celiac disease case study examples

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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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18.8: Case Study Conclusion: Celiac and Chapter Summary

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• Page ID 17147

• Suzanne Wakim & Mandeep Grewal
• Butte College

Case Study Conclusion: Please Don’t Pass the Bread

The garlic bread stuffed with spaghetti shown in Figure \(\PageIndex{1}\) may or may not look appetizing to you, but for people with celiac disease, it is certainly off-limits. Bread and pasta are traditionally made with wheat, which contains proteins called gluten. As you learned in the beginning of the chapter, even trace amounts of gluten can damage the digestive system of people with celiac disease. When Rania and Tui met for lunch, Rania chose a restaurant that she knew could provide her with gluten-free food because she has this disease.

When people with celiac disease eat gluten, it causes an autoimmune reaction that results in inflammation and flattening of the villi of the small intestine. What do you think happens if the villi are inflamed and flattened? Think about what you have learned about the functions of the villi and small intestine. The small intestine is where most chemical digestion and absorption of nutrients occurs in the body. The villi increase the surface area in the small intestine to maximize the digestion of food and absorption of nutrients into the blood and lymph. If the villi are inflamed and flattened, there is less surface area where digestion and absorption can occur. Therefore, damage from celiac disease can result in inadequate absorption of nutrients, called malabsorption.

Malabsorption explains why there can be so many different types of symptoms of celiac disease, ranging from diarrhea and other forms of digestive distress to anemia, nutritional deficiencies, skin rashes, osteoporosis, bone pain, depression, anxiety, and rarer but potentially serious complications such as cancer. Our bodies need to digest and absorb adequate amounts of nutrients in order to function properly and stay healthy. Lack of nutrients can affect and damage cells, tissues, and organs throughout the body, sometimes seriously and irreversibly. A person with celiac disease can limit and often heal intestinal damage just by not eating gluten. In fact, eliminating all gluten from the diet is the main treatment for celiac disease. In some people with celiac disease, a gluten-free diet may not be enough, and steroids and other medications may be used to reduce the inflammation in the small intestine.

Celiac disease is an autoimmune disorder in which the body’s immune system attacks its own tissues. It is thought to be caused by the presence of particular genes in combination with exposure to gluten. What are some other autoimmune disorders that you read about in this chapter that affect the digestive system? The two main inflammatory bowel diseases, Crohn’s disease and ulcerative colitis are both due to the body’s immune system attacking the digestive system, resulting in inflammation. Crohn’s disease can affect any part of the GI tract, most commonly the ileum of the small intestine, while ulcerative colitis mainly affects the colon and rectum. Similar to celiac disease, treatments for these diseases also focus on reducing GI tract damage through lifestyle changes and medications.

Gluten is clearly dangerous for people with celiac disease, but should people who do not have celiac disease or other diagnosed medical problems with gluten also eliminate gluten from their diet? Many medical experts say no; because gluten-free diets are so restrictive, they may cause nutritional deficiencies without providing any proven health benefits. They can also be expensive and, as Tui’s cousin found out, difficult to maintain given that gluten is present in so many foods. It is estimated that only 1% of the population has celiac disease. Most people should enjoy a varied diet and consult with their doctor if they are concerned about celiac disease, other types of gluten intolerance, or food allergies.

Chapter Summary

In this chapter, you learned about the digestive system, which allows the body to obtain needed nutrients from food. Specifically, you learned that:

• The digestive system consists of organs that break down food, absorb its nutrients, and expel any remaining food waste.
• Most digestive organs form a long, continuous tube through which food passes, called the gastrointestinal (GI) tract. It starts at the mouth, which is followed by the pharynx, esophagus, stomach, small intestine, and large intestine.
• Organs of the GI tract have walls that consist of several tissue layers that enable them to carry out digestion and/or absorption. For example, the inner mucosa has cells that secrete digestive enzymes and other digestive substances and also cells that absorb nutrients. The muscle layer of the organs enables them to contract and relax in waves of peristalsis to move food through the GI tract.
• Mechanical digestion is a physical process in which food is broken into smaller pieces without becoming chemically changed. It occurs mainly in the mouth and stomach.
• Chemical digestion is a chemical process in which macromolecules including carbohydrates, proteins, lipids, and nucleic acids in food are changed into simple nutrient molecules that can be absorbed into body fluids. Carbohydrates are chemically digested to sugars, proteins to amino acids, lipids to fatty acids, and nucleic acids to individual nucleotides. Chemical digestion requires digestive enzymes. Gut flora carries out additional chemical digestion.
• Absorption occurs when the simple nutrient molecules that result from digestion are absorbed into blood or lymph. They are then circulated through the body.
• The mouth is the first organ of the GI tract. It has several structures that are specialized for digestion, including salivary glands, tongue, and teeth. Both mechanical digestion and chemical digestion of carbohydrates and fats begin in the mouth.
• The pharynx and esophagus move food from the mouth to the stomach but are not directly involved in the process of digestion or absorption. Food moves through the esophagus by peristalsis.
• Mechanical and chemical digestion continue in the stomach. Acid and digestive enzymes secreted by the stomach start the chemical digestion of proteins. The stomach turns masticated food into a semi-fluid mixture called chyme.
• The ileum carries out any remaining digestion and absorption of nutrients, but its main function is to absorb vitamin B12 and bile salts.
• The jejunum carries out most of the absorption of nutrients in the small intestine, including the absorption of simple sugars, amino acids, fatty acids, and many vitamins.
• The duodenum secretes digestive enzymes and also receives bile from the liver or gallbladder and digestive enzymes and bicarbonate from the pancreas. These digestive substances neutralize acidic chyme and allow for the chemical digestion of carbohydrates, proteins, lipids, and nucleic acids in the duodenum.
• The main function of the large intestine is to remove water and salts from chyme for recycling within the body and eliminating the remaining solid feces from the body through the anus. The large intestine is also the site where trillions of bacteria help digest certain compounds, produce vitamins, stimulate the immune system, and break down toxins, among other important functions.
• The main digestive function of the liver is the production of the alkaline liquid called bile. Bile is carried directly to the duodenum by the common bile duct or to the gallbladder first for storage. Bile neutralizes acidic chyme that enters the duodenum from the stomach and also emulsifies fat globules into smaller particles (micelles) that are easier to digest chemically.
• Other vital functions of the liver include regulating blood sugar levels by storing excess sugar as glycogen, storing many vitamins and minerals, synthesizing numerous proteins and lipids, and breaking down waste products and toxic substances.
• The gallbladder is a small, pouch-like organ near the liver. It stores and concentrates bile from the liver until it is needed in the duodenum to neutralize chyme and help digest lipids.
• The pancreas is a glandular organ that secretes both endocrine hormones and digestive enzymes. As an endocrine gland, the pancreas secretes insulin and glucagon to regulate blood sugar. As a digestive organ, the pancreas secretes digestive enzymes into the duodenum through ducts. Pancreatic digestive enzymes include amylase (starches); trypsin and chymotrypsin (proteins); lipase (lipids); and ribonucleases and deoxyribonucleases (RNA and DNA).
• Inflammatory bowel disease is a collection of inflammatory conditions primarily affecting the intestines. The diseases involve the immune system attacking the GI tract, and they have multiple genetic and environmental causes. Typical symptoms include abdominal pain and diarrhea, which show a pattern of repeated flare-ups interrupted by periods of remission. Lifestyle changes and medications may control flare-ups and extend remission. Surgery is sometimes required.
• The two principal inflammatory bowel diseases are Crohn’s disease and ulcerative colitis. Crohn’s disease may affect any part of the GI tract from the mouth to the anus, among other body tissues. Ulcerative colitis affects the colon and/or rectum.
• Some people have little pouches, called diverticula, in the lining of their large intestine, a condition called diverticulosis. People with diverticulosis may develop diverticulitis, in which one or more of the diverticula become infected and inflamed. Diverticulitis is generally treated with antibiotics and bowel rest; sometimes surgery is required.
• A peptic ulcer is a sore in the lining of the stomach (gastric ulcer) or duodenum (duodenal ulcer). The most common cause is infection with the bacterium Helicobacter pylori . NSAIDs such as aspirin can also cause peptic ulcers, and some lifestyle factors may play contributing roles. Antibiotics and acid reducers are typically prescribed; surgery is not often needed.
• Gastroenteritis, or infectious diarrhea, is an acute and usually self-limiting infection of the GI tract by pathogens, most often viruses. Symptoms typically include diarrhea, vomiting, and/or abdominal pain. Treatment includes replacing lost fluids; antibiotics are not usually effective.
• Giardiasis is a type of gastroenteritis caused by infection of the GI tract with the protozoa parasite Giardia lamblia . It may cause malnutrition. It is generally self-limiting, but severe or long-lasting cases may require antibiotics.

Chapter Summary Review

• Explain how the accessory organs of digestion interact with the GI tract.
• Small intestine
• Gallbladder
• True or False. Bile is one of the digestive fluids secreted in the stomach.
• True or False. The smell of food can stimulate the release of digestive enzymes.
• If the pH in the duodenum was too low (acidic), what effect do you think this would have on the processes of the digestive system?
• Is the stomach involved in chemical digestion, mechanical digestion, or both? Explain your answer.
• Is food passing through the GI tract generally more solid in the small intestine or the large intestine? Explain your answer.
• What is another name for the colon?
• Discuss whether digestion occurs in the large intestine.
• The large intestine
• The small intestine
• The pancreas
• What is lacteal? In your answer, be sure to describe both its location and function in the digestive system.
• Lipids are digested at different points in the digestive system. Describe how lipids are digested at two of these points.
• Describe two different functions of stomach acid.
• True or False . Proteins are only digested in the stomach.
• True or False . A peptic ulcer can occur in the small intestine.
• A small, pouch-like organ that stores and concentrates bile produced by a different organ.
• Produces insulin as well as digestive enzymes and other needed substances.
• Processes wastes in addition to aiding in digestive functions.
• What is the name of the rhythmic muscle contractions that move food through the GI tract?
• What are the major roles of the upper GI tract?
• small intestine
• large intestine
• What is the physiological cause of heartburn?
• Crohn’s disease
• Peptic ulcer
• Ulcerative colitis
• Gastroenteritis
• True or False. Smoking does not contribute to digestive system disorders.
• True or False. In addition to obtaining nutrients, the digestive system plays a role in protecting the body from pathogens.
• What are two ways in which the tongue participates in digestion?
• Where is the epiglottis located?
• If the epiglottis were to not close properly, what might happen?
• The GI tract goes from the mouth to which structure?

Attributions

• Spaghetti Stuffed Garlic Bread by Adam S licensed CC BY 2.0 via Flickr.com
• Text adapted from Human Biology by CK-12 licensed CC BY-NC 3.

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.

• Gujral N, Freeman HJ, Thomson AB (2021) Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol 18: 6036-6059.
• Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA (2013) ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 108: 656-676.
• Babar MI, Ahmad I, Rao MS, Iqbal R, Asghar S, et al. (2011) Celiac disease and celiac crisis in children. J Coll Physicians Surg Pak 21: 487-490.
• 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.

Clinical Studies Medical Case Reports

Celiac disease: is it compatible with a career in gymnastics?

September 2016: first presentation to primary care

Clara, a 24-year-old woman with a love for gymnastics, presented to her GP complaining of frequent facial flushing over the preceding 12 months. She noticed that over time, these flushing episodes had increased in frequency and seemed to be lasting longer. During late summer, the skin on her face had been feeling tight and itchy, and pus-filled pimples had developed.

Based on her symptom profile, Clara was diagnosed with rosacea. To reduce the risk of flare-ups, the GP proposed a management plan which involved avoidance of potential triggers, including:

•  Hot drinks
•  Spicy food
•  Aerobic exercise

October  2016: 3-week follow-up appointment

For 3 weeks, Clara avoided the potential triggers that her GP mentioned, which involved stopping her gymnastic training. However, she still had several flare-ups of rosacea and developed further symptoms, including diarrhoea, fatigue, and weight loss.

Investigations

Due to Clara's ongoing facial flushing and her new symptoms, the GP decided to request a range of blood tests to investigate other potential underlying pathologies, aside from rosacea:

• Vitamin D: low (15 nmol/L)
• Vitamin B12: low (140 pg/mL)
• Tissue transglutaminase (tTG) IgA: positive (52 U/mL, 5x ULN)
• Total IgA: normal (1.8 g/L)
• Specific IgE to a panel of food allergens: negative (<0.1 k A U/L)
• Tryptase: mildly elevated (16 mcg/L)

Clara tested negative for food allergy but was deficient in vitamins D and B12, despite having a balanced diet including meat and fish. In light of the unexplained vitamin B12 deficiency, the GP decided to test for pernicious anaemia with blood tests for antibodies against parietal cells and intrinsic factor, which later returned negative.

Unexplained iron, vitamin B12, or folate deficiency can be a sign of celiac disease. 1

Refined diagnosis

Following a repeat tTG IgA test (51 U/mL, 5x ULN), Clara was diagnosed with celiac disease, based on her symptoms, unexplained vitamin B12 deficiency, and elevated tTG IgA.

tTG IgA is the recommended first‑line test for celiac disease, together with total IgA to check for IgA deficiency. 2

Management plan

• Cholecalciferol (1,600 IU) for 6 months
• Intramuscular hydroxocobalamin (1 mg) three times a week for 2 weeks
• Gluten-free diet
• 3-monthly follow-up to assess response to treatment, including tTG IgA level

It is common practice for tTG IgA to be tested every 3 months, until normalised, and once a year as an indicator of diet adherence. 2

January 2017:   3-month follow-up appointment

After 3 months of strict adherence to a gluten-free diet, Clara’s rosacea and celiac disease symptoms had markedly improved. She no longer had troublesome diarrhoea and had regained the weight she previously lost. However, despite Clara's skin no longer feeling tight or itchy, she still had occasional bouts of facial flushing.

Clara told the GP that she now had much more energy and had been able to return to her gymnastics training; she felt that her quality of life had improved to near-normal.

Early diagnosis and treatment of celiac disease with a gluten-free diet implemented in coordination with a dietitian, could:

• Decrease the risk of some cancers, 3 complications in type 1 diabetes, 4 low birth weight of babies, 3 and delayed puberty 3,5
• Improve bone mineral density (if diagnosed at a young age), 3,6 dermatitis herpetiformis, 7 condition of intestinal mucosa, 7 anaemia, 5 and disease symptoms 3,7
• Resolve infertility, 3,5,8 spontaneous abortions, 3 and menstrual problems 3

Clara's repeat blood test results:

Due to the elevated tryptase, Clara's GP referred her to a specialist in mast cell disorders.

March 2017:   3-month follow-up appointment

3 months later, after consultation with a specialist in mast cell disorders, it was revealed that Clara had hereditary alpha-tryptasemia syndrome. This explained the chronically elevated tryptase, and Clara's trouble with persistent facial flushing.

Clara was still adhering to a strict gluten-free diet, and her tTG IgA level had dropped to 31 U/mL (3x ULN).

April 2020:   3 years later

Clara's tTG IgA level returned to normal in 2019, and she now had annual check-ups with the GP, to monitor diet adherence and symptoms associated with hereditary alpha-tryptasemia syndrome.

Her bowel symptoms and fatigue had entirely resolved on a gluten-free diet, and she was enjoying national success as a gymnast. She decided to leave her full-time office job to pursue a career in gymnastics.

In April 2020, her younger brother was diagnosed with celiac disease at the age of 25 years, after living with intermittent abdominal pain and bloating for several years.

First-degree relatives have a 10 percent chance of developing celiac disease. 9

Screening for first-degree relatives, and case-finding in second-degree relatives, can help identify patients earlier, thus reducing the risk of complications. 10,11

COMING SOON Case study 2: Diagnostic delay in coeliac disease

IgA: immunoglobulin A; IgE: immunoglobulin E; ULN: upper limit of normal

The people, places, and events depicted in these case studies and photographs do not represent actual patients, nor are they affiliated in any way with Thermo Fisher Scientific.

• Halfdanarson T R, Litzow M R, Murray J A. Hematologic manifestations of celiac disease. Blood 2007;109(2):412-421
• Al-Toma A, Volta U et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J 2019;7(5):583-613
• Murch S, Jenkins H et al. Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children. Arch Dis Child 2013;98(10):806-811
• Elfström P, Sundström J, Ludvigsson J F. Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes. Aliment Pharmacol Ther 2014;40(10):1123-1132
• Bozzola M, Meazza C, Villani A. Auxo-endocrinological approach to celiac children. Diseases 2015;3(2):111-121
• Grace-Farfaglia P. Bones of contention: bone mineral density recovery in celiac disease--a systematic review. Nutrients 2015;7(5):3347-3369
• Ciacci C, Ciclitira P et al. The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis. United European Gastroenterol J 2015;3(2):121-135
• Shah S, Leffler D. Celiac disease: an underappreciated issue in women's health. Womens Health (Lond) 2010;6(5):753-766
• Lewis D, Haridy J, Newnham E D. Testing for coeliac disease. Aust Prescr 2017;40(3):105-108
• Bonamico M, Ferri M et al. Serologic and genetic markers of celiac disease: a sequential study in the screening of first degree relatives. J Pediatr Gastroenterol Nutr 2006;42(2):150-154
• Singh P, Arora S et al. Risk of celiac disease in the first- and second-degree relatives of patients with celiac disease: a systematic review and meta-analysis. Am J Gastroenterol 2015;110(11):1539-1548

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• Volume 7, Issue 1
• Life-threatening onset of coeliac disease: a case report and literature review
• Article Text
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• Matteo Guarino 1 ,
• Edoardo Gambuti 1 ,
• Franco Alfano 1 ,
• Andrea Strada 2 ,
• http://orcid.org/0000-0002-6297-7576 Rachele Ciccocioppo 3 ,
• Lisa Lungaro 1 ,
• Giorgio Zoli 1 ,
• Umberto Volta 4 ,
• Roberto De Giorgio 1 ,
• http://orcid.org/0000-0002-4244-4529 Giacomo Caio 1 , 5
• 1 Department of Morphology, Surgery and Experimental Medicine , University of Ferrara , Ferrara , Italy
• 2 Department of Emergency Medicine , St. Anna University Hospital , Ferrara , Italy
• 3 Department of Medicine , A.O.U.I. Policlinico G.B. Rossi and University of Verona , Verona , Italy
• 4 Department of Medical and Surgical Sciences , University of Bologna , Bologna , italy
• 5 Celiac Center and Mucosal Immunology and Biology Reaserch Center , Massachusetts General Hospital - Harvard Medical School , Boston , MA , United States
• Correspondence to Dr Giacomo Caio; caigmp{at}unife.it

Background Coeliac disease (CD) results from an immune-mediated reaction to gluten in genetically predisposed individuals. In rare cases CD may occur with acute features deferring the diagnosis and exposing these patients to possible life-threatening complications. Herein we present the case of a young woman with a coeliac crisis, that is, a sudden clinical onset characterised by severe electrolyte imbalance due to an unknown (previously unrecognised) CD.

Methods This is a case report and literature review revealing that coeliac crisis is under-reported, with a total of 48 adult cases so far published. The diagnosis in our case was established by histopathological analysis of multiple duodenal biopsies. The patient’s serum was tested by enzyme-linked immunoassay to detect antitransglutaminase IgA antibodies.

Results In contrast to cases reported in the literature, with male gender predominance and a mean age of 50±17 years, our patient was a young female case of coeliac crisis. However, like in our patient, a higher incidence of coeliac crisis was associated with the human leucocyte antigen (HLA)-DQ2 haplotype, versus HLA-DQ8, and a severe (Marsh-Oberhüber 3c) duodenal mucosa atrophy. Notably, there is no clear correlation between the antitissue transglutaminase 2 IgA antibody titre and coeliac crisis onset/severity, as confirmed by our case report.

Conclusions The present case highlights that CD may manifest quite abruptly with a severe malabsorption syndrome, that is, electrolyte abnormalities and hypoproteinaemia. Our case should alert physicians, in particular those in the emergency setting, that even a typically chronic disorder, such as CD, may show life-threatening complications requiring urgent management.

• gluten-free diet
• malabsorption
• intestinal failure
• coeliac disease

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjgast-2020-000406

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Introduction

Coeliac disease (CD) is a multisystemic, immune-mediated illness evoked by gluten ingestion in genetically susceptible individuals. 1 The main target organ of the autoimmune reaction against the enzyme tissue transglutaminase (TG2) is the small bowel, where the gluten-related inflammatory cascade causes a progressive mucosal damage leading to severe villous atrophy. 1 2 From a clinical standpoint, CD is a multifaceted chronic condition displaying a broad spectrum of intestinal (ranging from mild irritable bowel syndrome-like to severe malabsorption symptoms) and extraintestinal manifestations targeting several tissues and organs (eg, skin, endocrine/exocrine glands, nervous system, joint/muscles). As a result, CD remains a challenging condition to be diagnosed, thus causing a significant delay in establishing the appropriate therapy and increasing related morbidity. 3–5

A potentially life-threatening and neglected clinical manifestation of CD is the so-called ‘coeliac crisis’, characterised by acute, massive watery diarrhoea, severe dehydration and metabolic disturbances, leading to neuromuscular weakness, tetanic seizures, cardiac arrhythmias and even sudden death in extreme cases. 6–8 This condition is largely under-reported and under-recognised both in children and adults, with a total of 48 adult cases published so far. 6–46 In most cases, coeliac crisis develops due to voluntary or inadvertent gluten ingestion in patients with or without an established diagnosis of CD. Only rarely a coeliac crisis heralds the clinical onset of CD, requiring hospitalisation and rapid therapeutic management due to possible occurrence of severe complications with high morbidity and mortality. 9–13

Herein we describe the case of a patient admitted to our emergency department for a severe life-threatening coeliac crisis as the first manifestation of a previously unknown CD.

Case report

A 34-year-old woman was admitted to the emergency unit complaining of limb numbness and watery diarrhoea (8–10 bowel movements/day) which started 2 weeks earlier. The patient reported a weight loss of about 10 kg in the last 2 months in the absence of hyporexia. Her clinical history unravelled microcytic anaemia treated with oral iron replacement. Physical examination showed severe weakness of the limbs with a bilaterally positive Trousseau’s sign without cardiorespiratory abnormalities. Vital parameters were within the normal range. The abdomen was flat, without tenderness, while auscultation disclosed increased intestinal sounds. Her ECG showed a sinus rhythm with type 1 atrioventricular block, flat T waves associated with U waves and an elongated QTc interval (570 ms). Laboratory tests revealed severe electrolyte imbalance, with hyponatraemia (133 mmol/L), hypokalaemia (1.6 mmol/L), hypocalcaemia (ionised calcium of 0.9 mmol/L), hypophosphataemia (1.6 mg/dL) and hypomagnesaemia (1.4 mmol/L). Furthermore, the patient had hypochromic microcytic anaemia (haemoglobin of 85 g/L, with a mean cell volume of 68 fL and a mean cell haemoglobin of 20.6 pg), normal platelet count (297×10ˆ9/L), iron (serum iron 18 µg/dL; ferritin 2 ng/mL) and folate deficiency (2 ng/mL), as well as hypoproteinaemia and hypoalbuminaemia (total serum protein 4.4 g/dL; albumin 2.6 g/dL). Due to severe electrolyte imbalance, a conspicuous electrolyte replacement was rapidly administered, leading to a slight improvement in electrocardiographic abnormalities. The patient was then admitted to the internal medicine ward for adequate investigation and treatment. During the hospitalisation, the common causes of infectious diarrhoea were excluded by stool cultures, and the faecal occult blood test resulted negative. Both ultrasound and abdominal X-ray examinations were unremarkable. Liver function tests revealed a slight increase of transaminases, with alanine transaminase and aspartate transaminase values of 47 U/L and 60 U/L (n.v. 5-35 for both parameters), respectively. Based on the lack of fever, normal C reactive protein and the presence of non-bloody, watery diarrhoea, the patient was further evaluated with an upper endoscopy. The examination revealed stigmata of villous atrophy at the duodenal level ( figure 1 ), where biopsies were taken from the bulb and the second portion. Histopathological analysis showed the presence of a severe villous atrophy (Marsh-Oberhüber grade 3c) ( figure 2 ) without any evidence of aberrant intraepithelial lymphocytes. 14 Based on the histopathological result, we used enzyme-linked immunoassay to test IgA anti-TG2, which turned to be positive at low titre (23 U/mL, n.v. <10 U/mL). This result was associated with the positivity of IgA antiendomysial antibodies (1:80) revealed by indirect immunofluorescence. 47 48 The genetic test showed human leucocyte antigen (HLA)-DQ2 positivity. Therefore, a firm diagnosis of CD was established and the patient started a gluten-free diet (GFD). Due to rapid improvement after gluten withdrawal, a course with steroid treatment was deemed not necessary. Since diarrhoea and paraesthesia showed significant improvement with complete regression in about a week, the patient was discharged in good health.

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Representative duodenal endoscopic picture showing decreased mucosal folds carrying a scalloping profile, together with a mosaic pattern and an increased vascular network (arrow), all suggestive of villous atrophy.

Representative microphotograph of the duodenal mucosa showing villous atrophy and crypt hyperplasia with dense inflammatory infiltrate of the lamina propria (Marsh-Oberhüber lesion grade 3c). H&E staining, original magnification 200×.

Discussion and review of the literature

In the vast majority of cases, the natural history of CD is characterised by chronic evolution without acute exacerbations. Conversely, coeliac crisis is burdened by severe acute symptoms such as abdominal pain and distension, massive diarrhoea and weight loss, causing a life-threatening malabsorption syndrome. In most cases, gluten is introduced inadvertently, whereas in some patients with poor compliance to GFD a voluntary ingestion may occur. 3 6 7 Only seldom a coeliac crisis can herald the onset of CD, 10 as it was in the herein reported case. Among the reported cases described in table 1 , there was a greater prevalence of female than male gender (28 vs 20), with a mean age of 50±17 years, which is higher than the age of the present case. 9–46 Like in the present case, a higher incidence of coeliac crisis has been reported in patients carrying the HLA-DQ2 haplotype of genetic susceptibility to the disease as compared with those with HLA-DQ8, whereas the biopsy specimens showed signs characteristic of Marsh-Oberhüber 3 (from ‘a’ to ‘c’) mucosal lesions. 1 Other common clinical features included weight loss, hypoproteinaemia and electrolyte abnormalities, whereas coagulation abnormalities (ie, prothrombin time elongation) along with markedly reduced platelet count were uncommon. No clear correlation was found between the anti-TG2 IgA antibody titre and coeliac crisis onset/severity, as also supported by our case showing only a twofold increase above the upper normal limit.

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Synopsis highlighting the main features of adult cases (n=48) with coeliac crisis published so far

Among the major features of this case were the abrupt onset of symptoms, in particular of those related to electrolyte imbalance, and the severity of the clinical picture prompting admission to the emergency department. Further to severe dehydration, the patient presented with neuromuscular weakness, a finding detected in other reports, 7 9 13–21 and electrocardiographic abnormalities due to the key role exerted by potassium in regulating cell excitability. Likely, hypocalcaemia and hypomagnesaemia also contributed to worsening cellular excitability. According to previous evidence, 6 9–13 hypoproteinaemia with hypalbuminaemia and metabolic acidosis were found in our patient as hallmarks of malabsorption, whereas paraesthesia was likely related to electrolyte imbalance. However, the variety of possible clinical pictures in coeliac crisis should be underlined, ranging from central nervous system involvement with tetraplegia/paraplegia and ataxia, 17–19 psychosis 22 as well as seizures, 23 24 to coagulopathy 11 25–27 and acute kidney injury. 28 29 In all cases described so far, coeliac crisis required urgent hospitalisation. The milestone treatment is fluid resuscitation with correction of the electrolyte imbalance, which can lead to life-threatening cardiac arrhythmias. Nutritional support is also of paramount importance, and clinicians should take coeliac crisis in mind during differential diagnosis of severe acute diarrhoea with weight loss, as patients’ prognosis can dramatically improve with a simple dietary intervention.

In our case, like in almost all cases described, GFD led to a dramatic improvement in clinical picture. Nutritional management should take into consideration the possible occurrence of a refeeding syndrome, which can be fatal if not recognised and treated properly, as described in one patient with coeliac crisis. 39 In less than 20% of cases (8 of 48 cases, 16%), corticosteroids were administered during management. 49 However, we decided not to use steroids since their usefulness was recently questioned. 38 50 It was reported previously that immunosuppression with corticosteroids and azathioprine for autoimmune hepatitis or prednisone for Bell’s palsy did not prevent the occurrence of coeliac crisis in patients. 17 51 Moreover, steroid therapy may increase electrolyte depletion, facilitating the occurrence of refeeding syndrome. 22 Finally, despite the acute onset of malabsorption syndrome in adulthood, our case did not show features of complicated CD 52 53 (ie, refractory CD), and the clinical picture dramatically improved in a few days with GFD, still the only effective treatment available. 54

The present case highlights the possibility that CD may manifest quite abruptly with a severe malabsorption syndrome and related electrolyte abnormalities and hypoproteinaemia. This would imply that even a typically chronic disorder, such as CD, may have an acute onset in a small proportion of patients, which emergency physicians should be aware of. Although rarely encountered in clinical practice, this acute onset of CD requires hospitalisation and immediate treatment (ie, electrolyte replacement and protein correction) in order to avoid life-threatening complications.

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Contributors MG, RDG and GC: design and conceptualisation. MG, EG and FA reviewed the literature and wrote the first draft of the manuscript. AS, RC, LL, GZ, UV, RDG and GC participated in the clinical assessment of the patient and critically reviewed the paper.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent for publication Obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

Data availability statement Data sharing not applicable as no data sets generated and/or analysed for this study.

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Coeliac disease — a case study

With the advent of more sensitive testing, it is estimated that the prevalence of coeliac disease has risen to as many as one in 300. Pharmacists need to have an appreciation of the difficulties faced by patients with coeliac disease and be able to offer good practical advice

The Pharmaceutical Journal  Vol 268 No 7182 p99-100 26 January 2002

Alison is a 32-year old woman who has a history of bowel frequency with occasional bouts of constipation going back over 15 years. About 12 months ago, she was diagnosed by her doctor as having irritable bowel syndrome (IBS) for which she has occasionally tried mebeverine tablets with little beneficial effect. Today she comes to the pharmacy and asks for a medicine for diarrhoea. On questioning, Alison says she had a meal in an Italian restaurant yesterday evening after which she began to suffer what she felt to be the worst bout of diarrhoea and abdominal pains she had experienced for several years. She then admits that her bowels do seem to have been more troublesome than normal recently, and she is beginning to feel very miserable.

How would you advise Alison?

The history here is not straightforward. Although the symptoms Alison describes could be indicative of IBS, other possibilities should be considered. Alison should therefore be referred to her general practitioner.

About a week later Alison returns to your pharmacy with a prescription for erythromycin for her four-year-old son. At the same time she tells you that her GP has referred her to a gastroenterologist for tests for coeliac disease.

What is coeliac disease.

Coeliac disease is a condition where there is a permanent intolerance to gluten. This results in stunting and disorganisation of the intestinal villi, with lymphocytic infiltration of the epithelial surface and malabsorption of nutrients.

What is gluten?

Gluten has been defined as the viscoelastic mass which remains when a wheat flour dough is washed exhaustively in tap water. 1 The term has now been extended to include all those proteins which are harmful to individuals with gluten sensitivity, ie, the storage proteins of wheat, rye, barley and, possibly, oats (the role of oats in this regard is now much in doubt). Within wheat gluten, it is the gliadin (a simple protein seperable from wheat gluten) fraction that is known to trigger disease in susceptible individuals.

How does gluten exert its harmful effects?

Several hypotheses have been developed as to the aetiology of coeliac disease. Initially, it was thought that incomplete brush border hydrolysis of gluten occurred as a result of a deficiency of mucosal peptidase or carbohydrase, leading to the formation of toxic products. However, inability to show low activity of such enzymes following treatment with a gluten-free diet rendered this idea untenable. There is now growing acceptance that the immune system is involved. Ingestion of gluten activates T-cells in the small intestine, which results in release of inflammatory mediators. This causes damage to the absorptive surface of the small bowel and malabsorption of nutrients.

Alison asks you what the tests for coeliac disease will involve and having read something about the condition, she wonders whether she should try a gluten-free diet straight away.

How do you respond how is coeliac disease diagnosed.

Biopsy of the small intestine is the gold standard for diagnosis of coeliac disease. There must be defined histological abnormalities (eg, villous atrophy) of the small intestinal mucosa in a patient eating a gluten-containing diet, which — and this is vital — revert to normal when gluten is removed from the diet. Conditions other than coeliac disease may also cause destruction of the villi; these include cows’ milk protein intolerance, soya protein intolerance, gastroenteritis in children, infections (eg, giardia and HIV), Zollinger-Ellison syndrome (a syndrome caused by non beta-cell tumour of pancreatic islets) and tropical sprue (inflammation of the mucous membrane of the alimentary tract characterised by diarrhoea and stomatitis). This means that the appearance of biopsy specimens is non-specific, and definitive diagnosis requires repeat biopsy to demonstrate histological improvement on a gluten-free diet. Thus, if Alison embarks on a gluten-free diet before the biopsy, she will risk either misdiagnosis or having to go through a much lengthier diagnostic process. Indeed, if there is any doubt whether the patient has coeliac disease, he or she should be rechallenged with gluten. A return of the mucosal abnormalities will then confirm the diagnosis.

Some patients have milder lesions, and in some cases microvillous architecture is normal. However, the epithelium may contain an increased number of lymphocytes, and the diagnosis may therefore rely on a raised intra-epithelial lymphocyte count, which must, of course, be shown to be gluten-dependent.

The growing recognition that coeliac disease involves the immune system has led to the identification of a variety of antibodies to both dietary and endogenous antigens in patients with untreated coeliac disease. These include both IgA and IgG anti-gliadin antibodies and also IgA anti-endomysium (connective tissue surrounding intestinal smooth muscle) antibodies. This in turn has led to the development of a variety of serological tests.

However, although these tests can be useful for population screening, they currently lack sufficient sensitivity and specificity for diagnosis. Patients with conditions other than coeliac disease, such as Crohn’s disease, also have raised serum anti-gliadin antibodies, although measurement of anti-endomysium antibodies is more specific. Within the endomysial tissue, it is now recognised that the target antigen is the enzyme known as tissue transglutaminase (tTG), and this has allowed the development of a cheap and simple enzyme-linked immunosorbant assay (ELISA) for IgA-tTG, 2 which could prove invaluable for screening in GP surgeries.

A few weeks later you see Alison in the queue at the local post office and she tells you that she has been diagnosed with coeliac disease. Clearly upset by this, she is also angry that she has suffered bowel problems for so long without receiving a proper diagnosis.

Why do you think this could have happened.

Coeliac disease may well be considerably underdiagnosed. Traditionally, the prevalence of coeliac disease in the UK was believed to be about one in 1,500. However, the advent of sensitive serological tests has encouraged more research into the condition, suggesting that the true prevalence may be higher and that about one in 300 of the general population may be gluten-sensitive. Moreover, 30 years ago, coeliac disease was almost exclusively a paediatric condition, and failure to have caught up with the fact that it is now more prevalent in adults than children may mean that a diagnosis is missed.

The presentation of the disease is highly variable and the classic symptoms of diarrhoea, weight loss and general malaise do not always occur. Some patients may be constipated and a few may be obese, while others, like Alison, may present with irritable-bowel like symptoms. Others may not present with gastrointestinal symptoms, but with depression, infertility, or fatigue and breathlessness, which in the case of coeliac disease are usually due to the anaemia resulting from poor absorption of iron and folic acid. The difficulty is, of course, that many illnesses can start in this way.

In addition, the clinical features of coeliac disease may sometimes be overshadowed by the more dramatic manifestations of diseases that are associated with it, thus delaying diagnosis. Conditions linked with coeliac disease include dermatitis herpetiformis, epil-epsy, type 1 diabetes mellitus and Down’s syndrome. The possibility that there might be a connection between coeliac disease and autism and multiple sclerosis has also attracted interest, but evidence for these associations is not conclusive.

Diagnosis may also be delayed because of clinically silent lesions. It is now thought that the clinically obvious forms of coeliac disease may actually form the tip of the iceberg, underneath which there is a large base of silent gluten sensitivity. In these cases there are no signs and symptoms although there is histological evidence of enteropathy. In addition, there is a group of patients who have positive serological tests for gluten sensitivity, but in whom a small bowel biopsy appears normal. The term “latent coeliac disease” is applied to these individuals meaning that they do not currently have symptoms while consuming a normal gluten-containing diet, but they will develop gluten-sensitive enteropathy in later life.

What is the treatment for coeliac disease? How soon can Alison expect to feel better?

Dietary avoidance of gluten is central to the management of coeliac disease and most patients notice a significant improvement in their symptoms within a few days. Mucosal improvement takes longer and full recovery of the normal appearance of the villi may take up two to three months.

Wheat, rye, barley and triticale (a hybrid of wheat and rye) are the main sources of gluten, and foodstuffs made from these cereals, including bread, biscuits, cakes and pastry should be excluded. In the UK, as in many other countries, wheat forms an important part of the diet, and cutting out bread and cereals may encourage the consumption of excessive fat. A large number of processed, gluten-free foods such as bread, pasta, cakes and biscuits are available commercially, some of which are available on prescription for those with a definite diagnosis. Some of these products are made from naturally gluten-free foods such as soya, rice and maize; others are based on wheat starch rendered gluten-free. The latter are prepared by washing flour so that the water-insoluble gluten is removed leaving the starch behind.

Can Alison eat oats?

Traditionally, oats were excluded from the diet of patients with coeliac disease, but this practice is now questioned. Oats contain less gluten than other cereals and a Finnish study showed no adverse nutritional or mucosal effects from a daily intake of 50g of oats. 3 Preliminary studies also suggest that oats are safe for children, although further confirmation is necessary. 4 Nevertheless, patients should take care to buy oats from a dedicated oats miller, as contamination with wheat during harvesting, storage and milling may occur. 1

A few weeks later Alison comes to the pharmacy for her repeat prescription for gluten-free flour. She tells you she has been doing fine until about 10 days ago when the diarrhoea returned on an almost daily basis. Clearly miserable, she says she cannot understand it because she has been sticking to her diet closely.

What could be the cause of alison’s diarrhoea.

Many manufactured foods contain gluten because cereal proteins are often used as fillers or binders, and these are a frequent cause of dietary problems. Other substances that may contain gluten include malt, malt extract, malt flavouring, beer and lager (malting enzymes do not fully break down barley gluten so gliadin-like substances may remain). In addition, malt extract is frequently used as a flavouring agent in foods such as breakfast cereals, which may be consumed by patients with coeliac disease as a convenient snack instead of bread. 1 The use of breakfast cereals should therefore be considered in any individual not responding to an apparently gluten-free diet. Patients should be wary of all processed foods unless specifically advised they are gluten-free. Coeliac UK (formerly the Coeliac Society) works with food manufacturers to produce a regularly updated list of gluten-free foods.

The advent of new technology has also increased the hazards for people with coeliac disease. For example, some manufacturers have attempted to use gluten as a coating to make apples shine, and there have been moves to replace the traditional wax coating on Edam cheese with a gluten coating. 1 There is also a biodegradable cling film based on gluten. Tablets may occasionally contain gluten. Communion wafers are another potential risk, although gluten-free wafers are available.

Why is dietary compliance so important?

Compliance with the gluten-free diet is important not only because it prevents relapse, but also because it helps to reduce the risk of more sinister complications, in particular small bowel lymphoma, to which patients with coeliac disease are at increased risk. Poor compliance may also increase the risk of osteoporosis due to reduced absorption of calcium, failure to achieve peak bone mass and increased loss of bone in later life.

It has sometimes been thought that people can grow out of coeliac disease. This idea emerged when it was noted that not all coeliac patients relapsed when gluten was added to their diets. However, with tighter diagnostic criteria it became apparent that coeliac disease which had apparently disappeared did show histological relapse when gluten was added to the diet. Today this would be known as silent coeliac disease because there are no signs and symptoms. The gluten-free diet should be followed strictly and for life and pharmacists have a vital role in encouraging compliance.

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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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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.

Avoid common mistakes on your manuscript.

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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Department of Pediatrics Gastroenterology, Hospital Virgen de las Nieves, Granada, Spain

Miguel Ángel López Casado

Department of Experimental Biology, University of Jaén, Jaén, Spain

Pedro Lorite, Candelaria Ponce de León, Teresa Palomeque & Maria Isabel Torres

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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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Received : 17 October 2017

Accepted : 06 July 2018

Published : 25 August 2018

Issue Date : December 2018

DOI : https://doi.org/10.1007/s00005-018-0520-z

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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.

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