CELIAC DISEASE – What you need to know

1. Dr Ofelia Marin PEDIATRIC GASTROENTEROLOGIST Private practice Billings Montana CELIAC DISEASE –What you need to know

2. The most under diagnosed disease in the U.S.A. Underdiagnosed by ~25%. Patients often experience symptoms for years before being diagnosed, average time to diagnosis is 8 years. Undiagnosed, untreated disease predisposes patients to osteoporosis, anemia, chronic gastrointestinal upset, developmental and learning disabilities in children, and certain forms of aggressive cancers especially lymphatic cancers. Its proper descriptive name is “gluten sensitive enteropathy” which indicates that it occurs as a consequence of ingesting grain products at contain gluten- such as wheat. Source:www.gluten.net Facts about Celiac Disease

3. YOU DO NOT OUTGROW CELIAC DISEASE YOUNG CHILDREN MAY SUFFER FOR 1/3 TO ½ OF THEIR LIVES BEFORE OBTAINING A DIAGNOSIS. MANY PATIENTS SEE PHYSICIANS AND NUMEROUS SPECIALISTS FOR SYMPTOMS AND ARE MANY TIMES MISDIAGNOSED. THEY DO NOT RESPOND TO DRUGS/THERAPIES AND AT THIS POINT THERE SHOULD BE A CONCERN FOR UNDERLYING CAUSES.

4. THEY MAY HAVE WHEAT INTOLERANCE AND IRRITABLE BOWEL MANY PEOPLE THINK HAVE CELIAC DISEASE AND MAY NOT!

5. Celiac disease multisystem disorder Primary target of injury is the small intestine triggered by gluten the main storage protein in certain grains. Gluten damages the small intestine so that it is unable to absorb nutrients properly. As food malabsorption continues and the disease progresses the manifestations become more varied and complex. Once recognized as rare diarrhea disease of children now is known predominantly as the disease of adults and the majority of people are asymptomatic or consult doctors for other complaints.

6. Pathogenesis: 1 A component of gluten, gliaden, interacts with a specific genetic form of HLA receptor on an antigen presenting cell. 2. Tissue transglutaminase converts glutamine residues to glutamic acid residues making an even more potent antigen. 3. T helper cells are activated and, in turn, activate B and killer T cells. 4. Plasma cell antibodies bind to gliadin bound to enterocytes, tissue transglutaminase and reticular fibers surrounding gut smooth muscle (endomysial ab’s). 5. T cells release (inappropriate) inflammatory cytokines as well as inflict tissue damage. Source:NEJM 346:180, 2002

7. Celiac disease progression As the disease progresses and is not diagnosed until later in adulthood many patients develop many other problems from years of inflammation and malabsorption of mineral, vitamins and other necessary nutrients. Bone loss result osteopenia, osteoporosis, anemia, malignancies small intestine, peripheral neuropathies ( tingling extremities) Hyposplenism ( underactive spleen) Liver disease

8. Unusual manifestation of celiac ds Liver disease- autoimmune hepatitis –nonspecific hepatitis, fatty liver, primary sclerosing cholangitis and primary biliary cirrhosis. CEC- celiac disease/epilepsy/ calcification of the cerebral cortex. Splenic calcification rare occur in children without cerebral cortex calcifications.

9. Biopsy of the intestine in a patient with no active disease following challenge with gluten (~ 1 week). What is particularly notable is the infiltration of the epithelium by lymphocytes (you can see the increased number of nuclei but it’s hard to determine specific cell types!) Enterocytes also show damage.

10. Normal intestinal biopsy Small intestinal biopsy in a patient with active celiac disease

11. Arrows indicate intraepithelial lymphocytes which, in this disease, are destructive. Arrowheads indicate plasma cells which are secreting ab’s against gliaden bound to enterocytes as well against reticulin and tissue transglutaminase resulting in tissue destruction. Source:NEJM

12. Biopsy from which the previous high power micrograph was taken. Villous atrophy, crypt hyperplasia (it almost looks like the colon) are evident. From what region of the small intestine was this biopsy taken? Duodenum, see Brunner’s glands? Source:NEJM

13. When the patient adheres to a strict gluten-free diet, the damaged intestinal mucosa (often but not always ) completely regenerates includingreformation of normal villi. This is a normal biopsy. series. Source:NEJM

14. Sprue Normal As the damage recedes, the ragged, lymphocyte infiltrated-enterocytes are replaced by normal columnar ones, thus assuring normal transport from the lumen into the body. Source:NEJM

15. This series takes you through active disease, repair (better cell and crypt morphology, decreased cell infiltration) and repair (reformation of villi and normal crypt:villus ratio -- difficult to see) in this micrograph. Source: Gastrointestinal Mucosal Biopsy by Harvey Goldman; Churchill Livingston

16. Study of this disease reveals that the genes that regulate the differentiation of the four main cell types found in the epithelium: 1. enterocyte, 2. goblet, 3. Paneth, and 4. enteroendocrine can restore the normal populations of these cells as the disease recedes. • Beyond that, the genes that regulated villus and crypt formation (complicated processes) during embryonic histogenesis can be reactivated in the adult to restore tissue architecture. • It’s learning how to harness these genes to restore normal tissue architecture that remains a major challenge in medicine.

17. FLAT MUCOSA SEEN IN ORDER CONDITIONS CELIAC DISEASE (OF COURSE) TEMPORARY FOOD SENSITIVITY- COW’S AND SOY MILK IN BABIES (OUTGROW BY 9 MONTHS TO 1 YEAR). GASTROENTERITIS- VIRAL. PARASITES OR BACTERIAL AUTOIMMUNE ENTEROPATHY MALNUTRITION-PROTEIN ENERGY TROPICAL SPRUE- MALABSORPTION DISEASE FOUND IN TROPICAL REGIONS- CAUSE UNKNOWN-PARASITE-VIRUS-BACTERIA-FOLIC ACID DEF-RANCID FAT TUBERCULOSIS OF SMALL INTESTINE ACQUIRED HYPOGAMMAGLOBINEMIA REINVESTIGATE IF THE DIAGNOSIS OF CELIAC DISEASE IS MADE BEFORE 1 YEAR OF AGE AND THE SEROLOGY IS NEGATIVE.

18. The role of the physician is that of diagnosis. Treatment is almost entirely dependent on the patient. Cure is almost entirely dependent on the innate ability of the body to restore normal cell populations and tissue architecture (recapitulating, to a great degree, embryonic histogenesis.) The Course of Celiac Disease

19. CELIAC DISEASE IN VARIOUS COUNTRIES CELIAC DISEASE IS HIGHEST IN THE IRISH POPULATION CELIAC DISEASE IS MORE COMMON IN MONOZYGOTIC TWINS (SHARE THE SAME PLACENTA) 86%.

20. GLOBALIZATION OF CELIAC DISEASE UNTIL RECENTLY GEOGRAPHIC DISTRIBUTION WAS RESTRICTED Mostly developed countries USA-CANADA-AUSTRALIA. It is also common in the Asian continent due to urbanization and increased wheat consumption (not just rice) It is more common in Northern India due to higher wheat consumption compared to Southern India.

21. FACTS AND STATISTICS: 1 out of every 133 Americans (about 3 million people) has CD. ( 1% OF POPULATION OF THE US) 97% of Americans estimated to have CD are not diagnosed. CD has over 300 known symptoms although some people experience none. Age of diagnosis is key: If you are diagnosed between age 2-4, your chance of getting an additional autoimmune disorder is 10.5%. Over the age of 20, that rockets up to 34%. 30% of the US population is estimated to have the genes necessary for CD. 2.5 babies are born every minute in the USA with the genetic makeup to have CD. There are 15 states in the US with populations less than the total number of Celiacs in the US. CD affects more people in the US than Crohn’s Disease, Cystic Fibrosis, Multiple Sclerosis and Parkinson’s disease combined. People with CD dine out 80% less than they used to before diagnosis and believe less than 10% of eating establishments have a ‘very good’ or ‘good’ understanding of GF diets. It takes an average of 11 years for patients to be properly diagnosed with CD even though a simple blood test exists.

22. The US Department of Agriculture projects that the GF industries revenues will reach $1.7 Billion by 2010. GF foods are, on average, 242% more expensive then their non-GF counterparts. The Food Allergen Labeling & Consumer Protection Act became law in 2006 allowing for easier reading of food labels for those with CD. What took so long? 12% of people in the US who have Down Syndrome also have CD. 6% of people in the US who have Type 1 Diabetes also have CD. Among people who have a first-degree relative diagnosed with Celiac, as many as 1 in 22 people may have the disease. There are currently 0 drugs available to treat CD.

23. CLINICAL EXPRESSION VARIES OCCASIONAL PATIENTS DEVELOP CELIAC DISEASE LATER IN TIME DESPITE A PREVIOULY NORMAL SMALL INTESTINAL BIOPSY. CLINICAL EXPRESSION VARIES IN DIFFERENT AGES OF LIFE- MOST SEVERE BEING IN CHILDHOOD 1-5 YEARS OF AGE- LESS SEVERE IN ADOLESCENTS AND MORE SEVERE AGAIN IN ADULT LIFE

24. PRESENT VARIOUS WAYS CLASSICAL PRESENTATION IN INFANCY- 9 TO 18 MONTHS ABDOMINAL DISTENTION – FTT- FREQUENT STOOLS – IRRITABLE LESS THAN 9 MONTHS OF AGE- SEVERE DIARRHEA ( NO INFECTION)-ABDOMINAL DISTENTION NOT USUALLY NOTED OLDER KIDS –SHORT- ANEMIA DON’T RESOLVE ON IRON TX-RICKETS-OSTEOPOROSIS-PERSONALITY ISSURES-DELAYED PUBERTY ADULTS- INFERTILITY ( SHOULD BE PART OF THE WORKUP)

25. Nerological problems associated with celiac disease Unexplained neurological problems Screen for celiac disease Ataxia,dementia, seizures and neuropathies.

26. Autoimmune disease and celiac autoimmune disease affects 3 % of celiac Celiac disease patients have autoimmune disease 30% of the time Thyroid, sjogren, Addison, autoimmune liver disease, biliary cirrhosis, cardiac ds, alopecia 2%, Rheumatoid arthritis 1 % Thyroid disease- hypo/hyper-Grave’s/Hashimoto Dental enamel problems- mouth ulcers Raynaud’s cold hands/feet constricted blood vessels.

27. Overweight patients misdiagnosed Few celiac patients are underweight at diagnosis and a large minority is overweight; these are less likely to present with classical features of diarrhea and reduced hemoglobin. Failed or delayed diagnosis of celiac disease may reflect lack of awareness of this large subgroup. The increase in weight of already overweight patients after dietary gluten exclusion is a potential cause of morbidity, and the gluten-free diet as conventionally prescribed needs to be modified accordingly.

28. Overweight diagnosis challenge University of Tampere, and the Department of Gastroenterology and Alimentary Tract Surgery at Tampere University Hospital, both in Tampere, Finland. To assess weight and disease-related issues, the researchers looked at 698 newly detected adults who were diagnosed with celiac disease by classical or extra-intestinal symptoms or by screening. The researchers measured BMI upon celiac diagnosis and after one year on a gluten-free diet. They then compared the results against data for the general population. Study data showed that 4% of patients were underweight at celiac diagnosis, 57% were normal weight, 28% were overweight and 11% were obese.

29. Gluten-free diet can pile on pounds One of the most asked questions when it comes to Celiac Disease is, can gluten intolerance cause weight gain? The truth is, yes. Many people believe that because you are not eating foods such as bread, pasta and full fat milk that your weight will drop dramatically, but for some this is not the case. Many time being gluten intolerant does not mean instant weight loss. Extra sugar is often added to increase the tasteL. People gain weight on gluten-free diet everyone's body is different, its impossible for me to give you a proper diagnosis for your possible weight gain. One of the mains reasons however, is the deficiency of minerals and vitamins which you used to eat in foods that contained gluten. This problem is easily rectified, with eating extra foods which contain these vital nutrients your body needs to work. Vitamin and mineral supplements are also another way of getting these into your body. . You must first check with your local doctor before starting any course of supplements. Nutrient loss is usually the main cause of weight gain among Gluten Intolerance sufferers, but also other reasons such as diet . fat. Now that you know a couple of reasons for possible weight gain, you can now start to look at which foods you are eating may be making you pile on the pounds. . You probably bought these without looking at their fat content values, and this is understandable. I know full well how not being able to eat certain foods can become difficult.

30. MODE OF PRESENTATION VARIABLE MOST COMMON PRESENTATION IS DIARRHEA-FEW HAVE CONSTIPATION ABDOMINAL PAIN-MISDIAGNOSED AS IRRITABLE BOWEL FTT-WEIGHT LOSS-VOMITING-PROTUBERANT ABDOMEN –MUSCLE WASTING-WEAK MUSCLES-fibromyalgia-chronic fatigue. - SKIN PROBLEMS-(eczema, contact dermatitis. ANOREXIA OR INCREASED APPETITE. EDEMA FROM PROTEIN MALABSORPTION-DECREASED PROTEIN ( IMPROVED ON GLUTEN-FREE DIET. EMOTIONAL PROBLEMS-WITHDRAWN-IRRITABLE-CLINGY-DEPRESSED-ANXIOUS-FORGETFULL ( FROM DEFICIENCY OF FOLIC ACID) LIVER PROBLEMS-CHRONIC LIVER DISEASE SPLEEN PROBLEMS-HYPOSPLEENISM PULMONARY PROBLEMS-FREQUENT PULMONARY INFECTION-(THOUGHT TO BE CYSTIC FIBROSIS AT TIMES). ABNORMAL PROTHROMBIN TIME ( DUE TO MALABSORPTION OF VITAMIN k) OSTEOPOROSIS – OSTEOPENIA AUTOIMMUNE DISORDERS-THYROID ( HYPO/HYPER)-DIABETES-Sjogren’s syndrome.

31. Sjogren’s syndrome Sjpgren’s syndrome is an autoimmune disorder associated with dryness (sicca syndrome) immune system attacks the exocrine glands and destroys them. 4 million people in the US have it and 9 out of 10 are women-women mostly get after menopause. (but can occur at any age) Causes arthritis. dryness of mouth, skin, nose and vagina Also affects pancreas, kidneys, lungs, liver, nervous system and brain.

32. DERMATITIS HERPETIFORMIS Characteristic rash Dermatitis herpetiformis is characterized by papulovesicular eruptions, usually distributed symmetrically on extensor surfaces (buttocks, back of neck, scalp, elbows, knees, back, hairline, groin, or face). The blisters vary in size from very small up to 1 cm across. The condition is extremely itchy, and the desire to scratch can be overwhelming. This sometimes causes the sufferer to scratch the blisters off before they are examined by a physician.8 Intense itching or burning sensations are sometimes felt before the blisters appear in a particular area. Untreated, the severity of DH can vary significantly over time, in response to the amount of gluten ingested. Dermatitis herpetiformis symptoms typically first appear in the early years of adulthood between 20 and 30 years of age. The rash rarely occurs on other mucous membranes, excepting the mouth or lips. The symptoms range in severity from mild to serious, but they are likely to disappear if gluten ingestion is avoided and appropriate treatment is administered. Dermatitis herpetiformis symptoms are chronic, and they tend to come and go, mostly in short periods of time. Sometimes, these symptoms may be accompanied by symptoms of celiac disease, commonly including abdominal pain, bloating or loose stool, and fatigue. TREATED BY DERMATOLOGIST WITH MEDICATION DAPSONE TILL GLUTEN FREE DIET USED.

33. DERMATITIS HERPETIFORMIS 10 % OF THE PEOPLE WITH CELIAC DISEASE HAVE DH. Male to female ratio 2:1 20% of the people with DH have normal intestinal biopsies. 30 % of the people with DH don’t have anti tissue transglutaminase and endomyseal antibody. Gluten in the skin produces IgA AB which bind to the skin. It takes 2 years on gluten free diet to get rid of the IgA skin deposits.

34. Dermatitis herpetiformis DH IS CELIAC DISEASE SMALL BOWEL BIOSPY MAY NOT BE NEEDED. DAPSONE- blocks the inflammatory in the skin and suppresses the itching ( also used to treat leprosy)

35. Other findings in celiac diseaseBRUISING Malabsorption of vit K- bleed/bruise ITP- idiopathic thrombocytopenic purpura due to autoimmune reaction to platelets Scurvy- decreased Vit C- fragille capillaries bruising.

36. CANCER IN CELIAC DISEASE 33X GREATER RISK OF INTESTINAL ADENOCARCINOMA 12 X GREATER CHANCE OF ESOPHAGEAL CANCER 9X GREATER FOR NON-HODKIN’S LYMPHOMA 5X GREATER FOR MELANOMA 23X GREATER FOR PAPILLARY THYROID CANCER

37. CELIAC DISEASE TREATMENT THE ONLY TREATMENT IS GLUTEN FREE DIET AT THIS TIME: Celiac disease patients vary in their tolerance– some patients a small amount without developing symptoms while others experience diarrhea with only minute amounts of gluten.

38. Treatment There is only one treatment, strict adherence to a gluten-free diet. Gluten-free foods are limited, and frequently unavailable. Gluten-free foods cost 2-3X that of normal foods. Unfortunately, purchase of gluten-free products is rarely covered by health insurance. The good news is that strict adherence to a gluten-free diet can have an extraordinary outcome as seen on the next slide. Source:www.glutin.net

39. TREATMENT MAY TAKE TIME IT MAY TAKE 2 TO 6 MONTHS BEFORE CLINICAL RESPONSE IS SEEN CATCH UP GROWTH OCCURS 2ND YEAR OF TREATMENT MANY HAVE DISACHARIDASE (SUGAR) DEFICIENCIES AT THE TIME OF DIAGNOSIS ESPECIALLY LACTOSE AND COW’S MILK ALSO BECAUSE OF THE PROTEIN TO COW’S MILK –MANY TIMES TEMPORARY GLUTEN IS LIFE LONG RESTRICTION

40. GLUTEN FREE-DIET INCLUDES Avoid all foods made from wheat, barley and rye Including breads, cereal, pasta, crackers, cakes, pies and gravies. Avoid oat unless states in pack as gluten free- use the same processing and can be contaminated.

41. PROCESSED FOODS MAY CONTAIN GLUTEN: CANNED SOUPS ( PROGRESSO HAS GLUTEN FREE SOUPS) SALAD DRESSINGS ICE CREAM CANDY BARS ( RICE BARS USUALLY OK) INSTANT COFFEE LUNCH MEAT-MUSTARD-KETCHUP YOGURT ( YOPLAIT GREEK OK)

42. OTHER GLUTEN PRODUCTS: TABLETS, CAPSULES VITAMINS- WHEAT STARCH IS A COMMON BINDER. AVOID BEER EXCEPT –REDBRIDGE- BRUNEHAUT HAUT AMBREE-NEW PLANET TREAD LIGHTLY AND OTHERS GLUTEN-FREE AVOID COW’S MILK OTHER DAIRY CONTAIN LACTOSE- UNTREATED CELIACS OFTEN LACTOSE INTOLERANTS- INTRODUCE LATER IF NO SIGNS OF LACTOSE INTOLERANCE

43. OTHER CONCERNS: Utensil contaminated-kitchen area- need new toaster READ FOOD LABELS THEY CAN CHANGE. CELIACS CAN HAVE MALABSORPTION AND DEVELOP VITAMIN AND MINERAL DEFICIENCIES- CAN TAKE MULTVIT DAILY WITH MINERAL- MANY VITAMINS DO NO HAVE MINERALS. OSTEOPOROSIS LOW CALCIUM TREAT WITH CALCIUM- VIT D AND OTHER TREATMENTS AVAILABLE SUCH AS AVISTA EXERCISE CAN HELP PREVENT OSTEOPOROSIS.

44. RESEARCH UNDER WAY POSSIBLE TREATMENT BLOCKING AN INFLAMMATORY PROTEIN CALLED INTERLEUKIN-15 ( IL-15) MAY HELP THE SYMPTOMS OF CELIAC DISEASE AND PREVENT THE DEVELOPMENT OF CELIAC DISEASE IN CERTAIN AT-RISK PEOPLE. RESEARCHERS BLOCKED IL-15 IN MICE GENETICALLY ALTERED TO HAVE CELIAC DISEASE AND FOUND THAT THE DISEASE SYMPTOMS WERE REVERSED, AND THE MICE WERE AGAIN ABLE TO EAT GLUTEN.

45. IL-15 RESEARCH MEDICATIONS THAT BLOCK IL-15 ARE BEING DEVELOPED FOR OTHER INFLAMMATORY DISEASES INCLUDING RA. Dr. BANA JABRI co-director of DIGESTIVE ds RESEARCH CORE CENTER UNIV OF CHICAGO- STATED IL-15 MAY BE CRITICAL ELEMENT THAT DRIVES THE TOLERANCE TO GLUTEN AND THAT PATHWAYS CAN BE BLOCKED TO POTENTIALLY DEVELOP THERAPIES FOR CELIAC DISEASE.

46. IL-15 is cytokine in the intestines CYTOKINES ARE PROTEIN MESSANGERS IN THE BODY They are the “bouncers”- help the body respond to stress, infections, noxious agents inflammation= villous atrophy

47. REASONS TO PURSUE TESTING FOR CELIAC DISEASE You may have one (or more) different reasons to pursue testing for celiac disease. Perhaps you suffer from celiac disease symptoms, which can range from diarrhea and weight loss to neurological problems and weight gain. You may have a close family member who was diagnosed with celiac disease, and have learned that guidelines recommend celiac disease testing for relatives, since the condition is genetic in nature. Or, you may suffer from one or more related autoimmune conditions, such as Sjögren's syndrome or psoriasis. Studies have shown that celiac disease is more common in people with these conditions. Regardless of your reasons for wanting to pursue a celiac disease diagnosis, testing for celiac disease is a fairly lengthy process involving blood tests and, ultimately, a procedure known as an endoscopy, used to look directly at your small intestine. In the best-case scenario, you'll have your answer within a few days or a week, but the diagnostic process can take much longer in some areas, especially where gastroenterologists (specialists in the digestive system) are in short supply. Celiac Disease Tests Celiac disease tests look for your body's reaction to gluten, a protein found in the grains wheat, barley and rye. In people with the condition, eating foods with gluten (which occurs at almost every meal on a standard gluten-containing diet) causes what's called an autoimmune reaction, in which your body's disease-fighting white blood cells mistakenly attack some of your own tissue. Different autoimmune diseases cause different types of damage in the body. In the case of celiac disease, the white blood cells attack the lining of your small intestine, causing what's known as villous atrophy. Ultimately, this can destroy the lining of your intestine, meaning you're unable to absorb nutrients from your food.

48. TESTING WHILE ON GLUTEN-FREE DIET Celiacdisease is diagnosed through blood test, ... If you are following a gluten free diet before testing, it may alter your test results and make them inaccurate. The only test that are accurate are genetic test while on gluten-free diet. Biopsies will be normal if on strict gluten-free diet. You have to be consuming gluten for at least 2 months for testing to be done.

49. STOOL TESTING FOR CELIAC DISEASE ENTEROLAB, A LABORATORY IN DALLAS TESTS FOR GLUTEN SENSITIVITY BY LOOKING FOR GLUTEN ANTIBODIES IN THE STOOL. ALTHOUGH THESE TESTS HAVE NOT YET BEEN VALIDATED BY OUTSIDE LABORATORIES OR THROUGH PEER REVIEWED RESEARCH. THESE TESTS ARE NOT USED BY PHYSICIANS TO DIAGNOSE CELIAC DISEASE.

50. TESTING FOR CELIAC DISEAE There are five blood tests commonly used to detect celiac disease, and they're usually used together, since no one test provides all the answers. If your body is undergoing an autoimmune reaction to gluten, one or more of these blood tests most likely will come up positive, indicating the need for further testing to see if you truly have celiac disease. However, it is possible for you to have negative blood test results and to still have celiac disease. Some people have too little of a particular antibody (a condition called IgA deficiency- 10 % OF POPULATIN), and require different blood tests to screen for celiac disease. In a few other cases, the blood test results simply don't reflect the amount of intestinal damage present. Therefore, if your blood tests are negative but your symptoms and family medical history still indicate a strong possibility of celiac disease, you should talk to your physician about further testing.