Celiac Disease 2024-2025 PDF

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024-2025 Digestive System Diseases CELIAC DIS...

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024-2025 Digestive System Diseases CELIAC DISEASE Monia Baldoni  CELIAC DISEASE  Chronic autoimmune disease of the small intestine triggered by the ingestion of gluten in genetically susceptible persons Causes chronic intestinal inflammation Impairs absorption of nutrients Contributes to systemic complications  CELIAC DISEASE Celiac Disease (CD) is an immune-mediated disorder that involves the small intestine, triggered by dietary gluten in genetically susceptible individuals, resulting from an aberrant interplay between environmental and genetic factors. The major component of the genetic predisposition, explaining about 40% of it, is the MHC class II association which depends on some HLA-related class II genes: the majority of CD patients are HLA-DQ2 positive (90%), while the remaining 10% are HLA- DQ8 positive. Environmental factors: ingestion of gliadin and glutenin, which are specific fractions of wheat - the so-called gluten - and similar alcohol-soluble proteins in other grains (rye, barley, spelt, and Kamut), trigger the development of the celiac enteropathy Why speak about Celiac Disease ?  CELIAC DISEASE Serological screening studies showed that CD is one the most common lifelong disorders, affecting around 1% of the population worldwide. CD is a common disorder in both north-western and south-eastern Europe and North and South America despite some inter-country variability. Despite its negative effects on human health, the CD phenotype has not disappeared over time, but is even increasing nowadays in areas with high level of both gluten consumption and CD-predisposing HLA-genotypes Geo-epidemiology of CD  Geo-epidemiology of CD Overall, the worldwide prevalence of CD among low-risk (general population) adults and children ranged from 0 to 5.6%, with a mean prevalence ratio of 1% In Europe, the overall prevalence of CD was 1%, with large variations between countries. Similar rates have been reported from the US population (0.9%), from many South American countries, and from developed countries mostly populated by individuals of European origin, e.g., Australia (0.4%) and New Zealand.  Geo-epidemiology of CD In areas of the developing world, rates overlapping European figures, especially in North Africa (i.e., 0.5% in Egypt, 0.8% in Libya, and 0.6% in Tunisia), Middle East (i.e., 0.8% in Iran and 1% in Turkey), and India (i.e., 0.4%), were found. The Saharawi population of Arab-Berber origin living in Algeria had the highest prevalence of CD (5.6%) among all world populations. In Burkina Faso, wheat consumption is almost negligible, and the prevalence of CD was null. No CD prevalence studies were found in China or other Far Eastern countries. Geographical distribution of wheat consumption expressed as g per capita/day Geographical distribution of HLA-DQ2 prevalence  Prevalence of CD Despite the advances in diagnosis, the overall prevalence of this disease remains still unclear. A variable frequency has been reported between European countries, although it is still uncertain whether it depends on the different screening tools, sample size, or a real variability of celiac disease prevalence. What is known is that many cases remain undiagnosed, as idealized with the “iceberg model” Typical cases of celiac disease are diagnosed because of suggestive symptoms. The submerged part of the iceberg represents all the undiagnosed cases that usually show atypical, minimal, or even absent symptoms  The celiac iceberg About 50% patients without diagnosis 1.000 Euro: case-finding cost 9.000 Euro: cost for each missed diagnosis 2007 Clinical presentation of celiac disease: yesterday ….. Almost exclusively a paediatric disease Gastrointestinal symptoms Few tests with poor sensitivity and specificity Diagnosis mainly obtained through the clinical signs London, 1938 …. and nowadays !! More adults than children Few symptoms or totally absent Prevalence of extraintestinal manifestations Availability of sensitive and specific diagnostic tests Predominantly serological diagnosis  CELIAC DISEASE The human gut had developed, over more than 2 million years, into a sophisticated organ that could tolerate food antigens that were staples of the human diet over hundreds of thousands of years Introduced 10,000 years ago during the transition from a nomadic lifestyle to agricultural settlements, gluten-containing grains are a recent addition to the human diet. The agricultural revolution of the Neolithic period generated a whole battery of food antigens previously unknown to man, including protein from cow, goat, and donkey milk, as well as birds’ eggs and cereals. Most individuals were able to adapt. Among those who could not, food intolerances appeared, and celiac disease was born. Gluten is one of the few digestion-resistant proteins consumed chronically in significant quantities and is constituted by several non-digestible immunogenic peptides.  CELIAC DISEASE Celiac disease was identified and named only 8,000 years after its onset. A clever Greek physician named Aretaeus of Cappadocia, living in the first century AD, wrote about “The Coeliac Affection.” In fact, he named it κοιλιακός “koiliakos” derived from the Greek word “koelia”, meaning abdomen. His description: “If the stomach be irretentive of the food and if it pass through undigested and crude, and nothing ascends into the body, we call such persons coeliacs”  CELIAC DISEASE In the early 19th century, Dr. Mathew Baillie, probably unaware of Aretaeus, published his observations on a chronic diarrheal disorder of adults causing malnutrition and characterized by a gas-distended abdomen. He even went on to suggest dietetic treatment, writing: “ Some patients have appeared to derive considerable advantage from living almost entirely upon rice.” Baillie’s observations, however, went practically unnoticed, and it was for the English Doctor Samuel Gee, a leading authority in pediatric diseases, to take full credit for the modern description of celiac disease some 75 years later, when he gave a lecture to medical students on the “celiac affection,” the milestone description of this disorder in modern times. “If the patient can be cured at all, it must be by means of the diet” CELIAC DISEASE Samuel Gee, 1888  CELIAC DISEASE In the 1920s a new dietetic treatment erupted on the scene and for decades established itself as the cornerstone of therapy: the banana diet. In 1924 Sidney Haas described his successful treatment of eight children whom he had diagnosed with celiac disease. Based on his previous success in treating a case of anorexia with a banana diet, he elected to try to experiment with the same diet in these eight children who were also anorexic. He published ten cases, eight of them treated (“clinically cured”) with the banana diet, whilst the two untreated died. This paper encountered enormous success and for decades the banana diet enjoyed wide popularity. Indeed, it benefited many celiac children and probably prevented many deaths. The diet specifically excluded bread, cookies, potatoes, and all cereals, and it’s easy to argue that its success was based on the elimination of gluten-containing grains.  CELIAC DISEASE In the early 40s Willem Karel Dicke had noticed that during bread shortages in the Netherlands caused by World War II, children with celiac disease improved. He also saw that when Allied planes dropped bread into the Netherlands, they quickly deteriorated. At the International Congress of Pediatrics (New York, 1947) Dicke submitted comments about the bread or cookies aggravating celiac disease, but he was not taken seriously. With the help of colleagues from Utrecht, a pediatrician and a biochemist who developed the fecal fat quantification technique, Dicke was able to show that the removal of wheat from the diet of celiac patients reduced fecal fat, while its reintroduction increased steatorrhea. A few years later, working with others, he produced a series of seminar papers, documenting for the first time the role that gluten from wheat and rye plays in celiac disease. These findings were presented at the International Congress of the International Pediatric Association (IPA) (Zurich, 1950) CELIAC DISEASE  CELIAC DISEASE The introduction of intestinal biopsy was instrumental in confirming the diagnosis of celiac disease, it highlighted the characteristic flattening of the mucosa when exposed to gluten. This finding was defined by Paulley in 1954, using laparotomy-obtained samples from adult individuals affected by idiopathic steatorrhea. The difficulty in obtaining samples able to yield data suggested the need for a viable method to obtain intestinal biopsies from these patients. The next breakthrough came in the mid-50s when the gastroenterologist Margot Shiner described a new peroral jejunal biopsy apparatus with which she successfully reached and biopsied the distal duodenum.  CELIAC DISEASE At the dawn 60’s we had three important elements: the knowledge that gluten is the triggering agent for celiac disease; the notion that there was a remarkable and easily identifiable mucosal lesion; and finally, the availability of an instrument to obtain biopsies and begin to unravel the mystery of celiac disease pathogenesis  CELIAC DISEASE During the 1980’s it became increasingly clear that CD could be associated with other conditions, mostly autoimmune disorders such as type 1 diabetes, but also some syndromes such as Down. It was also apparent that CD was changing patterns of presentation, becoming less an intestinal disorder, and more a variety of extra-intestinal symptoms and signs. After 1990, CD was increasingly accepted as an example of an autoimmune disease, associated with a specific gene (either HLA- DQ2 or DQ8) and the missing autoantigen was finally identified in the enzyme “tissue transglutaminase” (1997). At long last, there was universal acceptance that celiac disease is an autoimmune condition whose trigger (gluten) and autoantigen (tissue transglutaminase) are known.  CELIAC DISEASE Aetiology Presence of a protein in the diet: GLUTEN, which is the exogenous or environmental factor spiga  CELIAC DISEASE The Gluten is a protein component of wheat flour, barley, oats and rye. The most harmful component of these cereals is linked to the alcohol-soluble fractions (rich in prolamins) of the proteins: Gliadin (wheat) Hordein (barley) Secalin (rye) frumento orzo Avenin (oats) ???? (discordant results, usually tolerated up to 40-60 gr/day)  Cereals Cereals are the most important crops in the world. Basic food in European countries. Total annual grain yields exceed 2000 million tons Most economically important cereal crops are: Maize, Wheat, Rice Together they account for over 70% of the total cereal production.  Wheat Wheat is a type of grass. Wheat is a grass and belongs to the genus Triticum species aestivum. Wheat is grown globally and is the second most important cereal crop in the world behind maize and ahead of rice  Wheat The grain is inside the ears. The grain is the part of this cereal that we use to make food. Ears of wheat. Grain The chaff is what is left when the grain has been separated from the ear.  Protein content of cereals Protein content varies from 6 to 14% depending on cultivar. Wheat – 12-14% Some varieties rye and barley – up to 20% Amino acid profile of cereal proteins In all cereals lysine is deficient: First limiting essential amino acid, Amino acid score (AAS) – 40 to 50% Wheat – threonine deficiency Maize – tryptophan deficiency Rye, barley and rice – the most balanced amino acid composition  Wheat proteins Proteins are the principal factors of wheat quality for bread making. Bread-making quality depends on the quantity and quality of wheat proteins.  Wheat proteins albumins CITOPLASMATIC PROTEINS globulins Protolithic enzymes RESERVE HMW e LMW-glutenins PROTEINS Gliadins Gluten Leavened products Excellent bread-making properties  Albumin and globulin The amount of albumin and globulin fractions does not depend on climate conditions. It is a variety dependent feature. Albumins and globulins are considered to have nutritionally better amino acid compositions because of their higher lysine and methionine contents as compared to the rest of the proteins in the wheat grain. Serve as nutrient reserves for the germinating embryo. Do not have any impact on bread-making properties of wheat proteins. Gliadins and Glutenins are gluten proteins Wash out starch granules Dough Gluten: The rubbery mass that is left when wheat flour is washed with water to remove starch, non-starchy polysaccharides, and Gluten water-soluble constituents. Mix with alcohol/water Insoluble Soluble Gliadin and Glutenin are two fractions of Gluten Glutenin Gliadin Gluten proteins Unbalanced amino acid composition Good technological functionality  Gliadins: characteristics Constitute 30 to 40% of total flour protein content. Monomeric proteins that consist of a single polypeptide chain. Gliadins are polymorphic mixture of proteins soluble in 70% alcohol. Rich in proline and glutamine. Overall low level of charged amino acids.  Gliadins: classification Divided into four groups based on their molecular mobility in polyacrylamide gel electrophoresis: α, β, γ and ω α, β, and γ gliadins contain intra-chain disulfide bonds. A major component of gliadins. ω-gliadins lack cysteine residues and do not form disulfide bonds. A minor component of gliadins. Gliadins may associate with one another or with glutenins through hydrophobic interactions and hydrogen bonds. They contribute mainly to the viscosity of the dough system.  Glutenins: characteristics Glutenin is a highly heterogeneous mixture of polymers consisting of several different high- (HMW) and low-molecular-weight (LMW) glutenin subunits linked by disulfide bonds. Extractable in dilute acetic acid. Glutenins have high levels of glutamine and proline and low levels of charged amino acids (like gliadins). Glutenins can form the largest and most complex protein polymers in nature with molecular weights of more than 10 million.  Glutenins: characteristics Variations in both quantity and quality of glutenin strongly determine variations in bread- making performance. Largely responsible for gluten elasticity. HMW-glutenins constitute no more than 10% of total flour protein; But they are the most important determinants of bread-making quality.  Varieties of gliadin and glutenin cross-link together through disulfide, ionic, and hydrogen bonds to form gluten. http://2.bp.blogspot.com/-f_GiDPfFLmk/U5DaNwkvUjI/AAAAAAAAAEM/DutGtjgED6Y/s1600/gluten.jpg A model of the molecular structure of gluten. Linear polymers are developed by HMW glutenin subunits. Other polymers are developed by spheres.  Gluten: characteristics Gluten is comprised of 80–85% protein and 5% lipids. Quantity, composition (quality), type and viscoelastic properties of wheat gluten proteins determine bread- making properties of dough. Play a crucial role in forming the strong, cohesive dough that will retain gas and produce baked products.  CELIAC DISEASE Aetiology and pathogenesis Exogenous or environmental causal factor: gluten but.... not all subjects who eat gluten develop celiac disease. Gluten is a necessary factor, but it is NOT sufficient! Other factors are necessary for the pathogenic process  CELIAC DISEASE Aetiology and pathogenesis Genetic susceptibility! Patients depending factor  Genetic susceptibility The best-characterized genetic risk factor for celiac disease, accounting for 35-40% of the total genetic risk, is the presence of genes encoding for MHC class II proteins including human leukocyte antigen HLA-DQ2 and HLA- DQ8. Over 90% of affected subjects express HLA-DQ2 molecules; the remainder express HLA-DQ8. The frequency of celiac disease risk HLA genotypes among the general population is about 30% (25-35%), whereas only 3% of these HLA- compatible individuals will go to develop the disease. It is now accepted that HLA is one of the main but not sufficient factors involved in the onset of celiac disease, but a multitude of genetic factors are responsible in celiac disease susceptibility, as demonstrated by studies on monozygotic twins  Genetic susceptibility Both HLA-DQ2 and HLA-DQ8 codified for heterodimers located on Antigen-Presenting Cells (APCs) It has been ascertained that these heterodimers present gluten peptides to the antigen-specific T- lymphocytes in the intestinal mucosa, inducing their proliferation as well as cytokine production. In particular, the tissue-transglutaminase Type II, tTG2, may transform non-charged glutamine into negatively charged glutamic acid, and give rise at a stronger induction to the proliferating and pro- inflammatory activity of the T-lymphocytes.  Genetic susceptibility peptide  Cumulative risk of developing celiac autoimmunity or celiac disease by five years of age by HLA haplotype HLA-DQ2 homozygosis confers a much higher risk (25–30%) of developing early-onset CD in infants with a first-degree family member affected by the disease (TEDDY study). HLA DR-DQ Celiac disease Celiac disease Adjusted hazard ratio for celiac disease Adjusted hazard ratio for genotype autoimmunity autoimmunity celiac disease DR3–DQ2/DR3-DQ2 5.70 6.08 26% 11% (n = 1374, 21%) (95% CI 4.66-6.97) (95% CI 4.43-8.36) DR3-DQ2/DR4-DQ8 2.09 1.66 11% 3% (n = 2612, 41%) (95% CI 1.7-2.56) (95% CI 1.18-2.33) DR4-DQ8/DR4-DQ8 9% 3% 1.00 1.00 (n = 1303, 20%) DR4-DQ8/DR8-DQ4 2% 5 times cut-off) is almost always associated with CD, while a low-title positivity ( 1:40 correlates with a severe pathology with important tissue damage while a low titer (1:5) is an expression of infiltrative lesions.  Anti Gliadin Antibodies (AGA) IgA: Poor sensitivity, no longer usable in the diagnosis.  Deamidated Gliadin Peptide (DGP) IgA: Useful for children 20 epithelium>30 IEL per lesion architecture with or lymphocytosis IEL/1000 enterocytes) 100 enterocytes without crypt hyperplasia and ≥25 IELs/100 enterocytes Type 2 Marsh II enlarged crypt Type 2 Grade A Type 1 Microscopic enteritis increased and influx of Crypt IEL count (>20 IEL/100 inflammatory cells hyperplasia enterocytes and crypt hyperplasia) Type 3 Villus effacement and Marsh IIIa (partial Type 3A: Grade B1 Type 2 crypt hyperplasia villous atrophy) Partial villous-crypt ratio