Diseases of the gastrointestinal system Dr H Awad Lecture 5: diseases of the small intestine

Transcription

1 Diseases of the gastrointestinal system 2018 Dr H Awad Lecture 5: diseases of the small intestine

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3 Small intestinal villi

4 Small intestinal villi -Villi are tall, finger like mucosal projections, found in the small intestine. -most of food absorption occurs in the small intestine. -the villi increase the surface area through which absorption occurs, this maximises food absorption. -if the villi are lost or shortened, in certain diseases then absorption will decrease.

5 Small intestinal diseases the most important disease that affects the small intestine is malabsorption. Malabsorption means decreased absorption of food. If less food is absorbed, then there will be more food in the intestinal lumen. More food in the lumen results in increased concentration of nutrients and minerals this creates an osmotic gradient resulting in movement of water from the epithelial lining to the lumen So we will have more fluid in the lumen admixed with unabsorbed food this is passed as diarrhoea. In malabsorption, the diarrhoea contains large amount of unabsorbed fat, this is called steatorrhea Steatorrhea is defined as the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance and can be foul-smelling

6 Malabsorption is caused by disturbance of any of the stages of absorption. There are four stages of food absorption: 1. Intraluminal digestion: inside the lumen large molecules ( carbs, lipids, proteins) are digested into absorbable forms ( small molecules). 2.terminal digestion: hydrolysis of carbohydrates and peptides by disaccharidases and peptidases in the brush border of small intestinal mucosa. 3.transepithelial transport: nutrients transported across the epithelium 4. Lymphatic transport of absorbed lipids. ( note that lipids are transported through lymphatics whereas other nutrients are transported through blood) Interference with any of the four stages above causes malabsorption.

7 Intraluminal Digestion Terminal digestion Transepithelial transport Lymphatic transport

8 Types of malabsorption: Intraluminal digestion is affected if the enzymes responsible for digestion are decreased like in chronic pancreatitis or in cystic fibrosis Terminal digestion is affected in disaccharidase deficiency and in other diseases celiac disease and some infections. Transepithelial transport is affected in celiac and infections. Lymphatic transport affected in Whipple disease.

9 this table aims to show you the diverse causes of malabsorption.. I don't want you to memorise it!

10 Most important diseases that cause malabsorption Celiac disease Tropical spur ( tropical enteropathy) Lactase deficiency Whipple disease Infections. you will study these in microbiology.

11 Celiac disease Celiac disease is also known as celiac sprue or gluten sensitive enteropathy. It s an immune mediated disease triggered by ingestion of gluten-containing cereals in genetically predisposed individuals. Gluten is the main protein in wheat, rye,oat and barley. the main treatment is gluten free diet.

12 Gluten: found in wheat, oats (الشعير) barley and (ش وف ان) rye,

13 Gluten is the storage protein in these grains: it is digested to smaller components, including gliadin which is responsible for celiac disease. Oat

14 Wheat

15 note that gluten in the mentioned grains is a large protein. the gliadin in gluten is the peptide responsible for celiac disease

16 rice and corn are gluten free

17 Epidemiology 0.5-1% of white people have the disease. In Jordan Preliminary statistics indicate that there are around 120,000 people diagnosed with celiac disease, constituting 1.5 per cent of the population Friends of Celiac Disease Patients Charity Association, is a charity in Jordan taking care of celiac patients.

18 Pathogenesis/ overview of autoimmune diseases Celiac is an autoimmune disease. Autoimmune diseases occur when our cells recognise our normal internal (self) antigens as foreign. the cells that recognise antigen in our body are called antigen presenting cells, these recognise the antigen ( by their HLA proteins on their surface) and present it to the T helper cells. once T helpers recognise the antigen they are activated; they produce cytokines that can cause tissue damage. Also activated helpers can stimulate B lymphocytes to produce antibodies( immunoglobulins) and can stimulate cytotoxic T lymphocytes. the antibodies and cytotoxic T produce more damage to tissues. note that we have two types of T cells: helpers ( CD4 cells) that help : regulate all the immune response. And cytotoxic T cells ( CD 8) which kill other cells.

19 This summarises what s in the previous slide. APC = antigen presenting cell. Killer T = cytotoxic. note that also macrophages can be activated by T helpers.

20 Pathogenesis of celiac disease Celiac is caused by autoimmune reaction to gluten. Gluten is digested by luminal and brush border enzymes to several amino acids and peptides. One of these peptides is gliadin. Gliadin resists further degradation by GI enzymes. Gliadin is deaminated by tissue transglutaminase After deamination, gliadin can interact with HLA DQ2 or HLA DQ 8 on antigen presenting cells.( remember that APC recognises antigens by HLA= human leukocyte antigens) if this interaction happens, then gliadin can be presented to T helpers ( CD4 T cells) once activated T helpers produce cytokines. These cytokines cause damage of the intestinal epithelium, damaging the villi. When villi are damaged they become short so we loose surface area important for absorption.. so less absorption occurs ( malabsorption)

21 Pathogenesis of celiac.. continuation So: T helpers destroy villi by the cytokines.. but they also stimulate Cytotoxic T cells and B cells. Stimulated cytotoxic T cells kill enterocytes ( epithelial cells of the small intestine, which line the villi) Stimulated B cells produce antibodies including: anti tissue transglutaminase, anti deaminated gliadin, antiendomysial antibody. these antibodies are very helpful in diagnosing celiac but it s not clear if they play a role in destruction of enterocytes.

22 Note: for the gliadin to cause autoimmune reaction, it s important that it is transferred to the lumen of the intestine. Gliadin is a large molecule, it cannot normally pass through the epithelium That s why not every person with genetic predisposition will have celiac. Environmental factors are important for disease development, which could be viral infection that increases the permeability of the intestinal epithelium so gliadin can move to the lumen. Early weaning increases risk of celiac, probably because the epithelial cells and their junctions might not be fully developed in young babies, which increases the probability of gliadin to one to the lumen.

23 Genetic factors autoimmune diseases occur in genetically susceptible individuals. in the case of celiac, all patients have HLA DQ2 or DQ 8.. you should know why! However, not every person with HLA DQ2 or 8 will have the disease.. so other factors play a role. see next slide for a brief idea of what HLA proteins are. we don't know the other genetic factors yet. there is association with other autoimmune diseases like type 1 Diabetes and thyroiditis.(as a rule this is always correct: autoimmune diseases occur in clusters!)

24 HLA HLA = human leukocyte antigen (HLA) is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. they are surface proteins responsible for the regulation of the immune system. HLA genes are highly polymorphic; they have many different alleles allowing them to fine-tune the immune response.

25 Pathogenesis

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28 Morphology Biopsy from second portion of duodenum or proximal jejunum are needed to diagnose celiac disease. Why these sites? because they are exposed to the highest concentration of gluten. Biopsy shows: short villi ( villous atrophy) and increased lymphocytes in the epithelium ( increased intraepithelial lymphocytes). Please note that these features are not specific for celiac. The histological features of celiac disease can be seen in other diseases like viral infections and tropical sprue. SO: TO DIAGNOSE CELIAC YOU NEED CLINICOPATHOLOGICAL CORRELATION>

29 Clinicopathological correlation in celiac Many diseases require several lines of evidence to be diagnosed. in many diseases, no one single test is diagnostic of the disease. So: medical professionals must work in a team to reach the correct diagnosis. in celiac, to diagnose the patient with celiac you need: 1. clinical symptoms related to eating gluten, improvement of symptoms when stopping eating gluten, 2. Serological evidence; the presence of antibodies, 3. Histopathological features of villous atrophy and increased intraepithelial lymphocytes.

30 Villous atrophy

31 Villous atrophy

32 what do mean by increased intraepithelial lymphocytes As you know, within the GI epithelium there are lymphocytes to protect the mucosa ( MALT ) in the small intestine, normally there are 25 lymphocytes per 100 epithelial cells ( enterocytes). this is equivalent to 1 lymphocyte per 4 epithelial cells. In celiac the number of lymphocytes is increased, so you will have more than 25 lymphocytes per 100.

33 increased intraepithelial lymphocytes

34 Clinical features Coeliac disease can manifest in childhood or in adults. in children, it manifests between 6-24 months of age and affects males and females equally. Symptoms in children: irritability, diarrhoea, weight loss, failure to thrive, in adults most common age of onset is years Main symptoms in adults are abdominal pain and steatorrhea. The malabsorption in Celiac patients results in anaemia and vitamin deficiencies.

35 the disease in children starts at or after weaning; when they start eating solid food besides milk.

36 Serology IgA to tissue transglutaminase IgA or IgG to gliadin Antiendomysial Ab HLA DQ2 or 8 : high negative predictive value. but if positive not useful. this means a person with negative DQ2 or 8 cannot have celiac.

37 Complications increased rate of malignancy most common malignancy associated with celiac is Enteropathy associated T cell lymphoma, which is aggressive Adenocarcinoma risk is also increased. Refractory sprue: if the symptoms are not controlled despite strict gluten free diet.. then investigate for malignancy.

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