Pathophysiology of GIT I Oral cavity and salivary glands Esophagus Stomach and duodenum Small and large intestine GIT • 1- oesophagus • 2- organs of peritoneal cavity • 3- stomach (1.5l) • 4- gastroesophageal junction • 5- pylorus • 6- small intestine (4.5 – 6m) • 7- duodenum • 8- jejunum • 9- ileum • 10- ileocaecal valve • 11- large intestine • ascendant • horizontal • descendant • rectum + anus Pathophysiology of oral cavity Pathophysiology of oral cavity • salivary glands - salivation (1 - 1.5l/day) • continual production by small salivary glands • large glands secerns only upon stimulus • centrum in medulla oblongata  sal. glands (via n. facialis) • afferentation from upper centres (cortex, hypothalamus) upon stimuli (taste, smell, chewing, …) • enzymes and ions of saliva • -amylase (polysaccharides), lipase • lysozyme (bactericide) • K+, Na+, Cl-, HCO3• disease of oral cavity • abnormal secretion of saliva •  - inflammation (e.g. tonsillitis), mechanical irritation •  (xerostomy) - dehydration, Sjögren syndrome, drugs • abnormal chewing • painful mandibular joint • injury of tongue • painful teeth • mucosal inflammation • infections • herpetic (HSV-1), bacterial, candidiasis (in immune compromised patients) • diseases of temporomandibular joint • pain • dislocation (habitual) • precanceroses and tumors of oral cavity • leucoplakia • carcinoma – smokers, alcoholics • signs of systemic diseases in oral cavity • anaemia • vitamin and iron carrncy • malnutrition • cyanosis • Crohn’s disease Reflexive salivation Sjögren syndrome • syn. keratoconjunctivitis sicca • autoimmune reaction against salivary (xerostomy) and tear glands (xerophtalmy) • initiated by viral infection? • symptoms • difficulties of chewing and swallowing • difficult talking • dry cough • irritation, eye burning, foreign body feeling and reddening of eye • sometimes accompanied by joint and muscle pain • SS can coexist with other autoimmune diseases • rheumatoid arthritis • systemic lupus erythematodes • thyreopathy Pathophysiology of oesophagus Pathophysiology of oesophagus • anatomy and histology • upper 2/3 striated muscle + squamous epithelium • upper sphincter (m. cricopharyngeus) • bottom 1/3 smooth muscle • lower sphincter (smooth muscle) • in terminal part cylindrical epithelium • peristaltics • disorders of motility and swallowing • dysphagia (oropharyngeal or oesophageal) • painful swallowing (odynophagia) + block of passage • 1) functional • e.g. scleroderma, amyotrophic lateral sclerosis or vegetative neuropathy in diabetes mellitus, achalasia, reflux. esophagitis, Chagas disease • 2) mechanical obstruction • strictures, peptic ulcer, tumours Disorders of oesoph. motility • achalasia • inability to relax lower oesoph. sphincter + lack of peristaltics • due to inborn or acquired impairment of myenteric nerve plexus (Meissneri) and production of NO by NO synthase • Chagas disease • common in Middle and Latin America • affect approx. 15 mil. people • 25% of Latin-American population endangered • infection by parasite Trypanosoma cruzi • incest born • acute phase – only swelling in the site of bite • e.g. periorbitaly • chron. stage • GIT (megacolon and megaoesophagus) • heart (dilated cardiomyopathy) • later stages malnutrition and heart failure • dementia Hiatal hernias • protrusion (herniation) of the part of the stomach through the opening in the diaphragm into chest cavity (posterior mediastinum) • 1) sliding • 2) rolling (paraoesophageal) • risk factors • inborn larger diaphragm hiatus • obesity • increased intraabdominal pressure (e.g. chron. obstipation) • gravidity • complications • acute complete herniation • gastroesophageal reflux and Barrett’s oesophagus Gastroesophageal reflux (GER) • retrograde passage of gastric content up to oesophagus where it acts aggressively • due to HCl, enzymes – proteases (pepsin) and event. bile (when dudodeno-gastric reflux also present) • occasional reflux appears in healthy subjects • risk is substantially higher in hiatal hernia • anti-reflux barrier • lower oesoph. sphincter • mucosal rugae • angel between stomach and oesophagus • oesoph. peristaltics • symptoms (oesoph. reflux disease) • dysphagia • heart burn (pyrosis) • regurgitation • even up to mouth, risk of aspiration • vomiting • complications of GER • reflux esophagitis • ulcers, strictures, bleeding • Barrett’s oesophagus • approx. 10% patients with GER Barrett’s oesophagus • metaplasia of mucosa in long term GER • squamous epithelium changes to cylindrical •  risk of adenocarcinoma • up to 40x higher than in healthy subjects • pathogenesis not clear • suspected error of differentiation of pluripotent stem cells Barrett´s oesophagus Oesophageal diverticula • according to the mechanism of development • traction • passion • combined • according to localization • hypopharyngeal • Zenker’s (pulsion) • false (only mucosa) • regurgitation without dysphagia • risk of aspiration • epibronchial • often due to traction by mediastinal lymph node in TBC • epiphrenic • due to increased intraluminal pressure • regurgitation of fluid at night Oesophageal varices • due to portal hypertension (increased pressure in v. portae) • pre-hepatic (congestive heart failure) • hepatic (liver cirrhosis) • post-hepatic (thrombosis of v. portae) • blood circumventí liver and enters the syst. circulation (lower v. cava) via • portocaval anastomoses • risk of bleeding from superficially located veins Tumours of oesophagus • benign • leiomyoma • fibroma • haemangioma • malign • adenocarcinoma • late complication of chron. GER!!! • males > females • only 10% of patients survives 5 yrs after diagnosis • TNM classification • T = tumour (size and depth of invasion) • N = lymph nodes (regional and distant) • M = metastases (most often liver) Pathophysiology of stomach Gastric mucosa and glands Gastric mucosa (pits  glands) Function of stomach • motoric function • reservoir • mechanical crushing • emptying • secretion • upper 2/3 of stomach contain mainly parietal and chief cells • antrum contains mucous and G cells Details of stimulation and inhibition Principle of HCl secretion Resorption of B12 • stomach: binding to R factor (non-specific carrier protecting it from acid) • duodenum: IF • ileum (inside epithelia): transcobalamin (circulating) Interplay of paracrine GIT factors Disorders of gastric motility • vomiting reflex (emesis) • reflex act leading to expulsion of gastric content by mouth • initiated from emetic centre in reticular formation in oblongate medulla • in proximity of respiratory and vasomotor and salivation centres • therefore increased heart frequency and salivation • act of vomiting • deep inspirium followed • closure of glottis • contraction of diaphragm, abdominal and chest muscles (i.e. increase of intra-abdominal and intra-thoracic pressure) • contraction of pylorus and duodenum and – vice versa relaxation of stomach and lower oesoph. sphincter • stomach has obviously a passive role, everything is due to increased intraabdominal pressure • vomiting is usually preceded by nausea • sensoric stimuli (sight, smell, taste) • distension of stomach, slow emptying, gastritis • irritation of vestibular apparatus • pain • vomiting of central origin • meningitides, head trauma, tumours, epilepsy • usually without nausea Gastritis • acute • stress ( Cushing ulcer) • trauma, burns, after surgery • shock • infectious • post-radiation • alcohol • corrosive • systemic infection • bacterial and viral • uraemia • alimentary intoxication • chronic • type A - autoimmune ( atrophic gastritis) • type B – bacterial (infectious) • inflammation of antrum due to H. pylori infection (without achlorhydria and  gastrin) Atrophic gastritis = precancer state • destruction of mainly parietal cells by cytotoxic T-lymphocytes • compensatory  gastrin • antibodies against • intrinsic factor (IF) and complexes IF/B12 • Na/K-ATPase • carbonic anhydrase • gastrin receptor • consequences • achlorhydria leading to sideropenic anaemia • later megaloblastic (pernicious) anaemia • precancerosis Peptic disease of gastroduodenum • historically hyperacidity was the main etiologic factor blamed • but the true hyperacidity is present only in few cases (stress ulcer and gastrinoma) • disease is always a consequence of dysbalance between aggressive and protective factors • localization in dist. part of oesophagus, stomach, duodenum and prox. part of jejunum • aggressive factors • HCl • pepsin • bile • alcohol, nicotine, caffeine • Helicobacter pylori • accelerated emptying of stomach • protective factors • mucous • bicarbonate • adequate blood supply • prostaglandins • extent/severity • ulcer = mucosal defect penetrating muscularis mucosae • erosion = defect limited only to mucous • complications of pept. ulcer • bleeding • perforation • penetration • stricture Ulcerogenic factors • (A) hyperacidity • habitually increased secretion of parietal cells •  basal secretion •  number •  sensitivity to histamine or gastrin • gastrinoma (Zollinger-Ellison syndrome) • tumour from D-cells of pancreas • secretion of gastrin by D-cells is normally minimal • chronic gastritis type B – infection by H. pylori • in 75% patients with gastric ulcer • in  90% patients with duodenal ulcer • in  50% patients with dyspepsia • in  20% healthy • (B) loss of barrier function of stomach •  pepsin (in 50% cases)  increased permeability of mucosa  retrograde diffusion of H+ ions • impaired trophic • stress – low perfusion • drugs • NSAID (např. aspirin) • inhibitors of cyklooxygenase • corticoids • inhibitors of phospholipase A Helicobacter pylori • successful human microbial pathogen • infects >20% of population • induces chron. gastritis B-type, peptic ulcers and contributes likely to the development of gastric carcinoma • localization mainly in antral part and duodenum • mechanisms of action and resistance to acid environment • encapsulated flagellum enables H. pylori to move quickly in acidic surface and penetrate to the deeper layers (higher pH) • produces urease (and thus NH3) = local neutralization of HCl • produces protein stimulating production of gastrin =  HCl • activates proton pump • produces proteases and phospholipases = destruction of mucus • produces catalase = resistance to phagocytosis • do not penetrate through epithelium  minimal or none systemic immune reaction • IgA antibodies • infiltration by neutrophils Detection of H. pylori • invasive – by biopsy during gastroscopy • light microscopy • PCR • cultivation • intravital microscopy • non-invasive • aspiration of gastric juice by nasogastric tube with subsequent PCR • PCR from stool • breath test Symptoms of gastric vs. duodenal ulcer• stomach • etiologically more often contribution of loss of barrier function rather than true hyperacidity • chron. gastritis type B • duodenogastric reflux • drugs • older people • painful in a fasting state, relieved by meal • patients often put on weight • duodenum • protection of duodenum weak • Brunner’s glands secreting alkalic mucus • coordinated peristaltics mixing gastric content with pancreatic and biliary juices which then acidic content • etiologically more often hyperacidity and infection by H. pylori • genetic effects • often blood group 0 • HLA-B5 • younger people • neurotics (faster gastric motility) • painful after meal • seasonal manifestion Ulcerogenic drugs Principles of treatment Tumours • benign • rare • malign • lymphoma • also in small and large intestine • carcinoid • also in intestine, pancreas, bronchi and lungs • carcinoma • bordered  diffuse • aetiology • nutrition! • nitrates (conservation)  nitrits  nitrosamines (= mutagens) • carcinogens from smoked meat • lack of fiber (delayed emptying, longer contact of mutagens with gastric wall) • aphlatoxins • smoking • H. pylori/atrophic gastritis Small intestine – anatomy  histology Physiology of small intestine • cells of small intestine • enterocytes – enzyme digestion and resorption • goblet cells – production of mucus • Paneth (granular) cells – immune defense • APUD cells – production of hormones • blood supply (10% cardiac output) from a. mesenterica sup. • functions • digestion and resorption – large area • total length 4.5–6m (large functional reserve - approx. 1/3 sufficient) • further increased by villi • immunity • by far the largest immune organ!! • Peyer’s plaques + dispersed immune cells • non-specific: lysozyme, defensins, HCl, bile, mucous • specific: lymphocytes, IgA • motoric – peristaltics, segm. contractions • stimulated by: gastrin, CCK, motilin, serotonin, inzulin • inhibice: glukagon, sekretin, adrenalin • secretion • intestinal juice: water, NaCl, HCO3-, mucous, enzymes (carboxypeptidases, intest. lipase, disacharidases, maltase, lactase, izomaltase …) Intestinal secretion and absorption • enterocytes in in jejunum and ileum produce alkalic fluid • water • electrolytes • mucous • control of secretion • hormones • drugs • toxins (e.g. cholera, dysentery, E. coli) • types of intest. absorption • passive diffusion (conc. gradient) • aqueous pores (e.g. urea, some monosaccharides) • transmembrane (e.g. ethanol, FFA) • via tight junctions (e.g. ions, water) • carriers • ions, Glc, AA • active transport on the basolateral membrane • Na/K ATPase produces conc. gradients for secondary active transports Intestinal immunity Disorders of intestinal secretion and absorption = diarrhea• diarrhea = more frequent expulsion of stools (>3/day), often more liquid consistence  loss of fluid • due to imbalance between 3 main factors – secretion, resorption and motility • acute • infection • dietary error • alimentary intoxication • chronic • malabsorption (inflammatory bowel disease (Crohn disease, ulcerative colitis), chron. pancreatitis, liver and biliary diseases) • colorectal carcinoma • neurogenic • metabolic (uremia, hyperthyreosis, adrenal insufficiency) • etiology • infection, toxins, diet, neuropsychological (anxiety) • pathogeneses •  osmotic pressure (and thus water) in intest. lumen = osmotic • typically when large amount of undigested nutrients stays in lumen • malabsorption syndrome (pancreatic insufficiency, biliary, disacharidaae deficiency – e.g. lactase) • ingestion (overdose) of salts (Mg, sulfates), antacids • bacterial overgrowth, resection, obstruction of lymphatics •  secretion of Cl (and thus water) into lumen = secretory • bacterial enterotoxins (Vibrio cholerae, Shigella dysenteriae, E. coli, Clostridium difficile, Salmonella typhi) • inflammatory exudation (Crohn d., ulcerative colitis) • hypemotility • some regulatory peptides (VIP, serotonin, PGE) Cholera • Vibrio cholerae • produces toxin binding to monosialoganglioside receptor on the luminal membrane of enterocytes • activation of cAMP signaling cascade and CFTR channel • secretion of Cl and Na (and thus water) into the intest. lumen • production of up to 20l of fluid daily • transmission by contaminated water (rivers, wells, lakes) and food • V. cholerae carriers • in gallbladder • ~5% population in endemic areas Action of V. cholerae toxin Intest. motility disorders • peristaltics = coordinated contraction of muscular layers • necessary for mixing of lumen content with pancreatic juice and bile and aboral movement of digested content • regulation • peristaltics is spontaneous but intensity is regulated • hormonal (gastrin, secretin, CCK, motilin, VIP, somatostatin, enteroglukagon, opioids) • neural (vegetative nerv. syst.) • types of movement • fasting state • spontaneous contractions • migrating myoelectric complex (MMC) ~1x/1.5 hr. • after meals • segmentations ~ 10x/min • peristalsis • reflexes • intestino-intestinal • gastro-intestinal • ileogastric • trauma of other organs (e.g. gonads, kidneys, ..) lead to reflex. stop of peristaltics (sympathetic n.s.)  atonic (paralytic ileus) • disorders • hypomotility (extreme form = ileus) • hypermotility • drugs affecting intest. motility • purposefully – laxatives (secretory, osmotic, emolients, fiber) x prokinetics • side effects – opiates, sympatomimetics, anticholinergics, … Ileus • block of intestinal passage • mechanic = due to the external or internal obstruction • intraluminal: obstruction by tumor (e), bile stones (f), strictures, inflammation • extraluminal: adhesions, compression, herniation (a), invagination (b), strangulation (c), volvulus (d) • paralytic or spastic =  motility • postoperative • acute pancreatitis • pain (colic, trauma, myocardial infarction) • peritonitis • hypokalemia • at first peristaltics increased as an attempt to overcome the block • water, gases and content stagnate above the block • distension of intestine, hypoperfusion and later necrosis of the wall • if not quickly surgically solved then lethal – dehydration, ion dysbalance and toxemia (bacteria from lumen into circulation) Obstructive and paralytic ileus Digestion and absorption in small intestine • mechanism • (1) slow by passive diffusion • (2) fast (but saturable) by facilitated transports • localization • duodenum and jejunum • hexoses, AA, di- and tripeptides, vitamins, FA, monoacylglycerols, cholesterol, Ca, Fe, water, ions • ileum • vit. C and B12, bile acids, cholesterol, water, ions • saccharides (mainly poly- and disaccharides) • saliva -amylase  pancreatic -amylase  intest. enzymes (oligo- and disaccharides) • passivee absorption (pentoses), SGLT1 (glucose and galactose), GLUT5 (selectively for fructose) • proteins • endo- (pepsin, trypsin, chymotrypsin, elastase) and exopeptidases  pancreatic carboxy- and aminopeptidases  peptidases of enterocytes • passive absorption, facilitated (SLC, solute carriers – many types, Nadependent or not) and actively • absorption of intact proteins (e.g. Ig of maternal breast milk, antigens, toxins, …) possible in limited extent • lipids (TGA, cholesterol esters and phospholipids) • pancreatic lipase (min. salivary), cholesterolesterase, pospholipase A  emulsification (conj. bile acids!!)  absorption by diffusion  reesterification in enterocyte  chylomicrons Absorption of lipids in small intestine Malabsorption syndrome (MAS) • maldigestion = impaired enzymatic digestion in stomach or intestine • malabsorption = impaired absorption of digested compounds • MAS impairs the normal sequence: • mechanical processing of food (chewing, gastric motorics)  • digestion in gastric and intest. lumen by secreted enzymes (gastric, pancreas, bile)  • digestion by membrane enzymes fo enterocytes  • absorption by intest. epithelium  processing in enterocyte  • transport by blood and lymph to livet and syst. circulation • practically every GIT disease can lead in chronic duration to MAS • MAS can be global or specifically affect • basic nutrients • saccharides –flatulence, osmot. diarrhea (e.g. lactase deficiency) • proteins – muscle atrophy, edemas (e.g. chron. pankreatitis) • lipids – steatorhea, vitamin A, D, E, K deficiency (e.g. chron. pankreatitis, m. Crohn, m. Whipple, celiac d.) • vitamins • elements (Fe, Ca, Mg) • bile acids (impairment of enterohepatal cycle) • any combination MAS – selected examples – coeliac disease • = gluten-sensitive enteropathy • autoimmune reaction against intest. mucosa initiated by gluten and its products (gliadins) • gluten is a part of endosperm of cereals (wheat, rye, barley, oats) • diseases starts in child after breast feeding when flour is introduced • pathogenesis • gen. disposition – variants of MHC II genes (DQ2 and DQ8 haplotypes) • often associated with other autoimmunities, e.g. T1DM • external factors • gluten in diet • infection by adenoviruses (molecular mimicry) • clinical course • immunization (antibodies against gliadin, reticulin and transglutaminase), infiltration by cytotox. T-lymph.) – injury of enterocytes of small intestine • malabsorption of main nutrients, vitamins, elements • hypo-/malnutrition, slow growth, anemia, neuromuscular disorders • in 20-40 years risk of intest. lymphoma (50%) or carcinoma (10%) • disorders of fertility MAS - selected examples – lactase deficiency • leads to lactose intolerance • extremely frequent – mainly due to the fact that lifetime ability to digest milk (i.e. lactose) is considered a normal state • however, most mammals and part of human population loses the activity of lactase after weaning • the lifetime activity could be considered exceptional – persistence of lactase • genetic polymorphism (geographical distribution is evidently a consequence of genetic selection) in promoter of gene for lactase • highest prevalence of lactase persistence in Europe in Swedes a Danes (90 %) • Czech population  70 % • lowest in Turks ( 20 %) • outside Europe high fervency of persistence e.g. in desert nomadic populations in North Africa • the reason for selection of persistence haplotype in northwest Europe could be the richer source of calcium in low vit. D generation climate • manifestation • intestinal discomfort after fresh milk intake (not after diary fermented products such as cheese or yogurt) • diarrhea, flatulence, abdominal pain Lactose intolerance prevalence Inflammatory bowel diseases (IBD) • Crohn’s disease and ulcerative colitis • both exhibit some similar features • manifestation in young adults • genetic predisposition • abnormal reactivity of immune system (T-lymph.) to intest. bacteria • impairment of intest. epithelial barrier • localization • m. Crohn – any segment of GIT • ulcerative colitis – only colon • incidence rises in Europe and N. America • environmental factors Crohn’s disease • = ileitis terminalis, enteritis regionalis • chronic idiopathic inflammatory disease of commonly small intestine • but can affect any part of GIT beginning with oral cavity to anus • manifestation typically between 3. to 6. decade, more often women • pathogeneses (multifactorial) • genetic factors (= disposition) lead to abnormal immune response of intest. mucosa to natural commensal bacterial antigens (>500 bact. strains) • normally opposed by production of defensins • mutation in gene for CARD15 in patients • triggering factors nor known (infection?) = sterile animals protected • lipopolysaccharide, peptidoglycan, flagellin, … • clinical course – typically exacerbations (stomach pain, diarrhea, fever, seizures, blood in stools (enterororhagia)/remise • granulomatous type of inflammation affects all layers of intest. wall • ulcerations and bleeding • penetrated ulcers create fistulas (often perirectal) • affected areas interspersed by inaffected • extraintestinal manifestations • arthritis • uveitis Intestinal “controlled inflammation” • reaction to intraluminal bacteria – normally “controlled inflammation” • intracellular recognition of components of bacterial wall (pathogen-associated molecular patterns, PAMPs), e.g. muramyl-dipeptide (MDP) by NOD2 (product of CARD15 gene) lead to oligomerization and activation of NFk-B • secretion of chemokines and defensins by Paneth cells • variants of NOD2 associated with Crohn’s d. lead to deficient epithelial response, loss of barrier function and increased exposition to intest. microflora • impaired secretion of chemokines and defensins • altered expression of pattern-recognition receptors (PRRs), e.g. Toll-like receptors • production of inflammatory cytokines • activation of dendritic cells and production of Ig and activation of Th1 lymph. Complications of Crohn’s disease Pathophysiology of large intestine • functions • resorption of water (0.5-1l/24h) • along the whole length • motoric • pathology • obstipation • diverticulosis • event. diverticulitis • polyposis • carcinoma • hereditary • polyposis • non-polypose • non-hereditary (sporadic) Ulcerative colitis • max. incidence between 20 – 40. years of age • typically Caucasian race, north-south gradient • inflammation limited to mucosa • starts at the bottom of Lieberkuhn’s crypts (infiltration by immune cells) • mainly rectum and sigmoideum • hyperemia, abscesses and ulcerations, bleeding, pseudopolyps, event. strictures • clinical course • periodical = exacerbations x remissions (diarrhea, bleeding, abdominal pain, fever) • extraintestinal manifestations (5 – 15%): polyarthritis, osteoporosis, uveitis, cholangitis • chronic anemia, strictures, hemorrhoids, carcinoma Polyps of large intestine • polyp = any lesion/prominence into the lumen • types • solitary • multiple • familiar polyposis, FAP) • autosomal dominant • precancerosis, polyps in puberty, carcinoma after 30th year of age • polyps more common in rectum but also in ileum • mutation in APC gene (Wnt pathway) • Gardner’s syndrome • juvenile polyposis • etiology • hyperplasia in the inflammatory terrain • neoplastic • benign • malign Tumors of large intestine • benign • adenoma (adenomatous polyp) • fibroma • leiomyoma • hemangioma • malign • lymphoma • carcinoid • carcinoma • hereditary • polypose • FAP (mutation in APC gene) • Gardner’s syndrome • non-polypose • HNPCC or Lynch syndrome (mutation in mismatch repair genes) • Li-Fraumeni syndrome (mutation in p53 gene) • non-hereditary (sporadic) – most common Colorectal carcinoma Colorectal carcinoma • carcinogenesis in the intestine progresses slowly upon the exposure to dietary carcinogens and event. with contribution of genetic predisposition of the subject • risk factors • age, genetics, polyps, bowel inflammation, obstipation, diet, smoking • symptoms • bleeding, blood in stools • change of peristaltics • diarrhea • obstipation • tenesmus • intest. obstruction • pain • extraintestinal • liver metastases • icterus, pain, cholestasis = acholic stools • hematologic • sideropenic anemia, thrombosis • fatique • fever • anorexia, weight loss • stages • 0 in situ • I invasion into the wall • II • III presence in local lymph nodes • IV distant metastases