Chapter 17: SI and Colon Flashcards
What are signs of obstruction of the SI?
- Abdominal distension
- Vomitting
- Pain
- Constipation
- Tympanic
MCC of Small Bowel Obstruction
- Bulges (Hernias)
- Adhesions
- Intussception
- Volvulus
MCC SBO in the world
Hernias
MCC SBO in the USA
Adhesions
What is a hernia?
Weakness/defect in abdominal wall that allows a serosa lined pouch of peritoneum to protude (hernia sac) & can trap bowel segments externally.
Acquired hernias most typically occur ________ into which sites?
- Anteriorly
- Femoral and Inguinal canals
- Umbilicus
- Surgical scars
How do hernias cause obstruction?
External herniation (visceral protrusion)
Which type of hernia is most often associated with obstruction and why?
-
Inguinal hernias
- They have narrow orrifices and large sacs
-
Inguinal hernias
What is the sequalae of hernias?
- Incarceration: venous stasis + edema increase size of hernia loop => becomes permanent entrapment
- Strangulation: squeeze arteries and veins
- Infarction
What is an adhesion?
- Local inflammation that heals (fibrosis) and forms bands of scar tissue in peritoneal cavity, most often after surgery
*Also in trauma, infection, endometriosis
Adhesions can lead to the formation of ___________.
Internal hernias
- (Viscera can slide through fibrous bridges created by scar tissue/fibrous bridges => internal hernia)
- In women, adhesions can cause?
- Treatment of adhesions?
- Infertility bc ovum cannot be transported
- Surgery (lysis of adhesions; can lead to more adhesions)
What is a volvulus and where is it most common?
- Twisting of the bowel around mesentary, causing obstruction and infarction
- Sigmoid colon > cecum
Volvulus can lead to ___________
Toxic megacolon
What is the classic patient for volvulus?
Older patient (>70s)***and if in children, can be due to Meckels
- What is the most common cause of intestinal obstruction in children < 2 years old?
Intuscception (spontaneous or viral infection; rotavirus)
What is intussception?
Where is it most common?
- Proximal Intestinal segment gets trapped by a leading edge (lesion), and “telescopes” (with the mesentary) into the immediately distal segment due to peristalsis.
- MC: ileocecal junction (terminal ileum telescopes into cecum)
If untreated, intusseception can cause (3):
- Obstruction
- Bleeding (mesentary is pulled with it = compresses vessels ) => current jelly stool
- Infarction
Although typically idiopathic, some cases of intussusception have been associated with what?
Children: viral infections (rotavirus vaccine)
Adults (rare): intraluminal mass or tumor
What is the leading point seen in Intussception caused by a viral infection, like rotavirus?
- Reactive hyperplasia of Peyers patches and lymphoid tissue, causing them to trap the intestines
___________ is used diagnostically and therapeutically for intussusception in infants and young children?
Contrast enemas
What occurs when there is blood loss to the intestines?
- Slow and progressive blood loss = collateral blood supply compensates
- Abrupt blood loss= infarction of several meters
What symptoms are seen in ischemic bowel disease?
Ischemic Bowel Disease, typically occurs with a CV defect.
- 1. Abdominal pain
- 2. Hemtochezia
- 3. Decreased bowel sounds
___________ are at increased risk for ischemic bowel disease (2):
Watershed zones between major vessels (2)
- Splenic flexure via the marginal artery of dremmond (connects superior and inferior mesenteric a.)
-
Rectosigmoid colon
- IMA, pudendal, and iliac arteries end
What damage do we see in ischemic bowel disease and what part of the intestines is damaged?
Ranges from mucosal infarcation => transmural infarction of the epithelial cells at the top of the villus (bc at end of capillary), NOT the crypt epithelial cells (bc at end of capillary)
Causes of transmural infarctions due to ischemic bowel disease?
- A-fib, AAA, atherosclerosis, vascultiis =>
* Thrombosis/embolism of SMA
* thrombosis of mesenteric vein
- A-fib, AAA, atherosclerosis, vascultiis =>
Causes of mucosal infarctions due to ischemic bowel disease?
Hypotension
How does the route of intestinal capillaries running along [glands from crypt => surface epithelium] play a role in the pattern of atrophy and necrosis seen with ischemic intestinal disease?
- Surface epithelium is particularly vulnerable
- Morphological signature =
- Surface epithelium at the top of villus atrophies/necrosis => sloughs off
- Crypts are NL or hyperproliferative
In ischemic bowel disease, what does mucosal infarction look like?
- Patchy mucosal hemorrhage and ulceration with NL serosa
- Bowel wall: [thick with edema in mucosa].
What are the gross morphological characteristics of ischemic bowel disease especially with transmural infarction?
How does it look after initial insult and then later on?
- Large portions of the bowel are affected with a sharp line between infarcted and healthy tissue.
- Initially: congested and dusky to purple-red
- Later –> bowel wall becomes thick and rubbery d/t edema
- After 1-4 days, coagulative necrosis of muscularis propria => perforation.
In chronic ischemic bowel disease, what morphology do we see of the intestines?
Fibrous scarring of lamina propria
In both acute and chronic ischemic bowel disease, what happens when a bacterial super-infection occurs?
Pseudomembrane forms, like in C-diff
Ischemic bowel disease is most common in who?
Caused by what and will they die?
- 70s
- Caused:
- Vasoconstrictor use like cocaine
- Epithelial damage from CMV/E-Coli (O157:H7)
- Trauma
- Unlikely to be fatal
Acute colonic ischemia typically presents clinically how?
If severe; ____
- Sudden onset of cramping
- LLQ pain
- Need to poop
- Hematochezia
If severe: shock and vascular collapse
Mortality from acute colonic ischemia is doubled in patients with what type of presentation?
Why?
Right-sided colonic disease
- Since right side of colon is supplied by SMA, which also supplies much of the small intestine
Other than right-sided involvment in acute colonic ischemia what are other poor prognostic indicators?
- COPD
- If sx and signs last longer than 2 weeks
When is surgery indicated for ischemic bowel disease?
- Absent bowel sounds (paralytic ileus)
- Guarding/rebound develops
Which virus may cause ischemic GI disease due to viral tropism for endothelial cells?
CMV
Intermittent blood diarrhea + intestinal obstruction are most often seen in what type of GI infarction?
Mucosal and mural infarctions
Beyond clinical hx, the presence of what may provide an important clue to the etiology of radiation enterocolitis?
Presence of highly atypical “radiation fibroblasts” in stroma
Ischemic bowel disease can also be due to?
- CMV
- Radiation enterocolitis
- Necrotizing entercolitis
Sx’s of acute radiation enterocolitis?
Chronic?
- Anorexia
- Abdominal cramps
- Malasoprtive diarrhea
If chronic, more indolent and can present as inflammatory enterococolitis
What is the most commonly acquired GI emergency in neonates?
Necrotizing Enterocolitis (NEC)
Classic patient in necrotizing enterocolitis (NEC)
Premature/LBW baby (occurs when oral feeding begins) in the NICU with abdominal distension and N/V;
What is necrotizing entercolitis?
Intestinal transmural necrosis, causing obstruction, usually in the terminal ileum or colon; can perforate
- What is Aangiodysplasia?
- Where does it most commonly occur?
- Who is it most common in?
- Symptoms?
- Malformed, tortuous and dilated BV in the mucosa and submucosa of the cecum or ascending colon that occurs stress to GI wall => compression and obstruction of submucosal veins
- MC in older pts
- Hematochezia (20% of lower GIB)
- Malabsorption is defective absorption of nutrients due to an intestinal process, usually presenting as _________.
- Hallmark of malabsorption = ___________.
-
Chronic diarrhea
- Other: WL/anorexia, abdominal istenstion, gurgling (borborygmi)
- Steatorrhea
Malabsorption is most commonly due to: (4)
- Pancreatic insuffiency
- Celiacs
- Crohns
- Intestinal GVHD after hematopoietic stem cell transplant
- Malabsorption results from disturbances in at least 1 of the 4 processes of nutrient absorption (4):
- Interruption of Intraluminal digestion: Emulsification + break down of nutrients into absorbable forms
- Terminal digestion: Hydrolysis of carbs and proteins in enterocyte brush border
- Transepithelial transport: moving across small intestinal epithelium
- Lymphatic transport of absorbed lipids
Which 4 diseases are associated with a defect in intraluminal digestion?
- 1) Chronic pancreatitis
- 2) Cystic Fibrosis
- 3) Primary bile acid malabsorption
- 4) IBD
What are consqeuences of malabsorption?
- Anemia
- Mucositis
- Vitamin deficiences/ electrolyte (Ca/Mg)
- Bleeding
- Osteopenia and tetany
Describe how to categorize diarrhea
When presented a case of diarrhea, important to differentiate the type:
-
1. Steatorrhea
- Malabsorptive diarrhea due to problem with nutrient aborption
- Greasy, foul smelling, float
-
2. Inflammatory/exudative diarrhea (+ RBC/WBC)
- Bloody, purulent diarrhea due to inflammatory disease.
-
3. Watery diarrhea (two types)
- Secretory diarrhea: watery diarrhea (isotonic stool) that persists when fasting. Ex. Cholera
- Osmotic diarrhea: watery diarrhea often seen in lactose intolerance: Unabsoprbed solutes pull water (osmotic forces).
- More than 50mOsm concentrated than plasma.
Describe how the following diarrheas are affected by fasting:
- 1. Malabsorptive diarrhea
- 2. Exudative diarrhea
- 3. Secretory diarrhea
- 4. Osmotic diarrhea
- 1. Malabsorptive diarrhea: relieved by fasting
- 2. Exudative diarrhea: persists
- 3. Secretory diarrhea: persits
- 4. Osmotic diarrhea: relieved
- What is the disease that only has a problem with terminal digestion?
- Disaccharidase deficiency
- What is the only disease that only has a problem with lymphatic transport?
- Whipple disease
- What is the only disease that only has a problem with transepithelial transport?
- Abetalipoproteinemia
Painful, bloody, small-volume diarrhea is known as?
Dysentery
How does cystic fibrosis cause malabsoprtion?
What type of diarrhea does it cause?
- Loss of CFTR =>
- Defective HCO3-, Na+ and H20 secretion =>
- Defective luminal hydration =>
- Causes intestinal and pancreatic intraductal concentrations =>
- Pancreatic duct obstruction, low grade chronic autodigestion of the pancrease and exocrine pancreatic insufficiency
- Malapsorptive diarrhea.
How would we treat malabsorption in a patient with CF?
Oral enzymes
What is Celiacs Disease?
Where in the GI is damage most often seen?
- AI reaction (Type 4 HS) the causes destruction of small intestinal villi when exposed to gluten (bread)
- 2nd part of duodenum and jejunum
The pathogenic component of gluten that causes Celiacs disease is ________________.
-
a-gliadin
- In order to be pathogenic, gliadin => must be deaminated by tissue transglutaminase (tTG) => become immunogenic.
Once gluten => a-gliadin, how does it cause damage?
- Gliadn causes epithlial cell to express IL-15 –> activation/proliferation of CD8+ lymphocytes (Type 4 HR), which express NKG2D (receptor for MIC-A)
- Damaged enterocytes express MIC-A and are attacked by CD8+ cells
- Gliadin deposits in damaged epithelium => deaminated by tissue transglutaminase (tTG)
Deamidated gliadin peptides in the damaged epithelium interact with what on APC’s?
Leads to?
- Interact w/ HLA-DQ2 or DQ-8 on APC’s via MHC Class 2
- Stimulates Helper CD4+ T cells to produce cytokines => damage tissue
Celiacs Disease is associated with which genetic markers?
HLA DQ2 and HLA DQ8
Celiacs disease is a _______ hypersensitivity reaction.
Type 4: T-cell mediated tissue damage, but Ab are present
3 Key features on histology in a patient with Celiacs Disease?
- Which cells are seen in increased numbers?
In duodenum, we will see
- Flattening/atropgy of villus; loss of mucosal and brush border
- Crypt hyperplasia
- Intraepithelial CD8+ lymphocytes (in the lamina propria of villus)
Increased # of plasma cells, eosinophils, and mast cells
What is the clinical presentation of a patient with Celiacs Disease?
- Abdominal distension, bloating, diarrhea (steatorrhea), anemia
* *Failure to thrive if children
- Abdominal distension, bloating, diarrhea (steatorrhea), anemia
- Dermatitis herpetiformis: blistering skin lesion due to deposition of IgA Ab at the tips of the dermal papilla; goes away with gluten free diet.
Sensitive marker for Celiac Disease, even in the w/o of villous atrophy and epithelial damage?
What combo is most specific for diagnosis?
- intraepithelial CD8+ lymphocytes, particularly within villus
- histology + serology
- Serology: Ab to tTG*** or anti-endomysial (EMA)
Ages & sex Celiac Disease most commonly present?
- 30-60
- F: due to menstrual bleeding impairing abosprtion
What laborartory findings do we see in Celiacs Disease?
-
Without IgA defiency
- IgA Ab to ttG, endomysium or gliadin
-
If IgA defiency, (which is often increaed in patients with Celiacs disease)
- IgG Ab
Which characteristic rash is seen in some patients with Celiac Disease?
Cause?
- Dermatitis Herpetiformis –> itchy, blistering skin lesion formed when anti-gluten Ab that cross-react with BM proteins.
What are the 2 most sensitive serologic tests for Celiac disease?
If - => ?
If + =>?
- IgA anti-tTG Abs***
- IgA anti-endomysial Abs
If IgA deficient by sx, check IgG levels to tTG and EMA
If +, do a biopsy to confirm.
Which malignancies are most common in patients w/ Celiacs Disease?
- Enteropathy associated T-cell lymphoma (most common)
- SI adenocarcinoma
When a patient with Celiac disease is following a gluten-free diet but is still experiencing symptoms of refractory sprue weight-loss, abdominal pain, and diarrhea, what differential diagnoses must be considered?
- T cell lymphoma
- SI adenocarcinoma
In pediatric celiac disease (classic onset 6-24 months), MC in M/F?
No gender prefernce
What is tropic spure (environmental enteropathy)?
Histology and affects are similar to Celiacs disease, except? (3)
Damage to the SI villus due to an unknown organism, causing malabsorption.
- Occurs in tropical regions (Carribean); poor sanitation and hygeine
- Occurs after infectious diarrhea and responds to ABX
- Damage is most common in the distal bowel- jejujum and ileum
* which can cause vitB12/folate defiiency
- Damage is most common in the distal bowel- jejujum and ileum
The cause of Tropical Sprue isn’t known, but what are some of the likely involved factors?
- Defective intestinal barrier function
- Chronic exposure to fecal pathogens
- Repeat bouts of diarrhea within the first 2 or 3 years of life
What is the classic case of Tropical Sprue?
- Travel to tropics
- Chronic diarrhea (steatorrhea and watery diarrhea d/t sugar malabsoprtion)
- Malabsoprtion then occurs
Treated with ABX and follate suppliment, however sx may not be treated
What is Autoimmune enteropathy?
X-linked autoimmune disease that causes severe and persistant diarrhea in young children
A particularly severe familial form of Autoimmune Enteropathy is known as?
What is the underlying genetic defect?
- IPEX - immune dysregulation Polyendocrinopathy, Enteropthy, and X-linkage
- FOXP3 mutation => defective CD4+ Treg cells
Autoimmune Enteropathy
- Autoantibodies:
- Histology
- Treatment:
- Autoantibodies: enterocytes/goblet cells and parietal cells/islet cells
- Histology: neutrotrophils and intraepithelial lymphocytes
- Treatment: Immunosupression and HSC transplant
What is lactose intolerance?
- Deficiency in the lactase, a brush-border enzyme that breaks down lactose => glucose and galactose, causing the undigested/unabsorbed lactose to have an osmotic pull in the SI => osmotic diarrhea (watery) that is explosive and frothy.
In patients with lactose intolerance, on biopsy we will see _________.
NOTHING :) because defect is biochemical
Symptoms of lactose (disaccharide) deficiency
- 1. Osmotic diarrhea that is explosive and frothy
- Abdominal distension and flatulence due to bacterial fermentation of lactose.
Lactose (Disaccharide) Deficiency Causes
- Congenital lactase deficiency
- Acquired lactase deficiency
-
Congenital lactase deficiency => AR LOF of lactase gene
- rare
-
Acquired lactase deficiency =>
- ↓ of lactase gene overtime that is more common in Native Americans, AA, Chinese.
- Viral or bacterial infections of GI system that damage muscoa (bc lactase is located in distal tips of villus). May resolve over time
Patients can present with lactose tolerance after which GI diseases?
- Guardia
- Celiacs
- IBD
What is Abetalipoprotenemia?
Rare autosomal recessive disoder in infancy that cause by the inability of lipids to leave epithelial cells => intracellular accumulations.
What is the mutation in abetalipoproteinemia?
AR mutation in MTP (microsomal triglyceride transfer protein), which transfers lipids to APO B in ER => deficiency of lipoproteins with APO B=> cannot make chylomicrons (=> malabsorption) or VDL/LDL => intracellular accumulation of lipids.
What is seen histologically in Abetalipoproteinemia?
Stained how?
- Lipid vacuolization in SI epithelial cells
- Stains with oil red-O, particularly after fatty meal
When is the onset of Abetalipoproteinemia and what are the signs/symptoms?
What is seen serologically
- Presents in infancy
- Failure to thrive, diarrhea, and steatorrhea
- Complete absence of all liproteins with ApoB (serology)
- Cant to absorb fat-soluble vitamins (ADEK)
Failure to absorb essential FA’s in Abetalipoproteinemia leads to deficiencies of fat-soluble vitamins as well as lipid membrane defects that can be recognized by the presence of what in peripheral blood smears?
Acanthocytic red cells (Burr cells)
What is irritable bowel syndrome (IBS)?
-
Functional bowel disease (no pathological abnormality) that causes
- Chronic relapsing bowel pain (at least 3 days month/ last 3 months)
- Bloating
- Changes in stool frequency and form
IBS is most commonly seen in ______
F 20-40
Causes of IBS
- Psychologic stressors
- Diet
- Abnormal GI motility
- Disrupted brain-gut axis,
- immune activation
- Altered gut microbiome
How do we diagnose IBS?
Clinically, because gross and microscopic evaluation is NL.
- Adominal pain 3 days/month for the last 3 months
- Pain improves after pooping
- Change in stool frequency or form
Patients with _____________ of IBS are less likely to improve; long term sequaelae is _________.
- Longer duration
- Not serious
What has been identified as one cause of diarrhea-predominant IBS?
- Excess bile acid synthesis
- Bile acid malabsorption
Treatment of IBS
- Depends on signs and symptoms: 5HT3 ANT, opiods, anticholinergics or fecal transplant
- What is IBD (inflammatory bowel disease)?
- What is its course?
- Sx
- Group of chronic AI bowel diseases due to inappropriate mucosal immune responses to NL gut flora
- UC and Crohns
- Relapsing, remitting course with flares, where meds are increased
- Both disorders cause recurrent episodes of bloody diarrhea and abdominal pain
IBD is most common in ________ and where and why?
- White F (teens -20s) who are Ashkanazi Jews
- Developed countries, leading to hygeine hypothosis: increasing incidence is due to improved food storage conditions/ decreaed food contamination, and changes in gut microbiome composition => reduced frequency of enteric infection => immune regulation of mucosa does not develop
What is the difference between UC and Crohns, in terms of location and inflammation?
- UC: Continuous inflammation of the mucosa and submucosa (not full thickness, like in Crohns) that ALWAYS begins in the rectum => colon, forming ulcers and LLQ pain. Never involves SI
- Crohns: Segmental transmural granulomatous inflammation that occurs in any part of GI (mouth => anus), most commonly terminal ileum causing RLQ pain.
______ causes RLQ pain.
________ causes LLQ pain.
- Crohns = RLQ
- US = LLQ
How does smoking affect Crohns and UC?
- Improves outcomes in US
- Worsens outcomes in Crohns
[Insert chart here]
Mutation of which gene is most strongly associated with Chron disease?
What are some of the other implicated genes?
- NOD2 - affects NF-kB activation
- ATG12L1 = part of autophagy path
- IRGM = part of autophagy path
*All involved in recognition and response to intracellular pathogens
AR mutations in which cytokine and receptor genes are linked to severe, early onset IBD?
- IL-10 and the IL-10 receptor;
- TGFB
__________ polymorphisms have a reduced risk of Crohns and UC.
TH17 cells with IL-23 receptor polymorphisms
- Antibodies against ________ are common in Crohn’s disease, but uncommon in ulcerative colitis.
Flagellin
Which epithelial defect is associated with Chron Disease?
Tight junctions of intestinal epithelial cells due to NOD2 polymorphism
Which polymorphisms associated with epithelial barrier defects have been implicated in ulcerative colitis?
- ECM1 protein polymorphism —> typically inhibits MM9
- HNFA transcription factor polymorphisms
What is one of the morphologic hallmarks of Chron Disease?
Non-caseating granlomas of the intestinal wall
Relapsing blood diarrhea, Fistula, Fibrosing Strictures, and Perforations are all common findings in which IBD?
Chron Disease
What are the ulcers like in Chron Disease vs. UC?
- Chron = DEEP and knife-like - elongated, serpentine
- UC = SUPERFICIAL and BROAD-based
Which 5 extraintestial manifestations are associated with both Chron and UC?
- Migratory polyarthritis
- Ankylosing spondylitis
- Primary sclerosis cholangitis
- Sacroiliitis
- Uveitis
- Skin lesions
Erythema nodosum and clubbing are associated with what form of IBD and may develop before intestinal disease is recognized?
Chron disease
How is UC different from Chron disease grossly when viewing the gut wall, serosal surface, and appearance of strictures?
- Mural thickening is NOT present, are thin instead
- Serosal surface = normal
- Strictures do NOT occur
Toxic megacolon can result from damage to the muscularis propria in which form of IBD?
Ulcerative Colitis
Isolating islands of regenerating mucosa bulging into the intestinal lumen, creating pseudopolyps, is characterisitc of which form of IBD?
Ulcerative Colitis
Cobblestone mucosa, creeping fat, and strictures are associated w/ what form of IBD?
Chron disease
Which factors are associated with dysplasia => colitis assocated neoplasia in patients with Ulcerative Colitis and Colonic Chron Disease?
- Duration: (increases sharply 8-10 years)
- Extent: pts w/ pancolitis are at greater risk
3. Nature of inflammatory response: greater frequency and severity of active inflammatio (presence of neutrophils) = increased risk
Patients with IBD and which extraintestinal manifestation of the disease have a greatly increased risk of developing cancer and are generally enrolled for surveillance at the time of diagnosis?
Primary sclerosing cholangitis
- Cases of IBD without definitive features of either ulcerative colitis or Crohn disease are called ___________ (occur in 10% of patients)
- Indeterminate Colitis
What is the location of Indeterminate Colitis?
Colon only (does not involve small bowel) and in continous pattern; however not UC because can have features of Crohns
To determine whether indeterminate collitis is Crohns or UC, measure _____
p-ANCA or ASCA
- p-ANCA => UC
- ASCA => Crohns
- ____________ is a complication of ostomy and blind distal segment of colon, where normal fecal flow is diverted.
- Diversion Colitis
What is the goal of survellacnce biopsies?
ID dysplastic epithelium
- __________ is the most stiking feature of diversion colitis.
- ________ = treatment
- Numerous mucosal lymphoid follicles
- Reanastamosis
Microscopic colitis encompasses both _________ and ________, which both cause whst symptoms?
- Collagenous colitis
- Lymphocytic colitis
- Chronic, watery diarrhea WITHOUT weight loss.
UC in the entire colon is called ______
pancolitis
What are 3 features of collagenous colitis?
- Dense, subepithelial collagen layer
- Intraepithelial lymphocytes
- Mixed inflammatory infiltrate in lamina propria
What are 2 features of lymphocytic colitis?
- NL thickness of subepithelial layer
- Increase # of intraepithelial lymphocytes (1 T-cell/5 colonocytes)
________ is more common in middle-aged/older women.
Collagenous colitis.
Lymphocytic colitis is associated with ______________.
- Celiac disease
- AI disease (Graves, RA, autoimmune of lymphocytic gastritis)
GVHD (graft vs host disease) occurs after a HCS transplant.
__________ is the most common histological finding in GVHD that affects the small bowel and colon
Epithelial apoptosis of crypt cells
GVHD that affects the SI/colon most commonly causes __________.
Watery
-
Colonic diverticula (acquired pseudodiverticulum of mucosa and submucosa through muscularis propria) are most common in the __________.
- If multiple = ________
- If inflamed and irritated = _____
- Sigmoid colon (Sigmoid colonic diverticular disease) along the taeniae coli, where vasa recta traverse through the muscularis propria, creating weak spots
- Diverticulosis
- Diverticulitis
Sigmoid colonic diverticular disease is caused by _____.
- Increased wall stress (increased intraluminar pressure)
- - Exaggerated peristaltic contractions with spasmodic sequestration
- Unique structure of musclaris propria
What factors can contribute to the formation of colonic diverticuli?
- Increase straining when pooping
- Constipation
- Low-fiber diet
Colonic diverticula are occur on the _______ side of the colon in Western countries and the ______ side of the colon in Japan and developing countries due to dietary differences.
- Western = L (sigmoid colon along taenia coli, where vasa recta traverses muscularis propria)
- Japan and developing countries = R
Clinically, how will patients with colonic diverticula present?
Usually asymptomatic, but can present with
- Hematochezia, constipation and distension, feeling of always needing to poop
- Diverticulitis = appendicitis-like symptoms in the LLQ due to obstructed fecal flow
- Fistula
Treatment and management of colonic diverticula?
High fiber diet
Polyps, are most common in the ___________, that begin as _________.
- Colorectal region
- Raised protusions of the colonic mucosa
What are symptoms of polyps?
- Usually asympomatic, which is why colonoscopies are performed
- If large, can cause occult blood in stool that is confirmed with fecal occult blood test.
What are the 2 most common types of Polyps and are they benign?
- Hyperplastic polyps (benign, no malignant potential)
- Adenomatous polpyps (benign, but pre-malignant)
You get a phone call from your mom telling you that upon colonoscopy, the endoscopist found a polyp. What do you tell her?
Assure it is okay and probably benign, because the most common polyp is a Hyperplastic Polyp.
_________ is the most common neoplastic polyp.
Non-neoplastic polyps include: ___________.
- Adenoma
- Hyperplastic, inflammatory, harmartomous
Hyperplastic polyps:
- Single/many?
- Made up of what cells?
- Grossly, look like?
- Many
- Goblet and absorptive cells
- Smooth, nodular protrusions on mucosal folds
Hyperplastic polyps are many benign hyperplastic glands that are found in 60-70s, however because decreased cell turnover, we get a buildup of goblet and absorptive cells that look serrated and sawtooth on histo; smooth and nodular on mucosal fold
Appearance of hyperplastic polyps
-
Sawtooth, serrated restricted to upper 3rd of crypt with NL colonic mucosal cells (no dysplasia) caused by hyperplasia of glands
- Delayed shedding of goblet cells and absorptive cells due to decreased epithelial cell turnover => sawtooth appearance)
Hyperplastic polyps are usually found at ages _____.
60-70s
Clinically, it is important to differentiate hyperplastic polyps from _____________, which are histologically similar but have malignant potential
Sessile, serrated adenomas
Inflammatory polyps are benign polyps that are caused by
- Impaired relaxation of anorectal sphincter => creates a sharp angle at the anterior rectal shelf => leads to recurrent abrasion and ulceration of the rectal mucosa, which can form an inflammatory polyp.
Patients with inflammatory polyps present with a triad of:
- Rectal bleeding
- Mucus discharge
- Inflammatory lesion on anterior rectal wall
Complication of inflammatory polyp:
- Entrapped by poop and prolapse
(3) Histological features of inflammatory polyps
- Mixed inflammatory infiltrates
- Epithelial cells: Erosion and hyperlasia
- Lamina propria: fibromuscular hyperplasia
How do harmatomatous polyps occur?
- Sporadically
- Genetic syndrome
Due to germline mutation in tumor supressor genes or proto-oncogenes.
Are hamartomatous polyps pre-malignant?
- Yes.
What are Juvenile polyps?
Harmatotomatous polyps (benign, pre-malignant) that are pedunculated with cystic space that occur in children under 5.
- Sporadcally: single and not pre-maignant
- JVPS: 3-1000s and premalignant
BSI and colon mucosa (usually in the rectum)
What are the most common mutated genes/pathways in Juvenile Polyposis?
Which gene mutation is most common?
Initiating event: mucosal hyperplasia
- SMAD4 = most common mutation!
- BMPR1A
- TGF-β signaling pathway
Syndromic Juvenile Polyps have which inheritance pattern?
Autosomal dominant (3- 1000 polyps)
What are the risks of dysplasia in the sporadic vs. syndromic-type of juvenile polyps?
Which cancer may be manifested later in life?
- Sporadic = extremely rare bc often solitary lesions
- Syndromic = high risk for dysplasia –> Colonic adenocarcinoma by age 45
- Symptoms of Juvenile Polyps?
- Complications?
- Often autoamputate and cause painless rectal bleeding
-
Congenital malformation
- intussception
- intestinal obstruction
- Polyp proloapse
-
Exta-manifestion
- clubbing
- Pulmonary AV malformation
- polydactyl
What are some of the recognized extraintestinal manifestations of juvenile polyps?
- Clubbing
- Polydactyl
- Pulmonary AV malformation
Morphology of Juvenile Polyps
- Solitary, pedunculated with cystic spaces, filled with mucin and inflammatory debris.
- 30-50% develop colonic adenocarcinoma by age 45 if they have____________________
- juvenile polyposis syndrome (dysplasia present)
What is Peutz- Jeghers syndrome?
- AD disorder in young people (11 YO) where you get multiple harmartomas throughout GI tract (mostly SI) and mucocutaneous hyperpigmented spots (dark blue-brown macules) on lips, buccal mucosa and genitals (like freckles except freckles are not on buccal mucosa)
Peutz-Jeghers syndrome is inherited ______.
AD
The mucocutaneous hyperpigmentation associated w/ Peutz-Jeghers syndrome is similar to freckles, but how is it distinguised?
Presence on the buccal mucosa
Which gene mutation/pathways is most often present in patients w/ Peutz-Jeghers Syndrome?
- LOF (both alleles) of STK11 (tumor suppressor)
- lack of mutation does not exclude disease
- Causes loss of AMP kinase-related pathways regulating cell polarization and acting as a brake on growth/anabolic metabolism
Pts with Peutz-Jeghers Syndrome have a markedly increased risk of several malignancies, which malignancies are most common at birth, late childhood, and 2nd-3rd decades of life?
- Birth = sex cord tumors of testes
- Late childhood = gastric and small intestinal cancers
- 20s- 30s = colon, pancreatic, breast, lung, ovarian, and uterine cancers
What is the distinguishing morphological characteristics of Peutz-Jeghers polyps, which can be helpful in differentiating from those of Juvenile Polyps?
ARBORIZING network of CT and SMOOTH muscle intermixed w/ lamina propria
________ polyps are the most common neoplastic lesions that are benign precancerous lesions (=> colonic adenocarcinoma) and beome cancerous via the __________ pathway
- Colonic adenoma polyps
- Adenoma- carcinoma sequence
How can we classify colonic adenomatous polyps?
- Small, often pedunculated polyps => large sessile polyp
-
Shape:
- Sessile
- Pedunculated (on a stalk)
-
Histology
- Tubular (MC*)
- Villus (Less common)
What type of adenematous polyps have an increase risk of becoming colon cancer?
- Villus, which are often sessile with long projections that extend from surface
What is the frequency of colonic adenomas in the Western World and by what age?
How do they present clinically?
What are they associated with?
- 30% of people at 60 YO; slightly M predominance
- Clinically silent
- Western diet
In regards to colonic adenomas, what is the most important characteristic that correlates with malignancy?
Size
- I.e., cancer extremely rare in adenomas <1 cm, but 40% lesions >4 cm contain foci of cancer. Thus, majority do not undergo transformation.
- Sessile, serrated adenomas are more commonly found in the _______.
- What is their architecture?
- Right colon
- Potentially malignant, lack features of dysplasia.
- Serrated thoughout full gland.
_____________ occurs when dysplastic cells invade the lamina propria or muscularis mucosa.
What is a unique feature?
- Intramucosal carcinoma
- No lymphatic channels => rarely/does not metastasize
When does invasive adenocarcinoma?
Crosses submucosa and accesses lymphatics & can metastasis.
High Risk Polyps => new more frequent screenings; what puts people at high risk?
Villous histology
Genetics of cancer
- What are the 2 pathways to colon cancer?
- _______ is increased in colon cancer.
- _______ is mutated in advanced colorectal cancer.
- 2 pathways to colon cancer
- Chromosomal instability pathway
- microsateelite instability pathway
- ↑ COX 2 expression in colon cancer
- DCC gene (tumor supressor gene on Ch18q) is mutated in advanced colorectal cancers = tumor supressor gene on Chr18q used as a prognostic predictor (lower survival)
What is the chromosomal instability pathway (adenoma- carcinoma sequence)?
- A sequene of genetic events that lead to colon cancer over many years (10-40), as somatic mutation occur as we age.
- More common in L sided tumors (descending colon, sigmoid and rectum)
- Sequence
- [NL colon] => (Step 1: APC mutation) Loss of APC -> ↑ in B-catenin of WNT path - > + of oncogenes) => [Colon @ increased risk for polyps] => Step 2: KRAS mutation => [Tubular/ villous adenoma polyp on L side of colon] => Step 3: p53 mutation/SMAD2 and 4 => [Typical colorectal adenocarcinoma cancer in L side of colon]
- APC tumor supressor (adenomatous polyposis coli) does what?
- K-RAS protooncogene: Mutation does what?
- p53 tumor supressor: mutation does what?
- APC tumor supressor (adenomatous polyposis coli) that prevents accumulation of B-catenin, which + oncogenes.
- K-RAS protooncogene = leads to adenoma polyp formation
- p53 tumor supressor => mutation => tumor cell growth
What is FAP (familial adenomatous polyposis)?
AD disorder caused by a germine mutation of APC gene, a (-) regulator of WNT pathway on Chr5q.
=> create 1000s of typical/villous adenoma polyps => 100% by age 50 develop into typical colorectal adenocarcinoma
________ develops in 100% of patients with FAP, at what age?
Colorectal adenocarcinoma, often <30 YO always by 50YO.
FAP polyps are indistinguishable from ________.
Sporadic adenomas
Which extraintestinal manifestation associated with FAP can generally be detected at birth and therefore may be an adjunct to early screening?
Congenital hypertrophy of the retinal pigment epithelium
*Can also be seen in attenuated FAP but won’t present until age 40-50
Some polyposis patients without APC loss may have bi-allelic mutations of which gene and the what is the function of this gene normally?
When present this disorder is called?
- MYH –> base-excision repair gene
- MYH-associated polyposis
What is MYH associated polyposis?
- Bilallelic mutations of MYH that causes <100 sessile serrated adenomas polyps to develop later than FAP and get colon mucocinous adenocarcinoma >50YO.
How is MYH-associated polyposis (aka MUTYH-associated) different from FAP?
- Similar to the attenuated version
- Sessile serrated adenoma develop LATER (age 30-50) w/ FEWER than 100 adenomas
- *FAP must have at least 100 polyps and can often have 1000’si
- Colorectal MUCINOUS ADENOcancer appears later, often at ages 50 or older
- CIS: Adenomatous polyps are known precursors to the majority of colorectal adenocarcinomas (adenoma-carcinoma sequence). Which characteristic of an adenoma is the most important that correlates with risk of malignancy?
- Location in the colon
- Tubular vs villous
- Sessile vs pedunculated
- Polyp size
- Age of patient at presentation
Polyp size is the BEST predictor of malignany (4cm is the threshold)
What is the most common syndromic form of colon cancer?
- Hereditary nonpolyposis colorectal cancer (HNPCC; Lynch Syndrome)
What is Hereditary nonpolyposis colorectal cancer (HNPCC; Lynch Syndrome)?
- Mutation?
- What does it lead to?
- What is the precursor lesion?
-
AD mutation of MSH2/MLH1 DNA mismatch repair enzymes due to microsatellite instability that leads to
- right sided serrated sessile adenoma polyps =>
-
right sided colon mucocinous adenocarinoma (80% lifetime risk) at a younger age
- a number of cancers through body (endometrium, stomach, ovary, brain, pancrease)
- Can occur without a precursor lesion
What age range is typical for the classic-type FAP?
What age range is typical for the attenuated-type FAP?
- 10-15 YO
- 40-50 YO
- Which subtype of FAP is associated w/ Osteomas, Thyroid and Desmoid Tumors, and Skin Cysts?
- Which subtype of FAP is associated w/ Medulloblastoma and Glioblastomas?
Typically presents during which ages?
- Gardners syndrome (15-20)
- Turcot syndrome (15-20)
What is the normal histo features of the adenoma that arises from FAP?
What type of adenocarcinoma (typical or mucinous)?
- Tubular or Villous appearing adenoma
- Typical adenocarcinoma
*Image on left = tubular, image on right = villous
Which type of adenocarcinoma arises in HNPCC (typical or mucinous)?
Typical adenoma seen?
- Mucinous adenocarcinoma on right side
- Sessile Serrated adenoma
________ is the most common cancer in GI tract and occur more in _______
Colorectal adenocarcinoma
USA
- Colorectal cancer incidence peaks at which age?
-
60-70s
- younger in HNPCC and FAP
Several epidemiologic studies have shown that which pharmacologic agent may have a protective effect against colorectal carcinomas?
- NSAIDs, which inhibit COX-2
- COX-2 (& TLR4) is highly increased in colorectal cancers
Which gene/pathway mutation accounts for the majority of sporadic colonic adenocarcinoma?
-
Adenoma- Carcinoma sequence: (APC/ β-catenin (BOTH copies of APC must be inactivated)
- B-catenin mutation + protoncogenes via WNT signaling
What is the most common epigenetic event associated w/ colonic adenocarcinoma?
Methylation-induced gene silencing
As neoplastic progression of colonic adenocarcinomas continues what additional mutations may be acquired along the way?
- KRAS mutation
- Mutations in SMAD2 and SMAD4 –> TGF-β signaling
- Loss of function of TP53
In colonic adenocarcinomas, tumor suppressor genes may be silenced by methylation of which 2 regions?
- CpG-rich zone
- CpG island
Which chromosome is APC, KRAS, and TP53 located on?
- APC —> Cr. 5
- KRAS –> Cr. 12
- TP53 –> Cr. 17
In the sporadic-type of colonic adenocarcinoma involving the APC/WNT pathway, what type of adenoma is seen?
What type of adenocarcinoma (typical or mucinous) and is seen usually on what side of colon?
- Adenomas: tubular and villous
- Typical adenocarcinoma
What is Microsatellite Instability Pathway?
- Less common mechanism of colon CA development that occurs most often in RIGHT-sided (proximal) tumors; can arise de novo without a polyp
What causes microsatellite instabilities?
- Mutations in type 2 TGF-B- R and loss of BAX (pro-apoptotic) that cause defects in DNA mismatch repair enzymes caused by
A subset of microsatellite unstable colon cancers without mutations in DNA mismatch repair enzymes demonstrates which CpG island hypermethylated phenotype?
- Signature of this pathway = microsatellite instability + BRAF mutation + hypermethylation of MLH1
Colonic adenocarcinomas with mutations in DNA mismatch repair (MSH2, MLH1) or with microsatellite instabilities are commonly associated with what type of adenoma?
Produce what type of adenocarcinoma (typical or mucinous)?
On what side?
- Sessile serrated adenomas
- Mucionous adenocarcinoma
- RIGHT side
Patient who resents with right sided colon CA with multiple 1st family members with cancer. This is a classic case of?
HNPCC
Describe cancers that occur in the proximal RIGHT side of the colon (cecum and ascending colon).
- *Exophytic, polypoid tumors** often caused by micosatellite instability that bleed slowly and cause
- iron-deficiency anemia (fatigue and weakness) and WL
In contrast to tumors of the proximal colon, what are the characteristic morphologies of adenocarinomas in the distal (left) colon?
i.e., type of lesions, constriction or not, narrowing/thickening, obstructions?
- Circumferential/annular lesions that form “napkin ring obstruction” => change stool caliber (pencil then poop most often caused by adenoma-carcinoma sequence) => LLQ pain and blood streaked stools
Microscopically, what cells and morphology of these cells is seen in colonic adenocarcinomas?
Tall columnar cells that resemble dysplastic epithelium
Colonic adenocarcinomas that produce __________ are associated with poor prognosis.
mucin
What are the 2 most important prognostic factors for colonic adenocarcinomas?
1. Depth of invasion****
- Muscularis propria invasion = worse prognosis.
2. Presence of LN metastases
What is the most common site and other sites of metastases by colonic adenocarcinomas?
- MC: liver
- Other: regional LN, brain and lungs
The anal canal is divided into thirds, what type of cells are found in the upper, middle, and lower 1/3?
- Upper = columnar rectal epithelium
- Middle = transitional epithelium
- Lower = stratified squamous epithelium
*From top to bottom; ‘C’ comes before ‘S’
What cancers are most common in each of the 3 areas of the anal canal?
- Upper 1/3: Glandular carcinoma
- Middle 1/3: Cloacogenic carcinoma
- Lower 1/3: Squamous carcinoma, often associated with HPV and precursor lesions condylomas
In the anal canal, when the entire tumor displays a basaloid pattern, which term is used to describe the tumor?
Cloacogenic carcinoma
Hemorrhoids (anal varrices) are associated with what predisposing influences?
- Straining at defecation
- Constipation
- Venous stasis of pregnancy
- Portal HTN
What are the difference between external and internal hemorrhoids?
- External hemorrhoids occur with ectasia of the inferior hemorrhoidal plexus below the anorectal/pectinate line
- Extremely painful
- Internal hemorrhoid occur with ectasia of superior hemorrhoidal plexus above the anorectal line/pectinate
- Painless
- D/t straining
Mucinous cystadenocarcinomas of the appendix can invade the wall and lead to intraperitoneal seeding and spread, and in some advanced cases the abdomen fills with what?
This condition is called?
- Abdomen fills with tenacious, semisolid mucin
- Pseudomyxoma peritonei = disseminated intraperitoneal disease
What is peritonitis?
Inflammation of the mesothelial cells + CT that lines abdominal wall and covers abdominal organs due to:
- Bacterial infection
- Chemical irritation
- Perforation of abdominal viscera
What is sterile peritonitis due to?
Leakage of bile or pancreatic enzymes
- If perforates => irritating peritonitis worsed by bacterial superinfection
Perforation or rupture of the biliary system causes what type of peritonitis; may lead to?
- Sterile peritonitis that is highly irritating
- Bacterial superinfection
Which cause of peritonitis is associated with leakage of pancreatic enzymes + fat necrosis, damaing bowel and letting bacteria spread into peritoneal cavity?
- Acute hemorrhagic pancreatitis - peritonitis
What is released into the peritoneum with a rupture dermoid cyst of the ovary and what type of rxn ensues?
- Keratin is released
- Intense granulomatous rxn
- Irritation of the peritoneum due to objects introduced surgically (talc, sutures, watches) that can induce a foreign body type granuloma and fibrous scarring
- Irritation of the peritoneum due to hemorrhage into the peritoneal cavity
- Foreign material - peritonitis
- Endometriosis - peritonitis
What is bacterial peritonitis?
- Gi structure perforate => releases bacteria into the peritoneal cavity
Spontaneous bacterial peritonitis develops in the absence of a obvious source of contamination and is most often seen in whome? Less often?
- Most = cirrhosis and ascites
- Less = children with nephrotic syndrome
What are the 5 most common organisms associated with bacterial peritonitis?
- E. coli
- Streptococci
- S. aureus
- Enterococci
- C. perfingens
What is the morphology in peritoneal infection?
- Peritoneal membrane: superficial inflammation that is dull and grey
- => exudation and suppurtion
- Abcesses can form
Peritoneal tumors are RARE.
- Primary malignant tumors that ARISE from the peritoneal lining and are called?
- Almost always associated with what risk factor?
- Mesotheliomas (similar to tumors of the pleura and pericardium)
- Asbestos
What cancer develops in the peritoneum when other tumors directly spread or metastasize?
- Peritoneal carcinomatosis
- Pseudomyxoma peritonei?
-
Mucin produing tumor of the appendix that damages the peritoneum, producing mucin in the abdomen, causing ascites.
*
The _____ is the most terminal part of the lower GI tract/large intestine, which lies between the anal verge (anal orifice, anus) in the perineum below and the rectum above.
anal canal
Cancers in anal canal above pectinate line (and of the rectum) are __________.
Cancers of anal canal below pectinate line are usually ____________.
-
Above pectinate line (and of the rectum): adenocarcinoma.
- columnar epithelium
- Below pectinate line: squamous cell carcinoma (or basal cell carcinoma and melanoma).
* However, because the transitional zone is 2cm above pectinate line, you can have squamous cancer
Why are cancers in anal canal hard to treat?
- Infiltrate the anorectal ring and cause incontinence—a contraindication for sphincter preservation (by chemoradiotherapy for squamous cell carcinoma and low-anterior resection for adenocarcinoma)
Complications of appendicitucs
- Complications: pyelophlebitis, portal vein thrombosis, liver abscess, bacteremia
- Perforation = high morbidity.
Anal canal cancer (or rectal cancer infiltrating into the anal canal) spreads
to the __________________.
superficial inguinal LN
The anal canal just above the pectinate line for about 1-2 cm is called the anal pecten or transitional zone. Above this transitional zone, the anal canal is lined with ______________
(which is insensitive to cutting).
columnar epithelium
At the bottom of these anal columns are ___________.
anal sinuses/ crypts, which open the anal glands and anal papillae.
Infection of the anal glands is likely the initial event in causation of _________ and ________.
- Perianal abscess
- Fistula-in-ano
Acute appendicits can progress to ________.
to acute gangrenous appendicitis followed by perforation (suppurative peritonitis)
How are internal hemorrhoids removed?
- Injected with sclerosant or ligated w a rubber band without anesthesia (bc painless)
Who is more likely to get hemorrhoids?
- Females with inta-adbominal mass that impedes venous retrun
- Portal HTN ( => caput medusae).
Where can you see columnar => squamous metaplasia?
- Anus (above pectinate line)
- Esophagus
- Cervix
A 78 year old male presents with low back pain. Review of systems includes a 20 pack year smoking history. PMH includes hypertension and pancreatitis. Surgical history is notable for tubular adenomas (last colonoscopy age 75). X-ray reveals extensive sclerosis of boney pelvis as well as lumbar and thoracic vertebra (image). Which of the following combinations is most likely?
A. Thyroid mass, elevated serum calcium
B. Right bronchial mass, elevated PTHRP
C. Anterior rectal mass on DRE, elevated PSA
D. Macronodular cirrhosis, AST>ALT
E. Ankylosing spondylitis, HLA B27 positive
C. Anterior rectal mass on DRE, elevated PSA
The appendix is a _____________ of the cecum, most commonly located ________.
- True diverticulum
- Retrocecal
What is acute appendicits?
Special Test?
-
Acute inflammation of the appendix that occurs when the opening to the cecum becomes obstructed ( fecaliths or lymphoid hyperplasia) => increase intraluminal pressure and causes venous obstruction, causing periumbilical pain => RLQ, N/V, high peripheral white cell count.
- McBurneys point (1/3 distance from BB to iliac crest)
Who is more likely to get acute appendicits?
Adolescents and young children; M
DDX of acute appendicitis?
- Meckels diverticulum
- Mesenteric lymphandenitis
- Acute salpingitis
- Ectopic pregnancy
- Mittleschmirtz
How does acute appendicitis occur?
- Initiated by progressive increases in intraluminal pressure (d/t obstruction of the APPY lumen by poop (fecalith), tumor, or pinworms) => that disrupt venous outflow
- => ischemia - worsened by edema and exudate
- => bacterial invasion
- => inflammatory response: neutrophilic infiltration of the muscularis propria ( that is supporitive)
Diagnosis of acute appendicitis requires what morphological finding?
Neutrophils in muscularis propria
What is the most common tumor of the appendix?
Benign or malignant?
- Neuroendocrine carcinoid tumor = yellow
- Well-differentiated
- Typically benign; nodal metaseses is infrequent and distal spread is rare
A dilated appendix filled with mucin is called what?
Cancerous?
- Mucocele
- Spectrum from benign => malignant: Mucinous cystadenoma or Mucinous cystadenocarcinoma
What type of adenoma and tumor may be seen in the appendix and can enlarge/cause obstruction that mimics appendicitis?
Conventional adenomas or typical adenocarcinomas
