GI System Physiology

Question 1

GI Tract

Answer 1

1. tubular part- tube that food takes –> esophagus, stomach, small intestine, large intestine/colon, rectum
2. non-tubular part- contribute to the tube —> liver, pancreas, gallbladder

Question 2

layers of the tubular GI system

Answer 2

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

Question 3

GI tumorigenesis

Answer 3

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

Question 4

esophagus

Answer 4

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)

Question 5

esophagitis

Answer 5

-inflammation of the esophagus
-can be caused by medications, trauma, allergies, radiation, infections, reflux

Question 6

CMV esophagitis

Answer 6

-makes cells big and IHC shows the protein of CMV present in nucleus —> does not affect epithelium but endothelium
-more common in the immunosuppressed

Question 7

herpes esophagitis

Answer 7

-ulceration of the epithelium
-molding- the nuclei are squished
-multinucleation
-margination- viral protein has taken over the nucleus and squished DNA to the side

Question 8

esophageal tumorigenesis

Answer 8

metaplasia (no neoplasia) —> dysplasia (non-invasive neoplasia) —> adenocarcinoma (invasive neoplasia)

Question 9

barrett’s esophagus

Answer 9

intestinal epithelium instead of squamous epithelium

Question 10

intestinal metaplasia

Answer 10

-abnormal to have goblet cells in the esophagus (intestinal metaplasia)
-begin with intestinal metaplasia —> low grade dysplasia —> high grade dysplasia —> cancer

Question 11

barrett esophagus: risk factors

Answer 11

-chronic GERD
-advancing age
-male gender
-tobacco use
-central obesity

Question 12

how to diagnose esophageal cancer?

Answer 12

-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

Question 13

barrett’s —> adenocarcinoma

Answer 13

-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

Question 14

stomach

Answer 14

-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

Question 15

layers of the stomach

Answer 15

mucosa
submucosa (loose connective tissue)
muscularis propria
serosa

Question 16

stomach regions and their functions

Answer 16

-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)

Question 17

different units of the stomach

Answer 17

-esophagus —> fundus —> body (one unit)
-antrum and pylorus —> distal functional unit

Question 18

mucosa of the gastric fundus/body

Answer 18

-parietal and chief cells live in the glands
-parietal- pink and granular to produce acids
-chief- make pepsin

Question 19

the key cell: parietal cell

Answer 19

-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

Question 20

mucosa of the antrum

Answer 20

-lacks parietal and chief cells
-pits and glands you have endocrine cells to stimulate acid secretion

Question 21

key players in acid secretion

Answer 21

-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

Question 22

types of gastritis

Answer 22

-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

Question 23

helicobacter pylori

Answer 23

-curved organisms with flagellae over gastric epithelium
-look like helicopter blades or seagulls
-if you have an inflamed stomach, you look for these

Question 24

consequences of H. pylori infection

Answer 24

-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

Question 25

risk of HP and adenocarcinoma

Answer 25

now that we know HP can cause adenocarcinoma ---> discover HP and remove it to prevent surgeries of ulcers

Question 26

H. pylori is associated with metaplastic atrophic gastritis

Answer 26

-goblet cells in stomach -areas of intestinal metaplasia

Question 27

gastric tumorigenesis

Answer 27

metaplasia (no neoplasia) ---> dysplasia (non-invasive neoplasia) ---> adenocarcinoma (invasive neoplasia)

Question 28

risk factors for gastric adenocarcinoma

Answer 28

-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

Question 29

hereditary gastric adenocarcinoma

Answer 29

-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

Question 30

small intestine

Answer 30

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

Question 31

divisions of small intestine

Answer 31

1. duodenum- 25 cm/9 inches- adjusts pH and tonicity 2. jejunum- 280 cm/9 ft- digestion and absorption 3. illeum- 350 cm/11.4 ft- bile salt absorption

Question 32

layers of small bowel

Answer 32

mucosa submucosa muscularis propria serosa

Question 33

villi to crypt ratio

Answer 33

villi: crypt is 4:1

Question 34

villous epithelium

Answer 34

-pale goblet cells -microvili brush border -absorptive enterocytes

Question 35

microvilli

Answer 35

fingerlike projections to increase surface area

Question 36

functional unit of the small bowel

Answer 36

-villi- digestion and absorption -crypt- secretion

Question 37

absorption of sugar, protein, fat

Answer 37

-must be enzymatically broken down into functional units -specific transporters in enterocytes mediate absorption w/ different transporters for different sugars and amino acids

Question 38

GI tract efficiency

Answer 38

GI tract absorbs ~98-100% of what it takes in with water, proteins, carbs, salts, and fats

Question 39

malabsorptive disorders

Answer 39

-malabsorption-impaired uptake of any substance by small intestine -malabsorption syndrome- constellation of findings including diarrhea, steatorrhea, weight loss, and deficiency states

Question 40

celiac disease: the basics

Answer 40

-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)

Question 41

pathophysiology of celiac disease

Answer 41

-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

Question 42

histology of celiac disease

Answer 42

-villous blunting -increased lymphocytes in epithelium -increased plasma cells and lymphocytes in the lamina propria

Question 43

neoplasia of GI tract

Answer 43

primary cancers are exceedingly rare and metastases are much more common

Question 44

layers of the colon

Answer 44

mucosa submucosa muscularis propria serosa

Question 45

colorectal mucosa

Answer 45

-"test tubes in a rack" regular structure -absorbs fluid while the small bowel absorbed nutrients -more goblet cells to lubricate and few absorptive cells

Question 46

inflammatory bowel disease (IBD)

Answer 46

-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)

Question 47

pathogenesis of IBD

Answer 47

microbial antigens and adjuvants, environmental triggers, genetic susceptibility, and effector immune response

Question 48

histology of IBD

Answer 48

-mucosal inflammatory infiltrate with neutrophils abundant and cryptitis and crypt abscesses -basal plasmacytosis -crypt distortion -goblet cell depletion -paneth cell metaplasia

Question 49

what are the 2 categories of IBD?

Answer 49

1. ulcerative colitis- only inflammation of the mucosa 2. 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

Question 50

large intestine (colorectal) carcinoma

Answer 50

-most common cancer of the GI tract -third highest incidence and cause of cancer deaths

Question 51

colon tumorigenesis

Answer 51

-prototypic example of precancer ---> cancer sequence -different types of precancer represent different genetic pathways of tumorigenesis

Question 52

what is one of the main types of polyps in the colon?

Answer 52

tubular adenoma -neoplastic, pre-malignant -most common neoplastic polyp -have low grade dysplasia

Question 53

histology of tubular adenoma

Answer 53

-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

Question 54

multistep CRC carcinogenesis tumor progression model

Answer 54

normal colon ---> mucosa @ risk ---> adenomas ---> carcinoma -stepwise progression of precancer to cancer accompanied by different driver gene alterations

Question 55

what is the other main type of polyp in the colon?

Answer 55

sessile serrated adenoma where the crypts are dilated at the bases

Question 56

microsatellite instability pathway

Answer 56

normal colon ---> sessile serrated adenoma ---> carcinoma -loss of function of genes you get a bunch of point mutations

Question 57

familial adenomatous polyposis (FAP)

Answer 57

-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

Question 58

lynch syndrome (hereditary non-polyposis syndrome)

Answer 58

-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

Question 59

lifetime risk of colorectal CA

Answer 59

-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

Question 60

pancreas

Answer 60

-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

Question 61

histology of pancreas

Answer 61

-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

Question 62

what are the normal functions of the pancreas?

Answer 62

-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

Question 63

acute pancreatitis

Answer 63

glands will usually return to normal if underlying cause of inflammation is removed

Question 64

chronic pancreatitis

Answer 64

irreversible destruction of the pancreatic parenchyma

Question 65

causes of acute pancreatitis

Answer 65

-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

Question 66

genetic causes of acute pancreatitis

Answer 66

-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)

Question 67

chronic pancreatitis

Answer 67

-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

Question 68

histology of chronic pancreatitis

Answer 68

-parenchymal fibrosis -loss of acini -variably dilated ducts -"enlarged" islets -chronic inflammation

Question 69

complications of chronic pancreatitis

Answer 69

-pleural effusions -pancreatic pseudocysts -pain from perineural fibrosis -pancreatic calcification -ascites -stones in pancreatic duct -fat malabsorption -diabetes

Question 70

pancreatic ductal adenocarcinoma (PDAC)

Answer 70

-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

Question 71

PDAC pathologic feaures

Answer 71

-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

Question 72

PDAC and metastasis

Answer 72

-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

Question 73

PDAC epidemiology

Answer 73

-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

Question 74

genetic and epigenetic events in pancreatic cancer

Answer 74

-disease of somatic mutations in neoplastic cells -mutations (intragenic mutations) -large deletions -amplifications -genetic instability/chromothripsis -mitochondrial mutations -DNA methylation

Question 75

genetics of pancreatic cancer

Answer 75

-inherit a mutation (BRCA2) -do something to damage our DNA (smoking) -chance with 6 billion base pairs in every cell

Question 76

2 different precursor lesions

Answer 76

1. PanIN- small microscopic lesions at <5 mm 2. IPMN- larger cysts at >=10 mm

Question 77

genetic progression towards invasive pancreatic cancer

Answer 77

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