T cells become pro-inflammatory and why this occurs only in CD patients and not in healthy patients.

It is believed that the interferon (IFN)-γ production from these gluten-specific T cells may be the main cause of mucosal intestinal lesions (Mazzarella et al. 2008 ). Furthermore, shifts in intestinal permeability, secondary to changes in tight junctions or in food-antigen processing, have been associated with a loss of gluten tolerance (Lerner and Matthias 2015a ).

• Autoantibodies

TG2 is a deamidating enzyme that can increase the immunostimulatory effect of gluten and is a target autoantigen in the immune response (Di Sabatino et al. 2012 ). Autoantibodies to TG2 are usually used for diagnosis, showing high CD specificity and sensitivity (Sollid and Jabri 2011 ). The celiac disease-specific TG2-targeted autoantibodies are deposited in the small-bowel mucosa as well as in other tissues, and interestingly, extra-intestinal manifestations of the disease involving these particular tissues have been reported (Lindfors et al. 2010 ). As the TG2-targeted autoantibodies have experimentally been shown to modulate the function of different cell types in vitro similarly to what has been reported to occur in untreated celiac disease, they could constitute an important contribution to disease progression. So, subjects with negative serum TG2-specific antibodies still seem to produce these antibodies locally, as reflected by small-intestine deposits (Maglio et al. 2011 ). Antibodies to TG2 include IgA and IgG isotypes. IgA antibodies are more specific than IgG antibodies, and they are produced primarily in the mucosa of the intestine (Marzari et al. 2001 ). TG2 is involved in the formation of active transforming growth factor (TGF)-β by the crosslinking of the TGF-β binding protein and participates in the motility, as well as attachment, of fibroblasts and monocytes through interactions with fibronectin and integrins, causing CD villous atrophy (Akimov and Belkin 2001 ). Anti-TG2 IgA deposits are detectable in intestinal tissue before the development of overt CD, suggesting that antibody production occurs early in the disease alongside the gluten-specific T-cell response.

Anti-TG2 antibodies may play a part in certain non-intestinal symptoms of CD by interacting with TG2, in addition to cross-reacting with other transglutaminases. In this sense, deposits of anti-transglutaminase antibody have been detected in the brainstem and cerebellum of a patient showing cerebellar ataxia and gluten sensitivity and in certain idiopathic, neurological, and psychiatric disorders (Hadjivassiliou et al. 2006 ). In addition, anti-gliadin antibodies reportedly bind to neural cells and cross-react specifically with synapsin I (Alaedini et al. 2007 ). Immune reactivity to other autoantigens, including transglutaminase 3, actin, ganglioside, collagen, calreticulin and zonulin, has also been reported in CD (Alaedini and Green 2008 ). The clinical significance of these antibodies is not known, although some may be associated with specific clinical presentations or extra-intestinal manifestations of celiac disease.

Autoreactive Intraepithelial Lymphocytes

Dysregulated activation of intraepithelial lymphocytes (IELs) is a characteristic of CD that is implicated in the development of villous atrophy and epithelial cell injury. IELs constitute a population of antigen presentation like “innate” T cells that reside between enterocytes in the intestinal epithelium and can be activated by innate signals, acquiring a natural killer-like phenotype and cytotoxic effector functions (Jabri et al. 2000 )..

CD is characterized (1) by the presence of gluten-specific CD4 + T cells in the lamina propria and (2) by a prominent intraepithelial T-cell infiltration in the epithelial layer that promotes the development of small-intestine inflammation. The exact role of CD4 + T cells in celiac disease is still not clear, so the excessive production of IFN-γ may enhance HLA-E and MHC-I related chain (MIC) proteins expression by intestinal epithelial cells and promote cytotoxic responses by CD8αβ + - and/or CD4 + TCRαβ + -induced IELs through the innate CD94-NKG2D pathway (Sollid 2000 ). The upregulation of these NKG2 receptors seems to be driven by interleukin (IL)-15, which is expressed by CD enterocytes (Mention et al. 2003 ; Roberts et al. 2001 ). IL-15 seems to play a critical role in the expansion of IELs and in the induction of MIC molecules on intestinal epithelial cells (Hü et al. 2004 ).

IELs bearing the γδ T-cell receptor (TCR) are more abundant in the small intestinal mucosa of patients with CD compared with healthy individuals. Increased numbers of TCRγδ + IELs have also been observed in the small intestinal mucosa of CD patients with latent CD, or those on gluten-free diet (GFD) and in some first-degree relatives of CD patients with HLA-DQ2 (Holm et al. 1992 ). Additionally, the increase of intraepithelial TCRγδ + T cells is more pronounced in children than in adults with active CD (Savilahti et al. 1997 ). It has been proposed that the intraepithelial infiltration of TCRγδ + T cells could be used as a diagnostic marker to identify early stage CD (Jarvinen et al. 2003 ) or to predict the risk of CD development among at-risk subjects with positive CD-specific autoantibodies and normal intestinal biopsy (Paparo et al. 2005 ).

Similar to gluten-reactive T cells, gluten-specific B cells preferentially recognize deamidated gluten peptides (Iversen et al. 2015 ). Close interactions between CD4 + T cells and B cells may be important for amplifying the inflammatory response, as B cells can present antigen to T cells and they in turn can provide help for autoantibody production. Gluten-reactive CD4 + T cells provide help to both TG2-reactive B cells and deamidated gluten-reactive B cells. TG2-gluten complexes are internalized by TG2-reactive B cells through B-cell receptor-mediated endocytosis. After internalization, deamidated gluten peptides can be released and can bind to HLA-DQ2 or HLA-DQ8 to be presented to T cells. Cooperation between gluten-reactive T-cell and B-cell results in activation of both the T cells and B cells, leading the B cells to differentiate into antibody-producing plasma cells and the T cells to proliferate and clonally expand.

Genetics of Celiac Disease

The genetics of autoimmune diseases include the intracellular signaling that drives the activation of T and B cells, signaling by cytokines and their receptors, and pathways that mediate innate immunity and microbial responses, such as Toll-like receptors and nucleotide-binding oligomerization domain receptors (Sollid and Jabri 2013 ).

Similar to other autoimmune diseases, celiac disease is a polygenic disorder for which the MHC locus is the single most important genetic factor. The MHC locus accounts for 40–50% of the genetic variance in the disease. The great majority of patients carry a particular variant of HLA-DQ2 (DQA1*05:01, DQB1*02:01; also known as DQ2.5). Those who are not DQ2.5 are almost all HLA-DQ8 (DQA1*03, DQB1*03:02) or carry another variant of HLA-DQ2 (DQA1*02:01, DQB1:02:02; also known as DQ2.2) (Megiorni and Pizzuti 2012 ; Smyth et al. 2008 ; Sollid and Lie 2005 ). HLA can be considered a necessary, but not sufficient, factor for disease development. HLA testing is much used in the clinic to exclude the diagnosis of celiac disease.

Many of the susceptibility loci for celiac disease are shared with those for other autoimmune diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis (RA) (Gutierrez-Achury et al. 2011 ; Zhernakova et al. 2011 ), most of which encode genes involved in inflammatory and immune responses (Kumar et al. 2012 ). Some of them may act as regulators of proliferation and activity of T lymphocytes ( CTLA-4, ICOSLG , and IL18RAP ). Other genes have also been implicated in the activity of nuclear factor kappa B (REL, UBE2LE) and in signaling processes (SOCS1, SH2B3) or in more than one function, as in the activities of T lymphocytes and cytokines (IL2, IL21, ILI2A and IL23R) (Anaya et al. 2012 ; Larizza et al. 2012 ). The HLA locus still presents the most important association in individuals affected by more than one autoimmune disorder (double autoimmunity), and that carry more of the genetic risk markers that are shared between the two diseases independently. In this sense, the CTLA4 and IL2RA loci were more strongly associated with double autoimmunity than with either T1D or CD alone. HLA analyses indicated that the T1D high-risk genotype, DQ2.5 / DQ8 , provided the highest risk for developing double autoimmunity.

The HLA and non-HLA loci can be used as stratification factors in the construction of risk models to predict double autoimmunity appearance and for pathway enrichment analysis to enhance our understanding of the pathophysiology involved in the development of both autoimmune diseases.

Environmental Factors in Celiac Disease

Gluten is the environmental factor required to trigger the disease, but other factors may be involved in a model of a complex multifactorial disease. The intestinal infections, the amount and quality of ingested gluten, the composition of intestinal microbiota, and infant-feeding practices are all possible triggers of the switch from tolerance to an immune response to gluten (Prescott et al. 2008 ). In this sense, two randomized controlled trials have been performed to clarify the relationship between the age at which gluten is introduced to a child’s diet and the risk of CD, showing that timing of gluten introduction does not modify the risk of CD (Lionetti et al. 2014 ; Vriezinga et al. 2014 ). Also showed that breastfeeding duration or breastfeeding during gluten introduction have no effect on the risk of CD.

The study of Bouziat et al. ( 2017 ) provides support for the concept that viruses can disrupt intestinal immune homeostasis and initiate loss of oral tolerance and Th1 immunity to dietary antigen. The authors propose that viruses elicit pro-inflammatory immune responses to dietary antigen altering immune homeostasis and in particular outfit dendritic cells (DCs) with pro-inflammatory properties at sites, where oral tolerance is induced (Bouziat et al. 2017 ). Although reovirus infections may trigger development of Th1 immunity to gluten as well as activation of TG2, additional events will be required for induction of anti-TG2 antibodies and villous atrophy.

Many of the implicated environmental factors may act by altering the composition of the microbiome (Verdu et al. 2015 ). Epidemiological data support an association between dysbiosis and increased risk of CD but there is little understanding of how it might influence gluten-specific immunity in vivo. In vitro data supports the influence of microbes on immune responses to gluten, including roles in modifying T regulatory cells induction, epithelial cell stress and IEL activation, phenotypic and functional maturation of DCs and pro-inflammatory cytokine production (Verdu et al. 2015 ).

The Human Microbiome as a Modulator of Autoimmunity in Celiac Disease

The high increase in the incidence of autoimmune disorders cannot be explained only by genetic drift and is thought to be the result of changes in the environment.

The microbiota plays an important role in immune maturation and homeostasis; alterations in microbial composition or colonization may influence intestinal homeostasis and, consequently, immune responses to food antigens.

CD has been linked to alterations in microbial composition (named intestinal dysbiosis) that could promote the disease onset and progression, as for other autoimmune disorders, such as T1D, multiple sclerosis and RA (Edwards 2008 ; Leirisalo-Repo 2005 ). It is unknown whether dysbiosis is a disease-promoting factor.

Differences in microbial metabolites between faecal samples of CD patients and healthy controls point to a functional role of the microbiota in the pathogenesis of CD (Di Cagno et al. 2009 ; Tjellstrom et al. 2005 ). A significantly higher number of Gram-negative and potentially pro-inflammatory bacteria were found to be associated with the symptomatic presentation of CD (Nadal et al. 2007 ). The unbalanced microbiota in children with untreated CD seems only partially restored after long-term treatment with a gluten-free diet (Collado et al. 2008 ; Sanz et al. 2007 ).

Little is known about the association between dysbiosis and gluten-specific T-cell responses. The functional relevance of these associations in CD remains unclear. The dysbiosis in CD is hallmarked by an increase in gram-negative and Bacteroides species and by a decrease in Bifidobacteria and Lactobacilli (Cheng et al. 2013 ). As the intestinal microbiota is able to modulate the cytokine environment, an unfavourable microbiota could amplify the immune response to gliadin in individuals with CD. Dysbiosis could represent an important trigger in CD pathogenesis, along with genetic (HLA haplotypes) and environmental (antibiotic administration, mode of delivery, and breastfeeding) factors (Losurdo et al. 2016 ).

Many studies have shown the presence of bacteria-derived proteolytic activities with the ability to hydrolyse gluten peptides in saliva, the duodenum and faeces (Caminero et al. 2012 ; Helmerhorst et al. 2010 ). Lactobacillus strains have the ability to completely hydrolyse the 33-mer peptide. However, the degradation products generated after the 33-mer hydrolysis are unknown and could also be highly immunogenic. It is fundamental to test these degradation products to determine whether the immunogenic epitopes are destroyed (Caminero et al. 2016 ). The opportunistic pathogens and core gut commensals generate distinct breakdown patterns of gluten with increased or decreased immunogenicity that could influence autoimmune risk. Gluten proteins are resistant to mammalian protease degradation but are good substrates for bacterial metabolic activity (Caminero et al. 2016 ). Proteases produced by environmental microorganisms have been proposed as pharmacologic therapy in CD (Lahdeaho et al. 2014 ; Tack et al. 2013 ).

Gluten-Free Diet and Autoimmune Disorders

It has been suggested that the intestinal-barrier dysfunction associated with undiagnosed CD might promote the onset of other autoimmune disorders by increasing the intestinal permeability to certain triggers (Shan et al. 2004 ). Diet intervention is a multifactorial approach, because gluten may affect not only the immune system and the gut microbiota but also other organs, such as the pancreas and liver. Ventura et al. ( 2012 ) were the first to report gluten-associated autoimmunity. The longer the duration of exposure to gluten before diagnosis of CD is, the higher the risk of developing autoimmune disorders later in life.

Epidemiological evidence suggests that a GFD may have a positive effect in the protection against T1D in humans with CD (Cosnes et al. 2008 ). However, the evidence is conflicting, as other studies found no protection (Viljamaa et al. 2005 ). The importance of gluten in T1D is highlighted by cohort studies finding that early introduction of gluten in the diet (before 3 months of age) increases the prevalence of diabetes autoantibodies in high-risk individuals (Ziegler et al. 2003 ). One of these studies showed signs of improved insulin sensitivity and insulin secretion in the GFD group compared to the group on a normal diet (Pastore et al. 2003 ).

Kaukinen et al. ( 2002 ) have described CD patients with severe liver injury displaying improvement after a GFD. One of these patients had early cirrhosis, and institution of a GFD led to the disappearance of ascites, although the micronodular cirrhosis persisted.

A later onset of CD is related to greater intestinal-barrier integrity and diminishing antigen triggers in the case of several autoimmune diseases. More large-scale prospective studies would be helpful to elucidate the way in which CD is related to other autoimmune conditions to clarify the possible influence that a GFD exerts on these conditions.

Others Autoimmune Disorders Associated with Celiac Disease

CD tends to coexist with several autoimmune diseases, including T1D, autoimmune thyroiditis, inflammatory bowel disease, rheumatoid arthritis, connective tissue disorders and psoriasis between others (Birkenfeld et al. 2009 ; Lerner and Matthias 2015a , b ; Viljamaa et al. 2005 ) (Table  1 ). The prevalence of co-existing autoimmune disease is estimated to be 3–10 times higher in CD patients than in the general population (Kakleas et al. 2015 ; Sategna Guidetti et al. 2001 ). In CD patients, a diagnosis of the disease early in life and a positive family history of autoimmunity are risk factors for developing other autoimmune diseases, while a GFD has a protective effect (Collin et al. 1994 ). More than 60% of CD-associated susceptibility loci are shared with at least one other autoimmune condition, such as T1D and RA (Rossi and Bot 2011 ), suggesting common pathogenic mechanisms. In particular, the recognition of peptides by HLA molecules, post-translational modifications of self-antigens (PTMs) required for optimal peptide binding, and immune mechanisms leading to tissue damage have been found. PTMs allow the generation of neo-self epitopes in the development of autoimmunity (Doyle and Mamula 2005 ). PTMs can occur spontaneously or arise by enzymatic modification, altering the protein structure, biological functions and. modifications of the proteolytic degradation. PTMs of self-proteins to which the immune system has not developed tolerance, include enzyme-dependent glycosylation, deamidation, citrullination, iodination, phosphorylation, methylation or chemical modifications such as disulfide bridge formation, oxidative modification or nitration, and many others (Arentz-Hansen et al. 2000 ; Collado et al. 2013 ).

Individuals affected by more than one autoimmune disorder may have an immune response more disturbed than those with only one disease. There may be an overlap in their aetiology due to shared genetic risk factors (Zhernakova et al. 2009 ) or due to synergistic effects of the genes involved in each disease separately (Cotsapas et al. 2011 ). The larger percentage of individuals developing more than one autoimmune disorder than expected suggests that common genetic loci and common biological pathways are involved in their pathogenesis. Regular screening in patients with one autoimmune disease for autoantibodies of other autoimmune diseases will be important for the clinical care of these patients and may provide some insights into the disease pathogenesis.

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Acknowledgements

This work was supported by Junta de Andalucia throughout the programme “Ayudas a grupos investigación BIO-220”.

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López Casado, M.Á., Lorite, P., Ponce de León, C. et al. Celiac Disease Autoimmunity. Arch. Immunol. Ther. Exp. 66 , 423–430 (2018). https://doi.org/10.1007/s00005-018-0520-z

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Celiac Crisis in an Adult Patient: Case Report and Review of the Literature

* corresponding author(s):.

We report a case of celiac crisis in a previously healthy 51-year-old female presenting with a month’s history of diarrhea, cachexia and an abnormal metabolic panel.The patient’s diarrhea resolved after initiation of a gluten free diet and she gained 4 kilograms during hospitalization. 

Celiac crisis is a very rare presentation of celiac disease in adults but nonetheless should be considered in patients with marked metabolic derangements in the setting of osmotic diarrhea.

Celiac crisis; Celiac disease; Gluten free diet; Hypokalemia; Tissue transglutaminase

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Introduction

Celiac Disease (CD) is an immune mediated inflammation of the small intestine caused by sensitivity to gluten and related proteins. Its prevalence ranges between 1:100 to 1:300 in most countries and manifests with a heterogeneous symptomatology [1]. Typical symptoms include chronic diarrhea and signs of malabsorption [2]. Celiac crisis is a fulminant manifestation of CD that presents with acute symptoms that often require hospitalization. It mainly affects pediatric patients under 2 years of age [3]. Due to its rarity in the adult population, with approximately 40 reported cases in the medical literature, clinicians need a high level of suspicion to recognize this clinical entity.

Case Presentation

A 51 years old woman was presented in the emergency department with a history of one month of diarrhea, accompanied by weight loss of 10 kilograms. The patient reported a frequency of 20 episodes of watery diarrhea per day with the absence of blood, mucus or steatorrhea. There was no history of fever, abdominal pain or recent travel abroad. She, also, denied any episode of night sweats or chills. She did not suffer from chronic illness or used any regular or illicit medication. Her family history was unremarkable. 

At the objective examination she appeared cachectic and fatigued, but with normal awareness. Her skin turgor and jugular venous pressure were decreased and her mucous membranes dry. Auscultation of the lungs and heart was normal with respiratory frequency 15 breaths per minute. Blood pressure was found to be 85/75 mmHg, saturation of oxygen98% and heart rate 105 beats per minute. The rest of the examination was unremarkable. 

Initial investigations revealed severe hypokalemia (K + : 1,8meq/L) and normal anion gap metabolic acidosis (PH: 7,30), consistent with the history of chronic diarrhea. Moreover, her serum sodium was 129 meq/L with urine sodium <5 mmol/L (hypovolemic hyponatraemia). The patient was treated with isotonic fluids and potassium intravenously and was admitted in the internal medicine department for further examination.

Additional laboratory examination indicated hypoalbuminemia (2.7 gr/dl), coagulopathy (INR: 4.4; APTT:55.9 sec) and positive tissue transgtlutaminase IgA antibodies (177U/ml). Stool examination did not suggest infectious etiology; neuroendocrine tumor work-up was negative while Computed Tomography (CT) of the upper and lower abdomen was free of pathological findings. Upper and lower endoscopies were performed and four biopsies were taken (stomach, duodenum and post bulbar duodenum). Histopathological exam describes increased intraepithelial lymphocytes, crypt hyperplasia and villous atrophy (Figure 1). 

The biopsy results together with the positive serological marker of CD are consistent with the diagnosis of CD.

The patient was started on low calorie gluten free diet (500 kcal/day) and received vitamin B complex in order to prevent refeeding syndrome. She showed clinical and laboratory improvement with the episodes of diarrhea limited to 1-2 daily and gained 4 kilograms in 15 days. The patient got referred to the CD clinic of the same hospital.

Celiac crisis is a rare and life-threatening form of CD fist described by Di Sant ‘Agnese in 1953 [4]. In 2010, Jamma and colleagues defined a celiac crisis as an acute presentation or rapid progression of gastrointestinal symptomatology, in CD patients, that requires medical attention [5]. Additionally, at least two of the following criteria have to be met. 

• • Weight loss > 5 kg
• • Neurological symptoms
• • Increased creatinine > 2g/dl
• • Hypoalbuminemia <3.0 g/dl
• • Severe dehydration or shock
• • Metabolic acidosis (PH <7,35)
• • Electrolyte abnormalities 

A recent review of the 42 reported cases described that, as CD, celiac crisis has a female predominance of 2:1. Furthermore, most of the patients (37/42) reported no past history of CD and their mean age of presentation was 50 years of age. Electrolyte imbalances, hypoproteinemia, metabolic acidosis and anemia were the most common abnormalities and the majority of patients indicated positive CD serology and advanced disease specific histopathological lesions (Marsh 3C stage) [6]. 

The present casefulfils five of the proposed criteria; weight loss of 10 kilograms, dehydration, severe hypokalemia/hyponatraemia, metabolic acidosis and hypoalbuminemia. Furthermore, it parallels the reported epidemiology of the disease as our patient was an otherwise healthy female of 51 years. 

Moreover, although, not a part of the diagnostic criteria, bleeding diathesis has been identified in celiac crisis patients [6-7]. We, too, found an abnormal coagulation panel, most probably due to vitamin K malabsorption. This assumption is strengthened with the normalization of the laboratory values after the start of gluten free feeding. 

Lastly, some reports suggest that celiac crisis is triggered by a preceding stimulus, such as surgery or infection [6,8]. In our case none was identified. 

Celiac crisis is an easy to treat but severe presentation of CD. Due to its rarity it often is low or non-existent in the differential diagnosis of diarrhea in adult patients. We suggest that all patients, fulfilling some of the criteria proposed by Jamma and colleagues or having increased levels of CD-related antibodies, should be placed on gluten free diet and undergo to endoscopic examination of the small bowel.

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• Andersen DH, Di Sant'agnese PA (1953) Idiopathic celiac disease. I. Mode of onset and diagnosis. Pediatrics 11: 207-223.
• Jamma S, Rubio-Tapia A, Kelly CP, Murray J, Najarian R, et al. (2010) Celiac crisis is a rare but serious complication of celiac disease in adults. Clin Gastroenterol Hepatol 8: 587-590.
• Balaban DV, Dima A, Jurcut C, Popp A, Jinga M (2019) Celiac crisis, a rare occurrence in adult celiac disease: A systematic review. World J Clin Cases 7: 311-319.
• MagroR, Pullicino E (2012) Coeliac crisis with severe hypokalemia in an adult. Malta Medical Journal 24: 36-39.
• Hammami S, Aref HL, Khalfa M, Kochtalli I, Hammami M (2018) Refeeding syndrome in adults with celiac crisis: a case report. J Med Case Rep 12: 22.

Citation:  Katsifis-Nezis D, Papazafiropoulou A, Vrakas S, Kampourogiani D, Kourkoulis P, et al. (2021) Celiac Crisis in an Adult Patient: Case Report and Review of the Literature. J Clin Stud Med Case Rep 8: 0116.

Copyright: © 2021  Dimitrios Katsifis-Nezis, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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T is a girl, 7 years of age, who presents to her pediatrician, Dr. G, with complaints of fatigue, abdominal cramping, and diarrhea. T weighed eight pounds, three ounces at birth, and her growth and development have been consistent and appropriate. She has no pre-existing conditions and is current on all of her immunizations.

T is afebrile and her vital signs are within normal limits. A diagnosis of viral gastritis is made. Dr. G advises T's mother (Mrs. H) to limit her daughter's diet to bland foods and give the symptoms time to run their course. Mrs. H is advised to call if symptoms do not improve.

At home, T rests and consumes chicken broth and gelatin. After three days, she is feeling better and ready to return to school. At school the next day, T lunches at 11:30 a.m. on tomato soup, a grilled cheese sandwich, and mixed fruit. T is feeling tired but otherwise well. She consumes all of her soup and fruit, but only a few bites of the sandwich. Around 1:00 p.m., T complains to her teacher of stomach cramping and asks to go to the restroom.

Mrs. H picks T up from school at 3:00 p.m.; T continues to experience stomach cramping and tells her mother that she has had three episodes of diarrhea that day. When she arrives home, T consumes nothing but gelatin and ginger ale and spends the rest of the day in bed. Although T feels better the next morning, Mrs. H keeps her at home and in bed and continues to give T only gelatin, chicken broth, and ginger ale. For the next two weeks, Mrs. H keeps T on a diet of soups and liquids to allow her stomach time to recover. When T appears to be improving, Mrs. H decides to slowly introduce other foods back into her diet.

Within two days, T relapses and experiences diarrhea, bloating, and stomach cramping. Mrs. H schedules a follow-up appointment with Dr. G, who re-evaluates T and discovers that she has lost one pound in body weight and that her stomach is tender to palpation. Dr. G orders additional workup, including blood work, with the following results:

Hemoglobin: 10.8 g/dL (Normal range: 11.5–14.5 g/dL)

Hematocrit: 34% (Normal range: 35% to 42%)

Platelets: 225 (Normal range: 250–500)

Sodium: 127 mEq/L (Normal range: 136–145 mEq/L)

Potassium: 3.3 mEq/L (Normal range: 3.5–5.0 mEq/L)

Calcium: 6.9 mg/dL (Normal range: 9.0–11.0 mg/dL)

Albumin: 2.6 g/dL (Normal range: 3.5–5.5 g/dL)

Mrs. H and T return to Dr. G's office to review the results of the blood work. T has continued to have spells of diarrhea and stomach pains, and she has lost an additional six ounces. Dr. G suspects that T has CD. He schedules further evaluation and an EGD.

Two weeks later, Mrs. H and T return to Dr. G's office for a consultation. Dr. G explains the study results, which revealed atrophy of intestinal villi. He explains that T is experiencing malabsorption of important nutrients, likely due to an intolerance to wheat, rye, or barley products in the foods she is eating. T is referred to a dietitian, Ms. D, who specializes in pediatric nutrition and CD.

T and her parents meet with Ms. D, who explains that CD is an immunologic response to wheat, rye, or barley products that causes destruction of the lining of the small intestine, which in turn causes malabsorption of important nutrients. Ms. D further explains that destruction of the lining leads to diarrhea, fatty stools, weight loss, foul-smelling gas, and iron-deficiency anemia. She reassures the family that, although it sounds frightening, CD is easily controlled with dietary changes and provides the family with a list of foods to avoid as well as sources of "hidden" gluten (e.g., school supplies).

Ms. D works with the family to develop one week's worth of gluten-free meals that T will be willing to eat. They openly and at length discuss challenges that the family may encounter. Ms. D recommends that the family explore a nearby CD support group, which can help them with the adjustments they need to make.

T and her mother return to Dr. G's office for a one-year check-up. T's laboratory tests are normal, and she is slowly gaining weight. Mrs. H reports that T has had some minor episodes of bloating and diarrhea after eating something on the forbidden list when at a friend's house. Dr. G states that T is progressing well and indicates that a few slips in the diet are to be expected, but reminds them that these should not be frequent.

One month later, Mrs. H finds T lying on her bed, crying. Mrs. H asks what is wrong, but T responds that she does not want to talk about it. When Mrs. H persists, T tells her that she was not invited to V's sleepover because V's mother is afraid that T will eat something she should not and get sick. She also reports taunting and feeling left out at school.

Mrs. H calls one of the mothers from the support group to discuss what is happening to T, and the mother provides Mrs. H with some helpful tips. Mrs. H then schedules a meeting with T's teacher to educate him about T's CD and to discuss ways to help lessen the alienation T is feeling. Mrs. H asks him to telephone her if another student's parent plans a celebration so that she can send in a special treat for T. He agrees and promises to be more aware of the way that T is being treated by her classmates.

Later in the week, Mrs. H calls V's mother and invites her to meet for coffee. When they meet the next day, Mrs. H explains what CD is and how it is controlled. She tells V's mother that she is not trying to force her to invite T to her home; she simply wants her to know that CD is nothing to fear. V's mother explains that she was not sure she wanted to take the risk of T becoming ill at her home if she ate something she was not supposed to have. Mrs. H responds that T is very knowledgeable about what she can and cannot eat and explains that small amounts of forbidden foods do not cause a severe reaction in T. That evening, V calls and invites T to the sleepover and apologizes for not having invited her sooner.

After the telephone call, Mr. and Mrs. H discussed some of the misconceptions that the school and their community had about CD. They decide to develop an educational program to present to area schools to increase awareness about CD. Six months later, they have presented the program to local schools and received positive responses and many questions. The next year, prior to the start of the school year, the couple is asked to return and present the information again.

T states that her school days improved greatly after the educational programs were presented.

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