GI System Physiology Flashcards
GI Tract
- tubular part- tube that food takes –> esophagus, stomach, small intestine, large intestine/colon, rectum
- non-tubular part- contribute to the tube —> liver, pancreas, gallbladder
layers of the tubular GI system
lumen
mucosa- varies from organ to organ since the GI tract has many jobs
submucosa- loose connective tissue
muscularis propria- 2 different layers of stomach muscle
subserosa- loose connective tissue
serosa- mesothelium layer and some parts of the GI tract do not have this
peritoneum
GI tumorigenesis
normal epithelium —> +/- chronic inflammation —> +/- metaplasia (one organ takes on the histology of another organ) —> low grade dysplasia (pre-cancerous state) —> high grade dysplasia (pre-cancerous state) —> cancer
esophagus
function: convey food to the stomach
distinctive histology: epithelium (different in every organ) is non-keratinizing squamous mucosa, submucosal glands to lubricate, muscularis propria is skeletal muscle in upper esophagus since there is voluntary control —> you need to swallow to accept food, does not have serosa (retroperitoneal)
esophagitis
-inflammation of the esophagus
-can be caused by medications, trauma, allergies, radiation, infections, reflux
CMV esophagitis
-makes cells big and IHC shows the protein of CMV present in nucleus —> does not affect epithelium but endothelium
-more common in the immunosuppressed
herpes esophagitis
-ulceration of the epithelium
-molding- the nuclei are squished
-multinucleation
-margination- viral protein has taken over the nucleus and squished DNA to the side
esophageal tumorigenesis
metaplasia (no neoplasia) —> dysplasia (non-invasive neoplasia) —> adenocarcinoma (invasive neoplasia)
barrett’s esophagus
intestinal epithelium instead of squamous epithelium
intestinal metaplasia
-abnormal to have goblet cells in the esophagus (intestinal metaplasia)
-begin with intestinal metaplasia —> low grade dysplasia —> high grade dysplasia —> cancer
barrett esophagus: risk factors
-chronic GERD
-advancing age
-male gender
-tobacco use
-central obesity
how to diagnose esophageal cancer?
-diagnose high grade dysplasia through endoscopic mucosal reception —> ID region and inject lifting agent to try to take out dysplasia
-stromal response so you rely on desmoplasia due to small tissue
barrett’s —> adenocarcinoma
-only 10% of those with barrett’s will develop adenocarcinoma, including prevalent (present @ initial endoscopy) and incident (develops subsequently)
-overall incidence is 0.1% to 0.3% in the first five years but ~9% @ 20 years with barrett’s
stomach
-mixes and churns food with gastric juices to form chyme
-begins chemical breakdown of proteins
-releases food into the duodenum as chyme
-absorbs some fat-soluble substances like alcohol and aspirin
-possess antimicrobial functions
-stimulates protein-digesting enzymes
-secretes intrinsic factor required for B12 absorption in the small intestine
layers of the stomach
mucosa
submucosa (loose connective tissue)
muscularis propria
serosa
stomach regions and their functions
-fundus/body: make pepsin, acid, and intrinsic factor plus has chief and parietal cells
-antrum- tells the body to make acid and has gastrin-producing endocrine cells (G-cells)
different units of the stomach
-esophagus —> fundus —> body (one unit)
-antrum and pylorus —> distal functional unit
mucosa of the gastric fundus/body
-parietal and chief cells live in the glands
-parietal- pink and granular to produce acids
-chief- make pepsin
the key cell: parietal cell
-filled with secretory vesicles
-H-K-ATPase acid-secreting pump or the “proton pump” —> pumping hydrogen into the stomach and making it a more acidic environment
-activated by Ca2+ and cAMP
-forms the basis for the proton pump inhibitors to control acid secretion —> make the contents less acidic for less damage to esophagus
-don’t stop GERD but make it less damaging
mucosa of the antrum
-lacks parietal and chief cells
-pits and glands you have endocrine cells to stimulate acid secretion
key players in acid secretion
-acetylcholine —> stimulates gas neurylation of G cells —> parietal to make acid and chief to make pepsin
-gastrin —> released from G cells –>stimulates HCl and pepsin secretion
-histamine —> released from ECL cells —> stimulates HCl secretion
-somatostatin —> secreted from D cells —> inhibits gastrin release
types of gastritis
-acute gastritis- acute hemorrhagic gastritis or acute infectious gastritis (bacterial with H. pylori and viral)
-chronic gastritis- common forms- “chemical gastritis from NSAIDs, bile reflux, others like acids, alcohol, smoking, heliobacter pylori gastritis, and autoimmune gastritis
-chronic gastritis- uncommon forms
helicobacter pylori
-curved organisms with flagellae over gastric epithelium
-look like helicopter blades or seagulls
-if you have an inflamed stomach, you look for these
consequences of H. pylori infection
-many are asymptomatic
-peptic ulcers in the duodenum and atrum
-atrophy and intestinal metaplasia of the mucosa
-increased risk of intestinal type adenocarcinoma
-MALT lymphoma
risk of HP and adenocarcinoma
now that we know HP can cause adenocarcinoma —> discover HP and remove it to prevent surgeries of ulcers
H. pylori is associated with metaplastic atrophic gastritis
-goblet cells in stomach
-areas of intestinal metaplasia
gastric tumorigenesis
metaplasia (no neoplasia) —> dysplasia (non-invasive neoplasia) —> adenocarcinoma (invasive neoplasia)
risk factors for gastric adenocarcinoma
-male >60 years
-H. pylori infection
-intestinal metaplasia
-chronic atrophic gastritis
-pernicious anemia
-familial andenomatous polyposis
-prior partial gastrectomy
-nitrate containing foods in diet
-cigarette smoking
hereditary gastric adenocarcinoma
-autosomal dominant
-gastric cancers develop in the youth
-mutated CDH1 gene (E-cadherin), a tumor-suppressor gene in epithelial cells
-“second hit” initiates neoplasia
-accounts for up to 40% of familial gastric cancer cases
-usually have to get a lot of biopsies and endoscopies
-can be very subtle due to the small size of cells —> nucleus looks like the gem of a ring
small intestine
function: absorb nutrients
distinctive histology: glandular mucosa with villous architecture to maximize absorption, submucosal glands in duodenum (brunner’s glands) to neutralize the gastric acid secretion, pancreatic juice (digestive enzymes) and bile (emulsifier) enter at the duodenal ampulla of vater to aid digestion
divisions of small intestine
- duodenum- 25 cm/9 inches- adjusts pH and tonicity
- jejunum- 280 cm/9 ft- digestion and absorption
- illeum- 350 cm/11.4 ft- bile salt absorption
layers of small bowel
mucosa
submucosa
muscularis propria
serosa
villi to crypt ratio
villi: crypt is 4:1
villous epithelium
-pale goblet cells
-microvili brush border
-absorptive enterocytes
microvilli
fingerlike projections to increase surface area
functional unit of the small bowel
-villi- digestion and absorption
-crypt- secretion
absorption of sugar, protein, fat
-must be enzymatically broken down into functional units
-specific transporters in enterocytes mediate absorption w/ different transporters for different sugars and amino acids
GI tract efficiency
GI tract absorbs ~98-100% of what it takes in with water, proteins, carbs, salts, and fats
malabsorptive disorders
-malabsorption-impaired uptake of any substance by small intestine
-malabsorption syndrome- constellation of findings including diarrhea, steatorrhea, weight loss, and deficiency states
celiac disease: the basics
-other names include gluten-sensitive enteropathy, celiac sprue, non-tropical sprue
-inability to tolerate gliadin- alcohol-soluble fraction of gluten
-gluten is commonly found in wheat, rye and barley
-chronic, autoimmune intestinal disorder
-when gluten is ingested in celiac disease patients, an immunologically mediated inflammatory response occurs which damages the mucosa of the intestines (small bowel atrophy and maldigestion and malabsorption)
pathophysiology of celiac disease
-combination of allergic reaction to gluten, innate and adaptive immunity, and genetics
-patient must have auto antibodies and multidisciplinary diagnosis
-if the patient stops eating gluten, intestine goes back to normal
histology of celiac disease
-villous blunting
-increased lymphocytes in epithelium
-increased plasma cells and lymphocytes in the lamina propria
neoplasia of GI tract
primary cancers are exceedingly rare and metastases are much more common
layers of the colon
mucosa
submucosa
muscularis propria
serosa
colorectal mucosa
-“test tubes in a rack” regular structure
-absorbs fluid while the small bowel absorbed nutrients
-more goblet cells to lubricate and few absorptive cells
inflammatory bowel disease (IBD)
-chronic inflammatory condition of the GI tract that affects ~1.4 million people in the US
-generally presents in patients in their teens or twenties with a second peak from 50-70
-etiology is unknown but in genetically predisposed hosts, there appears to be an intestinal mucosal immune reaction to an environmental factor with gut microbiota playing a central role (lack of exposure to microbes early in life can predispose to autoimmune conditions)
pathogenesis of IBD
microbial antigens and adjuvants, environmental triggers, genetic susceptibility, and effector immune response
histology of IBD
-mucosal inflammatory infiltrate with neutrophils abundant and cryptitis and crypt abscesses
-basal plasmacytosis
-crypt distortion
-goblet cell depletion
-paneth cell metaplasia
what are the 2 categories of IBD?
- ulcerative colitis- only inflammation of the mucosa
- crohn’s disease- inflammation of the entire wall of the GI tract
-UC affects the rectum then moves proximally in a continuum, whereas crohn’s is patchy and goes wherever it wants
-IBD can set off pathway to carcinoma so patients are monitored regularly
large intestine (colorectal) carcinoma
-most common cancer of the GI tract
-third highest incidence and cause of cancer deaths
colon tumorigenesis
-prototypic example of precancer —> cancer sequence
-different types of precancer represent different genetic pathways of tumorigenesis
what is one of the main types of polyps in the colon?
tubular adenoma
-neoplastic, pre-malignant
-most common neoplastic polyp
-have low grade dysplasia
histology of tubular adenoma
-high nucleus:cell ratio
-nuclear elongation
-nuclear pseudostratification
-nuclear changes extend to surface
-with colonoscopy, if you find pre-cancer, you can remove it @ the same time
multistep CRC carcinogenesis tumor progression model
normal colon —> mucosa @ risk —> adenomas —> carcinoma
-stepwise progression of precancer to cancer accompanied by different driver gene alterations
what is the other main type of polyp in the colon?
sessile serrated adenoma where the crypts are dilated at the bases
microsatellite instability pathway
normal colon —> sessile serrated adenoma —> carcinoma
-loss of function of genes you get a bunch of point mutations
familial adenomatous polyposis (FAP)
-one of the prototypical inherited disorders
-germline mutation in the APC gene
-fits knudson’s two-hit hypothesis for tumor suppressor genes
-affected patients have one inherited mutated allele, 2nd hit occurs in the neoplasm (inactivated germline mutation and one allele of APC —> patients inherit one mutated allele so already have one non-functioning copy of APC and 2nd hit occurs in the neoplasm)
-1000s of polyps —> with so many adenomas, one likely leads to cancer
lynch syndrome (hereditary non-polyposis syndrome)
-autosomal dominant inheritance pattern (only need to inherit one allele)
-germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2)
-inherit one defective allele, second “hit” results in neoplasm
-accelerated carcinogenesis (~1000x increased mutation rate)
-not just colon cancers but also endometrium, pancreas, ureter
lifetime risk of colorectal CA
-FAP- 100% if left with colons in- tubular adenomas and loss of APC
-lynch- 50% so patients are surveillanced to see if they have microsatellite instability
-sporadic- <10% and most are due to the APC but 10% of these are MSI —> important since lots of mutations are uniquely susceptible to immunotherapies
pancreas
-non-tubular organ on the side that makes digestive enzymes
-anatomy: head is nestled in the duodenum and tail is near the spleen
-not a lot near it to cause symptoms until advanced
-superior mesenteric artery and vein are very big and can make it difficult for pancreatic surgery
histology of pancreas
-acinar cells- make digestive enzymes that are secreted into pancreatic ducts and secrete out to duodenum
-islets of langerhans cells- endocrine cells that make glucagon and insulin (directly to blood)
-majority of the pancreas is acinar cells with abundant pink cytoplasms
what are the normal functions of the pancreas?
-exocrine (out)- acinar cells that secrete pancreatic enzymes into the pancreatic duct
-endocrine (in)- islets of langerhans cells secrete insulin and glucagon into blood vessels
acute pancreatitis
glands will usually return to normal if underlying cause of inflammation is removed
chronic pancreatitis
irreversible destruction of the pancreatic parenchyma
causes of acute pancreatitis
-2 most common causes are: alcohol (65% in the US) and biliary tract disease (gallstones)
-less common are obstruction of the pancreatic ductal system, drugs, trauma, infections, and genetics
genetic causes of acute pancreatitis
-cationic trypsinogen (PRSS1)- recurrent attacks of pancreatitis since childhood, most common is R122H mutation, and prevents proteolytic inactivation of trypsin —> can lead to autodigestion of pancreas
-protease inhibitor SPINK1- normally prevents trypsin-catalyzed premature activation of zymogens and mutation causes excess trypsin activity
-cystic fibrosis transmembrane regulator (CFTR)
chronic pancreatitis
-irreversible damage of pancreatic parenchyma (exocrine and endocrine insufficiencies)
-alcohol abuse is the single most common cause of CP
-recurrent acute pancreatitis can result in CP
-not a life-threatening emergency but 50% mortality by 20 years
histology of chronic pancreatitis
-parenchymal fibrosis
-loss of acini
-variably dilated ducts
-“enlarged” islets
-chronic inflammation
complications of chronic pancreatitis
-pleural effusions
-pancreatic pseudocysts
-pain from perineural fibrosis
-pancreatic calcification
-ascites
-stones in pancreatic duct
-fat malabsorption
-diabetes
pancreatic ductal adenocarcinoma (PDAC)
-painless obstructive jaundice
-back pain
-weight loss/cachexia
-trousseau sign- migratory thrombophlebitis (blood clots that moved)
-new onset diabetes mellitus- should newly diagnosed patients get tested?
ALL of these are late symptoms- only 10-15% present with resectable cancers
PDAC pathologic feaures
-grossly firm, white poorly defined masses
-microscopically they form glands and secrete mucin
-intense desmoplastic response
-poorly vascularized
-took a chunk of tissue —> majority would be fibroblasts and not cancer —> good @ invading other structures like perineurial invasion for local invasion and into veins for metastasis
PDAC and metastasis
-very common since it is so good @ invading into veins like the liver, lungs, and peritoneum
-unknown why but patients with only metastasis in their lungs are better off
PDAC epidemiology
-more common in the elderly
-smoking contributes
-diabetes
-diet high in meats and low in fruits/veggies
-obesity increases the risk
-chronic pancreatitis is both a risk factor and symptom of the disease
-non-O ABO blood group
genetic and epigenetic events in pancreatic cancer
-disease of somatic mutations in neoplastic cells
-mutations (intragenic mutations)
-large deletions
-amplifications
-genetic instability/chromothripsis
-mitochondrial mutations
-DNA methylation
genetics of pancreatic cancer
-inherit a mutation (BRCA2)
-do something to damage our DNA (smoking)
-chance with 6 billion base pairs in every cell
2 different precursor lesions
- PanIN- small microscopic lesions at <5 mm
- IPMN- larger cysts at >=10 mm
genetic progression towards invasive pancreatic cancer
normal —> PanIN-1A —> PanIN-1B —> PanIN-2 —> PanIN-3 —> invasive carcinoma
K-ras —> p16 —> p53 —> invasive carcinoma
-pre-cancers are independently cloned and eventually you get one that leads to cancer
