I. CONGENITAL DISORDERS Acute Gastritis Type A (auto-immune) Gastritis Type B (H.
stritis Type A (auto-immune) Gastritis
Gastroschisis: congenital malformation of the abdominal wall
leading to exposure of abdominal contents (so abdominal wall is
split, and abdominal contents are split) – the lateral, anterior,
posterior… all the walls don’t come together, so you can directly see
the contents of the abdomen (like intestines) à hole in abdominal
wall
Omphalocele: persistent HERNIATION of the bowel into the
umbilical cord due to failure of herniated intestines to go back into
body cavity during fetal development à contents of the abdomen
are present in a bubble that is both the AMNION à herniation of
bowel leading to reveal of contents BUT these abdominal contents
are covered by a bubble-like surface (peritoneum + amnion of
umbilical cord)
Diaphragmatic Hernia: herniation of abdominal contents into the
thoracic cavity due to weakness or absence of diaphragmatic tissue
Pyloric Stenosis: its an anatomical disorder (+ congenital)
What is it? Hypertrophy (thickening of the wall) of the pyloric smooth
muscle more common in MALES (+ infants) à tightening of the
pyloric sphincter so food cannot cross into duodenum
What is the typical clinical presentation?
1) Babies are NORMAL at birth (no pyloric stenosis at birth) – it
develops about 2 weeks AFTER birth (takes time for stenosis
to develop)
2) As food goes in stomach, pressure builds up because food
accumulating => PROJECTILE vomiting (not regurgitation)
that is NON-BILIOUS (because contents haven’t met bile in
duodenum just yet)
3) Olive-like mass can be felt on the physical exam – peristalsis
is so strong against the sphincter that pressure builds up
against it leading to hypertrophy (mass) – the actual waves
can also be felt
What’s the treatment? Myotomy (cut away the muscle)
When does it present? A few weeks after birth, more commonly in
boys + there’s a familial inheritance factor
II. MECHANICAL DISORDERS
Mechanical disorders of the stomach can come down to two types:
1) Anatomical (stricture, ulceration…)
2) Physiological (neural disorders, drug induced)
III. INFLAMMATION (Gastritis)
Acute Gastritis: = burning of the stomach by acid (direct + fast)
that can occur either through:
• Increased acid production
• Decreased mucosal secretion (protection)
Chronic Gastritis: inflammatory changes of mucosa due to acidic
damage eventually leading to
1) Mucosal atrophy
2) Epithelial Metaplasia (without erosions)
Can be divided into:
• Type A (auto-immune) à involves body/fundus
• Type B (H. pylori-induced) à involves antrum
• Reflux (bile), chemical gastropathy
Type B (H. pylori) gastritis: (most common form of gastritis – 90%) –
What is it? Acidic damage to the mucosa due to the imbalance
between acidic environment and mucosal defenses
•lined by columnar epithelium
•Efficient blood supply (if any acid leaks, blood vessel simply takes it
away)
•Surface mucus cells/Faviola cells that secrete both:
• mucus (lubricating + protecting)
• HCO3 to neutralize any acid that comes close)
What are common risk factors to developing acute gastritis?
•Increase in H+ production/secretion:
• Alcohol-induced (excessive alcohol consumption directly
damages the mucosa, slightly corrosive)
• Aspirin (increases H+ secretion)
• Cushing Ulcer (increased intracranial pressure will lead to
increased parasympathetic/vagal stimulation, which will in turn
lead to increased acetylcholine, leading to increased H+
production.. And indirectly gastrin secretion)
•Decrease in mucosal defenses:
• Severe burn (curling ulcer as a result) – leads to hypovolemia,
less blood flow to stomach (cant sweep away acid)
• Shock (decreased blood flow to all organs including stomach, less
mucosal protection, leading to multiple ‘stress’ ulcers)
• NSAID-induced because NSAIDs inhibit prostaglandin production
by inhibiting COX, and PGs are essential for:
1. Maintaining mucosal barrier (stimulate surface
mucosal cells to produce mucus and HCO3)
2. Decrease acid production (act on parietal cells
directly, remember Gi via cAMP)
3. Increase blood flow to mucosa barrier (to sweep
away acid)
• Heavy Smoking
• Radiation and chemotherapy drugs (inhibit regeneration of
gastric mucosa, decrease in defenses)
What are the pathological effects of acute gastritis? (consequences of
acid damage)
1)Superficial Inflammation
2)Erosion (loss of epithelium)
3)Ulceration (loss of entire mucosal layer)
Causes of acute gastric ulceration
- Shock
- Extensive burns
- Sepsis
- Severe trauma
- Increased intracranial pressure
What is it? Auto-immune destruction of gastric parietal cells (in
body/fundus of the stomach)
How does this destruction happen? Via Type IV HSR (T-cell
mediated) causes damage in the parietal cells of the stomach
leading to the formation of anti-parietal or anti-IF auto-antibodies
(they’re consequences)
What are the clinical features of Type A gastritis?
1) As parietal cells knocked out, thickness of mucosa
destroyed à mucosal atrophy
2) Destruction of parietal cells à Achlorhydria (low acid
production by stomach, gastrin levels will increase due to
lack of negative feedback, gastrin wants to compensate)
3) Hyper-gastrinemia + G-cell hyperplasia (due to increased
gastrin secreted to try and increase)
4) Vit. B12 deficiency + megaloblastic anemia (IF
destroyed, pernicious anemia à Vit. B12 not absorbed à
stops cell division à megaloblastic anemia)
5) Increased risk for gastric adenocarcinoma (chronic
inflammation induces intestinal metaplasia – normally, no
inflammatory cells in the wall of stomach, but in chronic
inflammation you have a ton of them – so the cells of
stomach are weirded out and start producing the cells that
are normally in contact with inflammatory cells like Peyer’s
patches = intestinal cells; thus you get intestinal metaplasia)
How does Type A gastritis appear on histology?
• Foviolar cells (surface mucus cells) wont have big mucus
granules within them
• GOBLET cells that are usually only in the small intestine
(intestinal metaplasia)
• Enterochromaffin cell hyperplasia (G-cell hyperplasia)
• Lymphoplasmacytic infiltrate within the lamina propria (+
gland infiltration/foci in glands)
Pernicious Anemia (BAB) – a cause of auto-immune gastritis
(Type A)
These patients lose parietal cells in stomach, thus lose IF à
cannot absorb Vit. B12
à Typical findings is high gastrin levels (negative feedback, keep
getting secreted in attempt to increase secretion of IF, doesn’t
work) – high gastrin can also lead to glandular hyperplasia
What are the different types of intestinal metaplasia?
Type I: complete metaplasia
à sialomucin expression only
Type II: incomplete metaplasia
à intestinal + gastric type mucin expression
Type III: incomplete metaplasia
à sulfomucin explession only
especially acquired in childhood
What is it? H-pylori induced acute and chronic inflammation of the
stomach (most commonly of the ANTRUM)
How does H. pylori induce inflammation? It produces ureases and
proteases that weaken and destroy the stomach’s mucosal defenses (it
simply sits on the surface of the stomach, does NOT invade)
What’s the classical clinical presentation of H. pylori gastritis?
1) Epigastric abdominal pain
2) Increased risk for:
1) Ulceration (because chronic inflammation, less
defenses, ulcer develops) à peptic ulceration
2) Gastric Adenocarcinoma (inflammation leads to
intestinal metaplasia)
3) MALT lymphoma (inflammation leads to the
generation of germinal centers within the gastric wall
and formation of post center B-cells in the marginal
zone around the GC à marginal zone leads to MALT
lymphoma, B-cell lymphoma)
What’s the treatment for H. pylori gastritis? it resolves gastritis and
reverses metaplasia (intestinal)
1) Triple Therapy
2) Quadruple Therapy (in case of allergy to clarithromycin)
How to diagnose H. pylori?
1) Positive Urea Breath test (so if its negative, you can be sure
infection is eradicated)
2) Positive Stool antigen (also if negative, confirms eradication)
What do we see on histology?
1) Mucosal chronic inflammation (lympho-plasmocytic infiltrate)
with neutrophils (indicate active inflammation) and lymphoid
aggregates
2) Intestinal Metaplasia (find intestinal cells in the stomach biopsy
3) Mucosal atrophy (very important)
4) Actual H. pylori bacteria
About H. pylori: it’s a curvilinear gram negative rod that is motile
(flagella) and urease positive thus neutralizing the local gastric acid; but
these ureases destroy the gastric mucosa and thus leave the stomach to
be defenseless.
Virulence = strain dependent (cytotoxic strains are strains with cagA
cytotoxin-associated gene or vacA vacuolating cytotoxin)
The bacteria surrounds its own self with a “bicarbonate cloud” to counter
gastric acidity, aided of course by it’s own ureases (it produces urease
which converts urea (abundant in saliva & gastric juices) to
ammonia and bicarbonate)
What are the stages of gastritis? (Type B)
1) Antral Predominant Stage (inflammation sticks to antrum)
2) Corpus gastritis (inflammation spreads to body and fundus – rest of
stomach)
3) Pan-atrophic gastritis (inflammation turns into atrophy of stomach)
Peptic Ulcer Disease
What is it? Solitary ulcer of the mucosa either involving proximal
duodenum or distal stomach that breaches the integrity and continuity of
mucosa and can extend through muscularis mucosa into submucosa or
even deeper.
Why does it form? Due to a disruption of the trilaminar lipoprotein cell
membrane of the mucosal cells + pH gradient between cell and
lumen of stomach
What are the different types?
1) Duodenal Ulcer:
• CAUSE: H. pylori (about 99% - almost always) and ZE syndrome
(1% - very rare; production of massive amounts of acid)
• PRESENTATION: Epigastric pain that improves with meals
(duodenum increases defenses and produces neutralizing
substances when anticipates food, thus pain improves because
less acid and corrosion)
• DIAGNOSIS: endoscopic biopsy showing ulcer + hypertrophy of
BRUNNER glands (mucus producing in duodenal wall)
• COMPLICATION: rupture of the ulcer (damage to underlying
blood vessel) leading to:
• Bleeding from the gastroduodenal artery (posterior
ulcer)
• Acute pancreatitis (posterior ulcer, if activates
pancreatic enzymes also)
2) Gastric Ulcer
• CAUSE: H. pylori (70%), NSAIDs (20%), bile reflux (10%)
• PRESENTATION: Epigastric pain that worsens with meals
(because when you start eating, the stomach will secrete more
acidic gastric juice and mucosa will be more damaged, even
though food temporarily increases pH but not enough)
• DIAGNOSIS: endoscopic biopsy showing ulcer located in the
lesser curvature of the stomach
• COMPLICATION: rupture of the ulcer (damage to underlying
blood vessel) leading to bleeding from the left gastric artery
(posterior ulcer)
What are the causes (differentials) of peptic ulcer disease? H. pylori,
NSAIDs, bile reflux, cancer
- Duodenal ulcers à NEVER malignant (duodenal carcinoma super
super rare, not really studied/biopsied)
- Gastric ulcers à can be caused by gastric CARCINOMA (thus
important to check malignant features) – on endoscopy:
- Benign = small, punched out, normal margins around it
- Malignant = large, irregular, abnormal margins around it
What are the major pathological factors responsible for ulcer
development?
1- Anatomical Factors (disruption of mucosal integrity = worse)
2- Neuroendocrine Status (hormones and neural signals – more vagal
stimulation/more gastrin/more acid = worse)
3- Vascular Factors (blood flow to stomach/duodenum – less blood flow
= worse)
What are the possible complications of gastric ulcers?
1. Bleeding (15-205) – posterior rupture
2. Perforation
3. Obstruction
Hypertrophic Gastropathies:
1) Menetrier’s disease
• WHAT: hyperplasia of superficial mucus cells – so basically you
would have too much mucus and HCO3 secreted, not enough
acid in stomach)
• CAUSE: excessive production of TGF-alpha (transforming
growth factor)
• PRESENTATION: epigastric discomfort, diarrhea (no activation
of enzymes, maldigestion.. No absorption), weight loss
(because you’re not absorbing anything)
1) Hypertrophic-hypersecretory (hyperplasia of parietal cells +
chief cells – oversecretion of pepsinogen and HCl)
2) ZE syndrome (gastrinoma, formation of tumor that keeps on
secreting gastrin leading to continuous acid secretion and
damage of the mucosal surface + secretory diarrhea)
• WHAT: A gastrin secreting tumor formed due to mucosal
hyperplasia/hypertrophy (of gastric glands) + excessive acid
secretion
• WHERE: In duodenum or pancreas (leftover G cells from fetus)
• PRESENTATION:
1) Abdominal pain that improves with food consumption
(temporarily increases the pH)
2) Chronic Diarrhea due to: (poor digestion, secretory diarrhea,
steatorrhea)
-- Excess acid secretion denatures pancreatic enzymes
secreted
-- Inhibits sodium/water resorption by intestine
3) Duodenal ulcers (due to all acid production that washes all
the way down) in the DISTAL duodenum (most occur in the
proximal duodenum/duodenal bulb – even jejunum) à
refractory to PPI therapy (doesn’t work)
4) Heartburn (if all that acid gets into the esophagus)
• DIAGNOSIS:
1) Fasting serum gastrin level >10x normal level (fasting to
prevent ‘unwanted’ gastrin secretion triggered by vagal response
or stomach distention)
2) Secretin test (differentiates gastrinoma from other causes of
increased gastrin) à if you give secretin and the gastrin level
increases even more, the ZE syndrome because:
-- Normally, the G cells inhibited by secretin
-- Gastrinoma are actually stimulated by secretin
• TREATMENT:
1) High dose PPIs (Omeprazole, lansoprazole, pantoprazole) –
standard therapy for ulcers, here try HIGH doses
2) Somatostatin (because it inhibits gastrin secretion in addition
to other GI hormones) – also called octreotide
3) Surgical Excision
Stages of intestinal-type gastric carcinoma are:
a- Chronic (active) gastritis
b- Chronic atrophic gastritis
c- Intestinal metaplasia
d- Dysplasia
e- Carcinoma
Benign Neoplasms
Hyperplastic Polyp (most common gastric polyp – 75-90%) –
hyper-proliferation of mucosal (foveolar) epithelium
What does it look like?
• Dome or olive-shaped
• Smooth surface and well-defined margins
• Majority <1.5 cm
• Often pedunculated (attached to a long stalk to tissue)
• Solitary (66%) or multiple (<10)
Where is it most commonly found? ANTRUM of stomach
Note: it’s higher in association with certain conditions:
pernicious anemia (22-37%), chronic gastritis (6%), partial gastrectomy (4-
20%)
Adenoma: (7-10% of gastric polyps) – hyper-proliferation of
gastric glands (in Japanese people, it’s very common and
usually measures <2 cm -- elsewhere in world, >4 cm)
What does it look like: soft, velvety, broad based, clear defined
margins, with a flat surface filled with papillary/villous crevices
that go down to it’s base (usually solitary)
Where is it located: ANTRUM of stomach
Complications: it has the potential to become malignant
• 6-75% chance to undergo malignant change – especially
in larger villous adenomas, not so much small flat
adenomas
• Can also co-exist with malignant adenocarcinomas (29-
59% of cases) if it’s not malignant itself
Malignant Tumors of the Stomach
A- Gastric Carcinoma: the malignant proliferation of surface
epithelial cells (adenocarcinoma)
Can be divided into two types:
a. Intestinal Type (infiltrative, 33%):
PRESENTATION: large irregular ulcer with undefined and
heaped up margins
WHERE: lesser curvature of antrum (like in gastric ulcer in
peptic ulcer disease)
RISK FACTORS:
-- Intestinal Metaplasia (chronic gastritis – type A and type B)
-- Smoked Foods (nitrosamines)
-- Blood Type A
PROGNOSIS: worst
HISTOLOGY:
-- cells how varying degree of differentiation
-- tumor cells are isolated and spread out all throughout tumor
b. Diffuse Type (expanding, 67%)
PRESENTATION:
-- signet ring cells - signet cells are cells with their nucleus pushed to the edge by the
tons of mucin being produced
-- These signet ring cells (tumor cells) diffusely infiltrate the gastric wall (infiltration
leads to cancer + reactive response of stroma = desmoplasia)
-- Grow as one mass by expansion – compression of surrounding tissue (diffusely
thickens the wall of the stomach)
RISK FACTORS: (not associated with intestinal metaplasia, H. pylori, or nitrosamines)
HISTOLOGY:
-- coherent relationship among cells regardless of maturation/differentiation (not
individual)
-- Desmoplasia results in thickening of the stomach wall (linitis plastica)
HEREDITARY DIFFUSE GASTRIC CARCINOMA: inherited, caused by a germ-line
truncating mutation of the CDH1 gene resulting in E-cadherin inactivation leading to
loss of cell adhesion BUT increase in cell motility
What’s the prognosis?
à The early gastric carcinoma = confined to mucosa and submucosa (good prognosis
in japan)
à Metastasis = worst prognosis
-- Immediate metastasis: usually spread to Virchow node (left supraclavicular node)
-- Distant metastasis:
1. Usually involves liver
2. Peri-umbilical region (Sister Mary Joseph nodule) seen with intestinal type
(infiltrative)
3. Bilateral ovaries (Krukenburg tumor) seen with diffuse type (expanding -
mucinous)
What’s the presentation?
-- Weight loss
-- Abdominal pain
-- Anemia
-- Early satiety (not hungry) – especially in diffuse type (stomach can’t expand
because it’s so thick)
-- Acanthosis nigricans – thickening + darkening of skin in axial region
-- Leser-Trelat Sign – patient gets dozens of seborrheic keratosis
What’s the pathogenesis (how did it develop)? It could have started out as:
1. Adenoma
2. Chronic gastritis due to H. pylori with associated epithelial changes (most
common)
B- Malignant Lymphoma: the stomach is the most common site of extra-nodal
lymphoma due to the associated lymphoid tissue (MALT lymphoma, mantle cell
lymphoma, follicular lymphoma, diffuse B cell lymphoma)
What are the possible causes of stomach MALT lymphoma? Genetic changes that
activate the NF-kappa B pathway
1. Fusion of apoptosis inhibitor (API-2) gene and MALT lymphoma associated
translocation (MALT1) gene à t(11;18)(q21;q21)
2. Translocation of BCL10 gene next to immunoglobulin heavy chain gene (IGH) à
t(11;14)(p22;q32)
What is the promoter agent of MALT lymphoma? H. pylori
à Thus cases MALT lymphoma are responsive to H.pylori medication
à Not responsive to antibiotics if:
-- Specific mutations detected
-- Lymphoma deeply infiltrating gastric wall
-- Transformation to diffuse large B-cell lymphoma (usually diffuse B cell
lymphoma that is more aggressive + made up of larger atypical lymphocytes)
Colonic Polyps: are raised protrusions of colonic mucosa
Types:
1- Hyperplastic: (benign, no malignant potential – BUT right-sided hyperplastic
polyps are associated with carcinoma)
Cause: due to hyperplasia of the glands (most common type of polyp)
Location: most commonly on left colon (rectosigmoid)
Microscopy:
-- Small (<5mm diameter)
-- ‘Serrated’ appearance on surface
-- Narrow base/crypts
-- Star-shaped lumen (cross-section)
2- Adenomatous: (benign, pre-malignant – may progress to adenocarcinoma via the
adenoma-carcinoma sequence)
Epidemiology: 4x greater risk if 1st degree family member affected (2nd most
common – increased incidence w/ age, 30% prevalence; increased risk in Blacks)
Cause: neoplastic proliferation of glands
Dysplastic Change: (can show low or high grade)
-- Loss of Mucin
-- Nuclear Elongation (hyperchromatic) à cancerous = polymorphic nuclei (different)
-- Nuclear Stratification (still ordered) à cancerous = haphazardly arranged
Cancerous Change: progression into adenoma-carcinoma via sequence:
1. APC (tumor suppressor gene on chromosome 5 – must knock out both copies)
mutations = increased risk for (adenoma) polyp formation
-- Sporadic = with age, both copies can get knocked out via mutations
-- Germline = Familial Adenomatous Polyposis Syndrome
2. K-ras mutations = leads to (adenoma) polyp formation
3. p53 mutation + increased COX expression = progression to adenocarcinoma
(after polyp) à aspirin protects against this sequence
Gross Appearance: increased risk of cancer with increased size
-- Pedunculated (attached to mucosa via stalk)
-- Sessile (blends with surrounding mucosa, harder to remove)
Clinical Manifestations: silent/asymptomatic, with occasional bleeding
Microscopy: can be a range from:
-- Tubular (surface is flat)
-- Villous (surface, >80%, covered in finger-like projections) à highest risk of cancer
Screening: very important, can occur via:
1. Colonoscopy (gold standard) since:
-- gross observation + biopsy testing (to check if hyperplastic or adenomatous polyp)
-- direct treatment by removing polyps
-- in case if adenoma, what was the risk for the patient to develop carcinoma?
High risk if: (two most critical factors)
(1) Size > 2 cm (advanced adenomas)
(2) Grade of dysplasia – high grade if:
-- Sessile pattern (gross)
-- Villous surface (histology)
2. Testing for fecal occult blood (only some pathology visible)
Treatment: endoscopic resection of adenomatous polyps before progression into
carcinoma (invasive) + biopsy/histological evaluation – surgical if endoscopic fails
3- Serrated Adenomas: Colonic Adenocarcinoma: (most common malignancy of the colon – Screening: begins at 50 years of age – goal is to (a) remove
96-98% of colorectal cancers, worldwide distribution + Lebanon) adenomatous polyps before carcinoma develops and (b) detect
Cause: combined features of both hyperplastic and adenomatous cancer early. Can be divided into two categories:
polyps. Most common in elderly females (median age = 61 yrs). 1- Stool tests (fecal occult blood testing, abnormal DNA
Epidemiology: 3rd most common cancer in world, and 2nd most
common cause of cancer death. testing) à detect cancer (mainly)
Locations: proximal (right) side of colon -- 6% chance of developing colorectal cancer 2- Structural tests (colonoscopy, CT scan, double-contrast
barium enema) à detect both adenoma + cancer
-- 8% of all malignancies in both men and women
Gross Appearance: >5 mm, Flat surface, sessile (embedded) -- peak incidence is 60-70 years (10% occur <50 yrs)
Gross Presentation: obstructing mass (1+) within colon that can
-- equally common in males and females
Microscopically: grow in one of two ways:
-- Inverted L-shaped + serrated crypts (sometimes T-shape) 1- Fungating/raised lesion (usually RIGHT-sided) leading to:
Location: equal distribution in the four major segments of the colon
-- Base of crypts are dilated (ascending, transverse, descending, sigmoid - mostly, rectum) -- iron deficiency anemia (next to terminal ileum)
-- vague pain (not in one quadrant)
Genetics: Often have microsatellite-instability mutations and DNA (associated with microsatellite instability pathway)
Pathogenesis: (genetic disease by definition) derives from columnar
methylation 2- “Napkin’ circumferential ring around colonic segment
glandular epithelium in colonic mucosa, under influence of:
-- Environmental and dietary habits (low fiber diets, obesity, high (usually LEFT-sided) leading to:
Types: -- left lower quadrant pain
alcohol consumption, low physical activity, smoking)
-- Traditional Serrated Adenomas (TSA) -- Genetic factors (97% sporadic, 3% familial): 2 major molecular -- blood-streaked stool
-- Sessile Serrated Adenomas (SSA) – most common subtype pathways: -- decreased stool caliber (squeezed by ring)
1- Adenoma-Carcinoma Sequence (most common, 80%) (associated with adenoma-carcinoma sequence)
--> like Familial Adenomatous Polyposis
Microscopic appearance of: Staging: CRUCIAL (via CT scan or endoscopic ultrasound)
2- Microsatellite Instability Pathway (microsatellites are repeating (endoscopic ultrasound > CT scan for detecting invaded LN)
Hyperplastic Polyps: (benign, no cancer risk) T: DEPTH of invasion (+ tumor size)
sequences of non-coding DNA that are replicated during cell division; if
--Small (< 5mm) they are copied the way they are = stability; defect in DNA repair N: Spread to regional lymph nodes
-- Serrated Surface M: Metastasis (distant spread) – especially involves liver
mechanisms = instability) à so other genes are also unstable
-- Narrow crypts at bottom --> like Lynch Syndrome
Stage 0: Carcinoma (CA) in situ
Serrated Sessile Adenoma: (premalignant) Stage 1: deep CA (superficial to wall), no LN, no metastasis
Presentation: obstructing mass in colon (necrotic. Ulceration,
-- larger (> 5mm) exophytic growth, ‘apple core’ lesion) in addition to: Stage 2: deep CA (through wall), no LN, no metastasis
-- Serrated surface -- rectal bleeding (+/- anemia) Stage 3: deep CA, 1-2 LN, no metastasis
-- Inverted L-shaped Stage 4: v. deep CA, 3-4 LN, metastasis (6 mo-2 yrs)
-- anorexia, weight loss
-- Dilated crypts at bottom -- change in bowel function
Treatment: surgical resection + adjuvant/neoadjuvant therapy
(depends on location, see later)
Traditional Serrated Adenoma: (benign, no dysplasia) (usually 5-FU as chemotherapeutic agent of choice)
-- Tubular/flat surface - Stage I = high cure rate
Metastasis: most common site of distant metastasis is the liver –
-- serrations within glands - Stage II = high relapse rate (5-FU + leucovorin)
diffuse lesions around liver (differential dx is military TB) and:
-- Virchow’s nodes (supraclavicular LN enlargement) - Stage III = 5-year survival ~ 40-45% (5-FU + oxaliplatin)
-- Sister Mary Joseph’s node (presence of umbilical mass) - Stage IV = 5-year survival ~ 6-8%
Post-Adenoma Resection Surveillance Intervals -- Ascites (abdominal swelling + fluid accumulation in peritoneum) (radiation therapy used more for rectal cancers)
(when to do colonoscopy)
-- Blumer’s shelf (spread of tumor to pelvis/rectum)
Notes:
Low-Risk Patients (1-2, small, tubular) ----------------------------- 5 years
High-Risk Patients (2+, large, villous) ------------------------------ 3 years Microscopically:: infiltrative pattern. 1-- patients with colorectal carcinoma have an overall increased
risk for Streptococcus bovis endocarditis (thus if patient is
V. High Risk Patients (10+, villous) --------------------------------- <3 years -- Infiltrative GLANDS in well to moderately differentiated cases
Post-polypectomy (large adenoma, piecemeal) ----------------- 2-6 months (invade muscle layers, can go into serosa) affected, must perform colonoscopy to check)
-- Infiltrative CELLS/sheets of cells in poorly differentiated cases
-- Haphazardly arranged cells 2– an important tumor marker is CEA (elevated in CR cancer,
-- mucinous cells (large intracytoplasmic vacuoles containing mucus – but not useful for screening) assesses treatment response
since these are glandular cells, overproduction of mucus) (should decrease) and recurrence.
3-- chemoprevention of colorectal cancer with NSAIDs (aspirin)
Cytologically: pathologically, colonic adenocarcinoma is graded based
possible as they reduce adenoma formation (and consequent
on the depth of invasion (sometimes, it is so invasive that it’s
CA development) by inhibiting COX and PG generation – not
penetrates uterus/ovary and get’s mistaken for gynecological cancer)
celecoxib due to CVA risk.
-- Low-grade (well-differentiated, so the glands are apparent) to high
grade nuclear atypia (polymorphic)
-- Nuclear overcrowding
-- Increased mitotic activity
-- Signet ring cell morphology (indicate more aggressive tumors)
Prognosis: dependent on TNM staging and vascular invasion (CT/PET
scan), even before surgery (might have multiple lesions that need to
be removed).
Other Colonic Neoplasms:
I- Carcinoid Tumor: (low-grade) malignant proliferation of neuro-endocrine
cells (at bottom of crypts, filled with neuro-endocrine granules, positive for
chromogranin)
Location: occurring anywhere along the gut, but most commonly along the
appendix and small bowel. Appendiceal and rectal carcinoids rarely
metastasize.
Pathogenesis: It grows as sub-mucosal polyp-like nodules (raise
islands/protrusions, intact mucosa) and tumor secretes serotonin (5-HIAA)
dumped into portal vein, metabolized in liver by MOA into 5-HIAA, to be
excreted in urine (thus high level of 5-HIAA in urine). No symptoms, yet.
Better prognosis than adenocarcinoma.
Microscopically:
-- trabeculae/sheets/island of cells (well-defined)
-- monotonous (identical) cells with eosinophilic cytoplasm and round
nuclei (high N/C ratio)
-- minimal pleomorphism + minimal mitotic activity (has to be >2%)
-- positive for neuroendocrine markers like chromogranin (specific, not
sensitive) and synaptophysin (sensitive, not specific) – brown color
Grading: based on many factors, including:
-- Tumor size
-- Ki-67 index is an immuno-histochemical stain that looks for proliferative
activity (>2% indicates malignancy)
-- Infiltration, angioinvasion, necrosis
Carcinoid Syndrome: after the tumor metastasizes into the liver, serotonin
is dumped into hepatic vein and enters systemic circulation, it then becomes
carcinoid syndrome which is defined by: (only get these symptoms once
metastasis to the liver)
- Bronchospasm
- Hepatomegaly
- Diarrhea (intestinal hypermotility)
- Flushing of skin (+ telangiectasia)
à Release of serotonin from tumor triggered by emotional stress or alcohol
consumption
Carcinoid Heart Disease: After metastasis, when serotonin gets into the
right side of the heart via the vena cava, it causes deposition of collagen
within the heart valves leading to fibrosis and:
-- tricuspid regurgitation
-- pulmonary valve stenosis
(ONLY right sided, because the lung has monoamine oxidase – serotonin
gets converted to 5-HIAA before reaching left side of heart)
II- Mesenchymal Tumors
A- Gastrointestinal Stromal Tumors (GIST)
Pathogenesis: tumor of the interstitial cells of Cajal (pacemaker
cells of GI tract, found in myenteric plexus, control enteric nervous
system) – unlike the other tumors, this one keeps the mucosa intact –
only invades BETWEEN skin layers
Location: predominantly in middle aged patients (40-50s):
-- Small Bowel Tumor (20-30%)
-- Gastric Cancer (50-60%)
-- Colorectal Cancer (<10%)
Morphological Variants:
1- Spindle Cell Type (70%) – elongated nuclei (cigar-shaped) –
nuclei arranged in whorls/fasicles
2- Epithelial Type (20%) – round nuclei with abundant cytoplasm
3- Mixed (10%)
Immunohistochemistry:
- positive for c-kit (CD117, tyrosine kinase protein) mutation in 80% of
cases à very sensitive, not specific
- Some (7/5%) are positive for PDGF receptor alpha
- DOG1 is a new marker that codes for a Cl- channel protein also
mutated in GIST – more specific than CD117 (which can be found in
other tumors)
Genetics: c-kit is a transmembrane kinase receptor found only on
mast cells (not neurons) required for development and function of the
interstitial cells of Cajal (ICC).
-- Normally, c-kit needs to bind to cytokine stem cell factor to be
activated (+ stimulate ICC)
-- When mutated, c-kit is continuously activated thus stimulates the
neoplastic proliferation of ICC (important for targeted therapy)
Staging: we assess the malignant potential of GIST by looking at:
1- Size (>5 cm = malignant) – bigger size, more aggressive
2- Mitotic Activity (> 5 counts per 50 hypermitotic fields/HPF)
B- Smooth Muscle Tumors (Leiomyoma)
(discussed previously – also spindle-like nuclei but negative for c-kit)
III- Malignant Lymphoma (non-Hodgkin, B-cell lymphoma)
Location: (extranodal) GI tract is the most common site:
Stomach > Small Intestine > Colon > Esophagus
Immunophenotype: most common is MALT lymphoma – other types:
-- Follicular Lymphoma
-- Mantle Cell Lymphoma (lymphomatous polyposis – presents as
multiple polyps, aggressive treatment – might need SC transplant)
-- Burkitt’s Lymphoma
-- Diffuse large B-cell lymphoma (worst)
Genetics of Colonic Adenocarcinoma II- Microsatellite Instability – de novo carcinoma
Mechanism: two distinct mechanisms can cause MMR deficiency:
OVERVIEW: (Mechanisms involved) 1- mutations in caretaker genes (MMR genes) -- HNPCC
2- mutations of BRAF, MAX, IGF2R (MLH1 promoters) – sporadic
-- DNA ploidy (aneuploid/diploid)
-- Mutations (APC, KRAS, BRAF, TP53) Location: right-sided tumors
-- DNA microsatellite instability (MSI)
-- DNA methylation
-- Loss of heterozygosity (LOH) –something abnormal occurs Types:
during cell division – once allele is lost entirely and replaced
1- Lynch Syndrome (HNPCC, autosomal dominant, mutation of
by a duplication of the other copy/other chromosome.
MMR genes – MSH2, MLH1, MSH6, PMS2)
-- Chromosomal loss/gain
2- Sporadic (epigenetic silencing like hypermethylation of MLH1 or
Molecular Mechanisms involved in Colon Cancer
BRAF mutations) à Hypermethylation of CpG islands (short tandem
1- Genes involved in the replication signaling pathway:
repeats/promoter sequences) leading to gene silencing = WORSE
-- K-ras (chr. 12)
prognosis
-- APC (chr. 5)
-- DCC (chr. 18)
2- Genes maintaining DNA fidelity (caretaker genes, Clinical Manifestation:
-- Early onset
microsatellite): MSH2, MLH1, MSH -- more common in females
3- DNA methylation (silencing promoter regions) -- associated with serrated polyps (serrated adenomas)
DNA Repair Mechanisms:
Histology: malignant counterpart of SSA
1- Nucleotide Excision Repair
-- poorly differentiated + mucinous (signet ring morphology)
2- Base Excision Repair
-- infiltrating lymphocytes within tumor glands
3- Mismatch Repair (MMR) Genes: whose products are
-- NEGATIVE immunohistochemical stain
critical in detecting and repairing microsatellites (longer
sequence = more unstable)
Prognosis:
-- MSI (instable, high-frequency) = better (HNPCC)
Consequences of Abnormal Repair Genes: -- MSS (stable, low-frequency) = worse (Sporadic)
1- Insertion/Deletion type mutations
2- Chromosomal Instability (CNI) – 85% of Colon Cancer
Notes:
3- Microsatellite Instability (MSI) which could be: 15% of
Colon Cancer -- Stage II MSI tumors do NOT benefit from 5-FU therapy (harmed)
-- we WANT immunohistochemical staining of repair genes to be
-- high frequency (better prognosis, respond more to therapy)
positive (brown)
-- low frequency (difficult to treat, less susceptible)
Epigenetic Changes to Genes:
Serrated Adenocarcinoma
1- Hypermethylation (silencing) of tumor suppressor genes
2- Hypomethylation (promotion) of proto-oncogenes Epidemiology: 10% of all CRC in females and 6% of males.
3- Deamination of methylated cytosine residues leading to
oncogenic point mutations (C à T) In females: over 18% of adenocarcinomas of the
ascending colon and cecum.
Locations: Cecum (52%, especially in women) and rectum (33%)
Mechanisms of Colorectal Cancers:
Histology: malignant counterpart of TSA
I- Chromosomal Instability – adenoma-carcinoma sequence
-- Mucinous differentiation.
-- Eosinophilic cytoplasm.
Mechanism: loss of tumor suppressor genes
-- Vesicular nuclei.
-- Absence of dirty necrosis (or ulceration) – main differentiating
Location: left-sided (rectosigmoid) tumors – presents as a
solitary mass factor with SSA
Genetics:
Types: -- BRAF mutation
1- Sporadic (acquired mutation in APC, p53, DCC, K-ras) -- Microsatellite instability (low-frequency, methylation of MGMT)
2- Familial (FAP, autosomal dominant, APC mutation) -- Microsatellite instability (high frequency, methylation of hMLH1)
3- MUTYH (biallelic, autosomal recessive)
Short Tandem Repeats = unstable non-coding DNA sequences that
Clinical Manifestation: FAP, MUTYH (associated with
are replicated during cell division, thus susceptible to damage
adenomatous polyps)
(especially the CA repeats). In case of any mutation, that will also be
inherited.
 CLINICAL
SYNDROME POLYP HISTOLOGY POLYP DISTRIBUTION AGE OF ONSET RISK OF COLON CANCER GENETIC LESION ASSOCIATED LESIONS
MANIFESTATIONS
Familial adenomatous Rectal bleeding, abdominal
Adenoma Large intestine, duodenum 16 yr 100% 5q (APC gene) Desmoids, CHRPE
polyposis pain, bowel obstruction
Possible rectal bleeding,
Orocutaneous melanin
Peutz-Jeghers syndrome Hamartoma Large and small intestine First decade Slightly above average 19p ( STK11) abdominal pain,
pigment spots, other tumors
intussusception
MUTYH-associated Rectal bleeding, abdominal
Adenoma Large intestine, duodenum 45-50 yr 75% (range, 50-100%) 1p ( MYH gene) CHRPE, osteomas
polyposis pain, bowel obstruction
Possible rectal bleeding,
Hamartoma (rarely
Juvenile polyposis Large and small intestine First decade ≈9% PTEN, SMAD4, BMPR1 abdominal pain, Pulmonary AVMs
adenoma)
intussusception
Hereditary nonpolyposis Rectal bleeding, abdominal Other tumors (e.g., ovary,
Adenoma Large intestine 40 yr 30% Mismatch repair genes *
colon cancer pain, bowel obstruction uterus, pancreas, stomach)

I- Familial Adenomatous Polyposis (FAP): autosomal dominant disorder
characterized by 100s-1000s of adenomatous colonic polyps (if not removed, 100%
will develop cancer). Also called familial polyposis coli (FPC).
à Colorectal carcinoma arises from adenoma-carcinoma sequence (usually LEFT
sided).
Genetics: (INCOMPLETE penetrance) due to an inherited APC mutation (tumor
suppressor gene that regulates intestinal epithelial cell growth, on chr. 5) – massive
risk for development of polyps
Clinical Manifestations: Adenomas begin in teen years, and clinical Sx in 20+ years,
which can have one of three variants (all include FAP -colon polyps, increased risk
of adenocarcinoma):
-- Gardner Syndrome: FAP and:
1- Mesenteric fibromatosis (non-neoplastic proliferations in retroperitoneum)
2- Osteomas (benign neoplasms most commonly in skull - mandibular)
3- Congenital Hypertrophy of retinal pigment epithelium (CHRPE)
4- Soft tissue tumors (sebaceous cysts, desmoid tumors)
5- Super-numerary teeth
II- Peutz-Jeghers Syndrome – autosomal dominant disorder whereby
hamartomatous polyps arise and spread throughout the GI tracts leading to
increased risk for colorectal, breast, and gynecological cancers.
Pathobiology: (HIGH penetrance) mutation in DTK11 gene (serine-threonine
kinase) on chr. 19 (leading to benign polyp formation)
Clinical Manifestations: (average age at diagnosis is in 20s)
(1) Mucocutaneous hyperpigmentation in lips, oral mucosa, and genital skin
(2) Small bowel intussusception + obstruction
(3) GI bleeding
III- MUTYH-associated polyposis – autosomal recessive disorder characterized
by colonic polyposis and high rate of colorectal cancer.
Genetics: mutation leads to defects in base-excision repair (+ other acquired
mutations in APC gene, K-ras gene… lead to CA via adenoma-carcinoma
sequence)
V- Hereditary Non-Polyposis Colorectal Cancer (HNPCC): (Lynch Syndrome)
whereby there is a germline mutation leads to an increased risk for colorectal,
ovarian, and endometrial carcinoma.
à Colorectal carcinoma arises DE NOVO at a relatively early age
(usually RIGHT sided).
Genetics: (HIGH penetrance) due to inherited loss-of-function mutation in DNA
mismatch repair enzymes (microsatellite instability, found in all cells) – most
common hereditary colorectal cancer
Clinical Manifestations: (median age for HNPCC is in the mid-40s) – increased
risk for intestinal (colonic, gastric, pancreatic) and extra-intestinal cancers
(especially ovarian, endometrial), skin lesions (Tuir-Morre variant)
Diagnosis: clinically, defined by the presence of all three:
(1) Colorectal cancer involving at least 2 generations
(2) 1+ family member with colorectal cancer <50 yrs
(3) 3+ family members with HNPCC (histologically verified, by presence of
cancer) – at least 1 is 1st degree relative of others + FAP negative

-- Turcot Syndrome: FAP and brain/CNS tumors (medulloblastoma tumor, glial
tumor)
-- Attenuated FAP with less than 100 colorectal polyps
Treatment: prophylactic removal of colon + rectum (or else all patients will develop
carcinoma by 40 yrs)
IV- Juvenile Polyp – non-neoplastic tumor made up of tissue normally present but
disorganized (hamartomatous, benign) usually presents as a solitary rectal polyp
that prolapses and bleeds (can lead to anemia).
Juvenile Polyposis – a whole bunch of juvenile polyps in stomach and colon –
since large number, increased risk of adenocarcinoma.
Familial Adenomatous Polyposis Lynch Syndrome
Small Intestine (Bowel)
Congenital Disorders
1) Duodenal Atresia: (ends in a blind loop) congenital failure of the small
bowel to turn into a functional duct – usually associated with Down syndrome
Clinical Features:
-- Polyhydraminios (too much amniotic fluid)
-- distention of stomach and blind loop of duodenum (“double-bubble sign”)
-- bilious vomiting
Why polyhydramnios? Remember that amniotic fluid is mostly generated form
the urine of the baby – and at the same time, we resorb some of that fluid by
swallowing that fluid (thus decreasing the volume). Without that physiologic
swallowing/resorption, too much amniotic fluid results.
Why double bubble sign? Both the stomach and the duodenum would be
distended, but the pyloric sphincter is very tight so it appears as two bubbles.
Why bilious vomiting? because bile released into the duodenum with nowhere
to empty, goes back up
2) Meckel’s Diverticulum: outpouching of all three layers of bowel wall
(TRUE) due to a failure of the vitelline duct (omphalomesenteric) to
completely involute.
What is the vitelline duct? Early in life, the midgut receives its nutrients from
the yolk sac via the vitelline duct (vital to receiving nutrients). It forms at 4th
week, and involutes (resorbs/closes) at 7th week. Persistence leads to
Meckel’s diverticulum. If the duct does not involute at all, there will be passing
of muconium via umbilicus – vitelline fistula.
Clinically, if you touch these patients you will fell a hardening at umbilicus
area (as if there are stools within; solid but soft). That’s because stool will be
caught in Meckel’s diverticulum.
Features: (rule of 2s)
-- seen in 2% of the population (most common congenital anomaly of GI tract)
-- it is 2 inches long located in the small bowel within 2 feet of the ileocecal
valve
-- presents within first 2 years of life
Clinical Presentation: most cases are asymptomatic, but those that do
present with: (SURGICAL resection is only treatment)
-- perforation/bleeding (because there is ectopic/heterotopic gastric
mucosa and other abnormal tissues within the diverticulum, which can
produce acid and destroy the normal mucosa, leading to bleeding) à may
lead to septic shock if bacteria leaks through
-- intussusception (if large enough)
-- obstruction
-- ischemic damage (if large enough and strangulates bowel itself)
-- volvulus (obstruction caused by twisting)
-- other symptoms depending on what ectopic tissue harbored
Symptoms mimicking appendicitis (inflammation) due to it’s location on the
RIGHT side
3) Duplication: separate loops of intestine share a common blood supply
with a major loop.
4) Enteric Cysts: thin-walled cystic formations in GI tract. The danger is that
it might cause obstruction.
Types of Mechanical Obstruction
(usually all treated by surgical resection)
1) Volvulus: twisting of the bowel along its mesentery (180 degrees or
more) leading to obstruction of bowel and disruption of blood supply to
that part of mesentery (infarction) due to resulting pressure. Surgical
resection only treatment.
Most common locations are locations with a ton of mesentery:
-- sigmoid colon (elderly)
-- cecum (young adults)
2) Intussusception: invagination/telescoping of the proximal segment
of the bowel (intussusceptum) into the distal segment
(intussuscipiens), in the direction of peristalsis.
Associated with:
-- infarction (+leading edge)
-- currant jelly stools
Most common cause: (that creates the leading edge)
-- lymphoid hyperplasia after viral infection in the MALT whereby
terminal ileum invaginates into cecum (children)
-- tumor acts as the lading edge (adults)
3) Adhesions: fibrous tissue developing after surgical procedures,
infection, or endometriosis. Leads to abdominal pain, which can be
episodic OR requires more surgery (vicious cycle).
4) Adynamic (paralytic) ileus: paralysis of a portion or of all the
intestinal tract due to acute intestinal obstruction in the absence of
mechanical/organic obstruction – halt of bowel movements. Surgical
resection in very advanced cases. Could be due to drugs,
neuromuscular disorders.
Types of Hernias:
Inguinal (direct/medial or indirect/lateral – depending on position
relative to inferior epigastric vessels), Umbilical, Femoral, or Scrotal –
due to defects in the muscular wall (abdominal).
Incarcerated: hernia CANNOT be reduced (trapped), but there is still a
bit of blood flow to organ. Have a bit more time to plan surgery
Strangulated: hernia CANNOT be reduced, and there is loss of blood
flow to herniated segment leading to ischemic injury with tissue
necrosis. Could be life-threatening – emergency.
Ischemic Bowel Disease: (infarction, ischemic enteritis)
Causes: – elderly patient with a/ fib, diabetes, vasculitis…
1- Transmural Infarction (thrombosis or embolism of SMA or
thrombosis of mesenteric vein)
2- Mucosal Infarction (slight decrease of blood supply due to marked
hypotension)
Where: in watershed zones of GI tract (where arterial supply end, no
direct major blood supply, most susceptible to ischemic injury) like
splenic flexure of colon, and watershed area of SMA – less
commonly in the sigmoid colon/rectum where IMA/pudendal/iliac
artery circulations end
Clinical Features: hypoxic injury followed by reperfusion injury
1- Abdominal Pain
2- Bloody Diarrhea
3- Decreased Bowel Sounds
(consider it if physical exam not representative of clinical symptoms –
tests negative, but patient in excruciating pain)
Histology: washing away of mucosal lining (no inflammatory infiltrate,
except if superimposed bacterial infection)
Note:
-- the small bowel needs a lot of ATP due to ton of digestion and
absorption necessary, thus highly susceptible to ischemic injury.
-- vasculitis or a. fib would cause thrombosis/embolism of SMA;
polycythemia vera or lupus anticoagulant (anti-phospholipid
syndrome) would cause thrombosis of mesenteric veins
Irritable Bowel Syndrome (IBS): relapsing abdominal pain with
bloating, flatulence, and change in bowel habits (either diarrhea and
constipation) that improves with defecation. Classically seen in
middle-aged females.
Cause: related to disturbed intestinal motility, but NO identifiable
pathologic changes.
Treatment: increased dietary fiber may improve Sx
Large Intestine (Colon) C- Vascular Disorders (3) Viruses: most common cause of infectious colitis (esp. in children)

A- Hirschprung disease: (congenital) defective relaxation and peristalsis
of the rectum and distal sigmoid colon – associated with Down Syndrome.
More common in boys (1 in 5000 live births – not too rare).
Pathophysiology: failure of ganglion cells to descend (from neural crest)
into submucosa (submucosal plexus, regulate blood flow and secretion)
and muscular layers (myenteric plexus, needed for peristalsis and
relaxation) of the large intestine (absence of ganglion cells in segments).
Genetics: at least eight susceptibility genes that control the migration and
differentiation of ganglion cell precursors into intestinal walls from neural
crest cells are associated, including:
-- RET gene
-- GDNF gene (glial-derived neurotrophic factor)
-- Endothelin gene
-- endothelin receptor gene (ETR3/ETRB)
(genes show carriable penetrance)
Clinical Features: (due to lack of peristalsis/relaxation + blood
flow/secretion regulation)
-- failure to pass meconium (dark green substance, first feces of infant)
-- empty rectal vault on digital rectal examination (DRE)
-- massive dilation of bowel proximal to obstruction with risk for rupture,
looks like malnourishment
-- constipation (if continued)
Sometimes, muscle hyperplasia occurs to compensate for loss; makes
things even worse.
Diagnosis: lack of ganglion cells on rectal suction biopsy (normal biopsy
only takes mucosa)
Treatment: resection of the area of involved bowel (keep the bowel w/
ganglion cells proximal to diseased segment)
Note: what does a ganglion cell normally look like? Single nucleus,
abundant cytoplasm embedded in the thick muscle layer.
B- Colonic Diverticuli: (false/pseudo-diverticulum) outpouching/herniation
of both mucosa and submucosa through muscularis propria – especially in
the left colon. Increased incidence with age (seen in older adults).
Location: sigmoid/left colon most common (especially in areas where
vasa recta crosses muscularis propria – forms a weak point in the colonic
wall – diverticulum thinning it out) – most common diverticulum of GI tract
1) Angiodysplasia: (acquired) malformation of mucosal and submucosal
capillary beds that arises in the cecum and right colon due to high wall
tension. More common in older adults, present also as hematochezia.
THUS – hematochezia can be caused by:
High stress (left colon) à Diverticuli
High stress (right colon) à Angiodysplasia (+ mainly elderly)
High stress (perianal area) à Hemorrhoids
2) Hemorrhoids (St. Fiacre’s curse): is the variceal dilatation of the anal
and peri-anal venous plexus, most commonly associated with
constipation (increased intraluminal venous pressure). Could be internal
or external. Especially seen in women due to venous stasis secondary to
pregnant/gravid uterus in the pelvis, pushing down on the veins.
Treated medically or surgically.
3) Hereditary Hemorrhagic Telangiectasia: autosomal dominant
disorder resulting in dilated thin-walled blood vessels, especially in the
nasopharynx and GI tract. Rupture of these blood vessels presents as
bleeding (spots).
D- Inflammatory Disorders
1) Radiation Enteritis: damaging effect of radiation therapy on the
mucosa of the GI tract, leading to vascular damage and ischemic injury.
2) Ischemic Colitis: (inflammatory/necrotizing) ischemic damage to the
colon leading to acute necrotizing inflammation spreading to both small
and large intestine. Most common acquired GI emergency of neonates
(especially premies) – immediate surgery
Pathogenesis: atherosclerosis of SMA blocking blood flow to
bowel/colon.
Affected Sites: splenic flexure, terminal ileum, ascending colon (right
side)
Clinical Presentation:
-- weight loss (pain, don’t eat as much)
-- post-prandial pain (after eating, when energy requirement of gut
increases)
-- bloody diarrhea (in case of complete infarction, continued/severe lack
of oxygen)
3) Infectious Colitis: could be caused by a variety of agents:
Pathogens:
-- rotaviruses (Responsible for destruction of enterocytes in small
intestine)
-- calciviruses (Norwalk-like agent, in seafood, most common non-
bacterial agent causing food poisoning/gastroenteritis in adults)
-- adenovirus
-- astrovirus.
Clinical Manifestation: Short incubation period followed by vomiting
and watery diarrhea.
Pathophysiology: activation of the enteric nervous system (increased
intestinal motility) leading to diarrhea.
Histopathology: Shortened villi and lymphocytic infiltration
(4) Opportunistic Infections: (intestinal) in patients with immune
deficiency states (up to 60% of HIV infected subjects have diarrhea)
• Giardia (Giardia lamblia)
• Crytosporidia (Cryptosporidium parvum) – sits at edges of cells
• Microsporidia (Enterocytozoon bieneusi, Septata intestinalis,
Encephalitozoon cumiculi).
• Cytomegalovirus, herpesvirus
• Mycobacterium avium-intracellulare – AIDS-defining
4) Pseudomembranous Colitis (antibiotic induced): characterized by
diffuse punctate formation of adherent inflammatory exudates
(pseudomembrane – a cap of bacteria cells) overlying injured mucosa.
Seen mostly following broad spectrum antibiotic therapy (C. difficile
overtakes intestinal flora)
5) NSAID-induced Colitis: has both acute and chronic manifestations

Cause: (related to wall stress/increased intraluminal pressure, anything (1) Bacteria: more common in immunocompromised patients
that increases wall stress will push the layers out)
-- Constipation Pathogens: V. cholera, Salmonella, Shigella, Whipple’s disease
-- low fiber diet (Tropheryma whipplei), Mycobacterium tuberculosis

Complications: usually asymptomatic, but complications include: Pathophysiology:

-- Obstruction (with fecal material) – rock-hard mass, looks like a tumor
-- Inflammation (diverticulitis) à left-sided appendicitis-like symptoms
-- Hematochezia (rectal bleeding/perforation because diverticulum right
next to vein/vasa recta)
-- Colo-vesicular Fistula (when wall inflamed and ruptures, it bursts and
attaches to a nearby tube like the bladder via adhesions) à presents as
air/stool in urine
Note: Diverticulosis (still intact), Diverticulitis (perforated/inflamed)
(1) Ingestion of preformed toxin (S. aureus, C. perfringens)
(2) Infection by toxigenic organism that release toxins (E. coli, V.
cholera, C. jejuni)
(3) Infection by enteroinvasion (Shigella, Salmonella, Yersinia
enterocolitis, E. coli, C. jejuni
(2) Protozoa: Entamoeba histolytica, Giardia, nematodes (roundworms),
flatworms.
Diarrhea
I- Definition (most important)
There are three ways to define diarrhea – one satisfied criteria is enough
1) FREQUENCY: > 3 bowel movements per day (less than 3 per
week is constipation)
2) CONSISTENCY: Abnormal stool consistency (v. important)
(Watery, soupy, viscous, semi-formed…)
3) WEIGHT of the stool > 200-300 gms/d (best objective way, not
really practical) – shows you the importance of the IC valve
Diarrhea could also be defined based on chronicity:
-- ACUTE diarrhea – lasts for < 14 days à mostly due to infectious
causes (gastroenteritis), could be a bit prolonged in case of alteration of
flora (but still less than a month!)
-- PERSISTENT diarrhea – lasts for > 14 days
-- CHRONIC diarrhea – lasts for > 28 days (VERY important – we start to
think about IBS, IBD…)
II- Major Pathologic Mechanisms: disruption of normal physiology
1) Decreased ABSORPTION of fluid and electrolytes
2) Increased SECRETION of fluid and electrolytes
3) Increased luminal OSMOLALITY (release more osmotically active
molecules, so more water has to be released also)
4) Changes/increased gut MOTILITY
III- Mechanistic Classification
Water Diarrhea (any lesion in GI tract – bowel/colon)
(1) Osmotic = secretion during day only
Causes: osmotically active agent pulling out water, like
-- Sorbitol (sugar substitute)
-- Lactose (diagnosed via hydrogen breath test or clinically)
-- Osmotic Laxative (lactulose, magnesium citrate)
Diarrhea: usually after consumption of osmotic agent
Further Tests: if osmotic agent identified, just remove it from diet (no
further work-up needed)
(2) Secretory = continuous secretion (night/day)
Causes:
-- Endocrine (imbalance in gut hormones)
-- Tumor (secreting fluid/electrolytes)
Diarrhea: LARGE amounts of fluid shed CONTINOUSLY (>1 L/day)
Effect of Fasting: unaltered – continued (because pathological cause is
still there; like continuous gastrin secretion in ZE syndrome)
Further Tests:
1. Stool cultures (to rule out chronic infection)
2. Imaging of small and large bowel (to check for any tumors or
polyps, or changes in mucosa)
3. Selective testing for secretory molecules like:
1. Gastin (useful to rule out ZE syndrome or Gastrinoma)
2. Vasoactive Intestinal Pilypeptide (to rule out VIPoma)
3. Serum serotonin or urine 5HIAA (to rule carcinoid)
Secretory Diarrhea Osmotic Diarrhea
Volume > 1 L/day < 1 L/day
Timing Night + Day Day
Fasting Effect Diarrhea continues Diarrhea stops
To differentiate between secretory and water diarrhea:
1) Measure stool electrolytes
2) Calculate osmotic stool gap – it’s a calculation that takes into
account the concentration of Na+ and K+ ions in the stool.
Normally: Osmotic Gap = 290 – 2([Na+] + [K+]) – b/w 50 & 250
à blood is HYPER-osmotic relative to stool (less electrolytes, more
water/diluted)
Secretory: <50 mOsm/kg
à barely any osmotic gap between blood and stool (since a LOT of
water is being released continuously without osmotically activate
molecules)
Osmotic: >125 mOsm/kg
à greater osmotic gap between blood and stool because many
osmotically active molecules (lactose, sorbitol) are pulling out the water
Inflammatory Diarrhea (usually indicates colonic origin)
Diarrhea: filled with blood and mucus (could start out as watery, without
blood; if watery doesn’t 100% rule out inflammatory) – small volume
Presentation: frequent bowel movements, tenesmus, fever, severe
abdominal pain (systemic) - NO dehydration
Testing:
1. Fecal calprotectin (magic marker) - contained in cytoplasm of
neutrophils, usually shed in stool à when it goes above the cut-off point,
it signals inflammatory issues present + endoscopy needed
2. Endoscopy (to show abnormal gut morphology)
3. Occult Blood (will find fecal leukocytes)
Differential Diagnosis: Inflammatory Bowel Disease (UC/CD)
Fatty Diarrhea (known as steatorrhea)
Diarrhea: greasy, malodorous
Differential Diagnosis:
-- Fat malabsorption (Especially if accompanied by weight loss)
-- chronic pancreatitis
Testing: quantitative stool fat measurement (GOLD standard) – need to
consume >100 g of fat before study; positive result is 7 g of fat in stool
per 24 hours
IV- Chronic Diarrhea: could be caused by:
Irritable Bowel Syndrome (IBS)
Functional Diarrhea (classified differently than IBS)
Pts should have continuous or recurrent passage of loose (mushy)
or watery stools in >75% of stools WITHOUT abdominal pain or
discomfort for at least 3 months with symptom onset at least 6
months before diagnosis
Chronic Infections (persisting infections like Giardia or C. difficile –
especially in patients with known risk factors like an
immunosuppressed state, consumption of contaminated water…)
Cholecystectomy (self-resolving) caused by EXCESSIVE bile acids
entering the colon (no control b/c no gallbladder). This overwhelms
the capacity of the terminal ileum to reabsorb bile salts; the
remaining bile salts are either:
-- taken up by colon (5%)
-- stays in colon and pulls water (cholerheic diarrhea)
-- overwhelms porto-hepatic circulation when reabsorbed (thus, to
compensate, liver stops water absorption and promotes release of
electrolytes – worsens diarrhea)
à Treated with bile acid sequestrant
Inflammatory Bowel Disease
Microscopic Colitis –
Diarrhea: CHRONIC (intermittent) + WATERY (secretory)
diarrhea w/out bleeding –up to 2L/day of diarrhea EVERY DAY
Epidemiology: Usually in middle-aged females, but kids can have
it too.
Types: Can be divided into two subtypes:
1. Lymphocytic Colitis (you see epithelial lymphocytes on biopsy)
2. Collagenous Colitis (NO lymphocytic infiltrate)
Diagnosis: Colonic biopsy (histologically) from colonoscopy.
Macroscopically (observation), the colonic mucosa looks normal –
maybe with a bit of edema/erythema.
Note:
Organic disease is the term used to describe any health condition in
which there is an observable and measurable disease process
à If diarrhea accompanied by weight loss + waking up at night to go
to bathroom, indicates organicity
Functional disease is when you do all these lab tests and
everything and they’re normal but the patient is not and is still having
symptoms, such as:
• Irritable Bowel Syndrome (IBS) – normal blood tests and
calprotectin, BUT
• Chronic fatigue syndrome (CFS)
• Fibromyalgia
Malabsorption: (impaired absorption of nutrients) divided into:
Primary Malabsorption – from congenital defects in membrane
transport system of small intestinal epithelium
Secondary Malabsorption – caused by:
1) Defects in the epithelial ABSORBTIVE surface
2) Maldigestion (won’t absorb it if not in correct form)
MANIFESTATION: pale, greasy, voluminous, malodorous stools w/
• Weight Loss (calories malabsorbed)
• Steatorrhea (fat malabsorbed)
• Edema (proteins malabsorbed)
• Bloating (lactose malabsorbed)
(1) Lactose Intolerance: (congenital or acquired) due to decreased
function of lactase enzyme in the brush border of enterocytes,
presenting with abdominal distention and diarrhea upon consumption of
milk products.
Pathophysiology: (congenital or with age) crush border lactase is lost,
thus lactose cannot be digested. Since (unfermented) lactose is
osmotically active, will draw water towards itself.
Clinical Presentation: watery diarrhea (osmotic), abdominal distention
and bloating (CO2 and H2 gases produced by colonic bacteria).
Treatment: empiric lactose-free diet (leads to resolution of symtpms)
Testing: if necessary, Hydrogen Breath Test (after oral ingestion of
lactose to check if there is overproduction due to lactose fermentation
by gut microflora)
(2) Fat Malabsorption (95% of ingested lipid absorbed normally)
Causes: could be due to: among other things
A- Chronic pancreatitis (pancreatic insufficiency, no digestion of fat)
B- Whipple’s disease (mucosal damage of small bowel)
C- ZE syndrome (inactivation of pancreatic lipase by acid, less lipolysis)
D- Cystic Fibrosis
Clinical Presentation: steatorrhea
Testing: Stool test for fat while patient is on 100 gm fat diet; of positive
then further testing needed:
-- pancreatic imaging (check for pancreatitis)
-- secretin stimulation test (gold standard for pancreas function)
-- small bowel biopsy (check for Whipple’s)
(3) Tropical Sprue: damage to the small bowel villi due an unknown
organism resulting in malabsorption and diarrhea.
Very similar to celiac disease, except:
1- occurs in Tropical regions (like Caribbean) where infectious agent is
located
2- occurs after infectious diarrhea (thus, responds to antibiotics)
3- damage mainly to jejunum and ileum , duodenum is less involved.
à symptoms tie back to what gets absorbed in the jejunum (folic acid)
and ileum (Vit. 12).
(4) Celiac Disease: it’s an immune-mediated damage of the small
bowel villi due to gluten exposure associated with HLA DQ2/DQ8.
Genetics: associated with HLA DQ2 and DQ8 (MHC-II) and sometimes
with HLA B8 (MHC-I)
Activation of IL-5 by these peptide sequences also mediates the
immune response.
Pathophysiology: type IV hypersensitivity to gluten (alcohol soluble
protein found in wheat, barley, and rye
1- gluten is broken down into gliadin (most immunogenic component,
rich in Pro residues, which prevents digestion by enteric enzymes)
2- gliadin deamidated by tissue transglutaminase (tTG)
3- deamidated gliadin taken up and presented on MHC-II by APCs
4- Helper T cells mediate tissue damage
à all nutrients are malabsorbed due to villous atrophy
Histopathology:
-- diffuse villous atrophy (+ blunting of villi – much shorter)
-- loss of circular mucosal duodenal folds, fissures, grooves
-- basal crypt hyperplasia
-- intraepithelial lymphocytosis (lymphocytes in epithelium itself)
-- inflammatory cell (lymphocytes) infiltration of lamina propria
Clinical Presentation:
Children: malabsorption
-- abdominal distention/bloating
-- diarrhea
-- failure to thrive (FTT, underweight, short stature)
Adults (20s-30s)
-- iron deficiency anemia (celiac work-up = must, villi destroyed)
-- megaloblastic anemia (Vit B12 deficiency; villi destroyed)
-- chronic diarrhea (malabsorption)
-- abdominal distention/bloating
-- osteoporosis (due to calcium deficiency; check bone densitometry)
-- glossitis, with recurrent ulcers
-- dermatitis herpetiformis (exclusive to CD; due to deposition of IgA
at tips of dermal papillae, leading to destruction of DE junction, with
formation of blisters and vesicles at dermal papillae)
-- increased risk of lymphoma (enteropathy-associated T-cell
lymphoma) and small bowel carcinoma, despite good dietary control
Diarrhea: Watery (osmotic) – due to blunted villi
Resolution: gluten-free diet (improves within 2 weeks)
Laboratory Findings:
-- anti-tTG antibodies (IgA)
-- anti-gliadin antibodies (IgA)
-- anti-endomysial antibodies (IgA)
-- anti-reticulin antibodies (IgA)
(in case of IgA deficiency, also test for IgG antibodies)
Diagnosis: duodenal biopsy to show: (damage most severe at
duodenum, jejunum and ileum less involved)
-- flattening (blunted) of villi
-- basal crypt hyperplasia (become deeper)
-- increased intra-epithelial lymphocytes
Genetic testing (to check for HLA DQ2-DQ8)
(5) Whipple Disease: (inflammatory colitis) systemic tissue damage to
(all around body) characterized by:
-- Histology shows foamy macrophages (sheets of histiocytes) that stain
positive for PAS
-- macrophages’ lysosomes are filled with partially destroyed Tropheryma
whippelii organisms
-- macrophages pile up in the lamina propria of small bowel and
compress the lacteals
-- results in fat malabsorption and steatorrhea (chylomicrons can come
through)
-- common sites of involvement include:
* small bowel (main)
* synovium of joints (arthritis)
* cardiac valves
* lymph nodes
* CNS
(6) Abetalipoproteinemia: autosomal recessive deficiency of
apolipoprotein B-48 and B-100
-- B-48 (carries chylomicron + contributes to formation) à fat
malabsorption
-- B-100 (carries VLDL and LDL in plasma) à absent plasma VLDL and
LDL
(7) Small Intestinal Bacterial Overgrowth (SIBO): when endogenous
defenses against bacterial overgrowth impaired.
Normal Endogenous Defenses:
-- Gastric Acid (#1 barrier)
-- intestinal motility (stasis – bacterial proliferation)
-- Intact ileocecal valve
-- immunoglobulins in intestinal secretions
-- bacteriostatic properties of pancreatic/biliary secretions
Etiology: (cases)
-- disorders interfere w/ defenses (achlorhydria, pancreatic insufficiency)
-- anatomical causes (fistula, diverticula, ileocecal resection)
-- Motility issues (scleroderma, obstruction)
-- IBS, Crohn’s disease, short bowel syndrome
Location: duodenum and proximal ileum contain small numbers of
bacteria (<104, aerobes/anaerobes and lactobacilli) – BUT with SIBO, the
distal ileum is the transition zone (to dense colonization - >105 BFU per
ml of proximal jejunal aspiration)
Diagnosis: mainly clinical (can test it by giving patient antibiotics)
-- Quantitative culture of jejunal aspirate (>105 BFU per ml) – requires
anaerobic sample collection
-- radioactively labeled xylose breath test (measure radioactively labeled
CO2 due to bacterial fermentation)
-- hydrogen breath test (after administration of oral lactulose/glucose) –
problem is low sensitivity/specificity
Symptoms:
-- Bloating, abdominal pain, diarrhea, weight loss
-- Vit B12 deficiency (atrophic glossitis, neurological problems)
-- Anemia (Fe deficiency, Vit. B12 deficiency)
-- Small intestinal slash, polyneuropathy
Note: Bacteroides not found in jejunum of healthy people
Inflammatory Bowel Disease: a chronic relapsing/recurrent Epidemiology: Extra-intestinal Manifestations of IBD (usually more in Ulcerative Colitis Crohn’s Disease
bouts of inflammation of the bowel, possibly due to an Peak Age of Onset: b/w 15-30 or 60-80 yrs Crohn’s Disease)
abnormal immune response to enteric flora. Gender: 1:1 (sometimes females more) Inflammation Continuous Segmental/Patchy
In General: pattern
Types: can be divided into: B- Crohn’s Disease: TRANSMURAL inflammation 1- aphthous stomatitis (Recurrent ulcers)
1. Ulcerative Colitis 2- arthritis (hands, knees, back - sacroiliitis) Inflammation Colon Anywhere along GI tract
2. Crohn’s Disease Distribution: can affect any segment in the GI tract 3- erythema nodosum Location (especially terminal ileum)
3. IBD-U (unclassified) Small Bowel Alone (33%), Ileocolic (45%), Colon Alone (20%) 4- pyoderma gangrenosum
à Most commonly affected site is the terminal ileum 5- Episcleritis and uveitis Rectal Always Rare
Diagnosis: of exclusion (many differentials to bloody diarrhea Involvement
and abdominal pain). Presentation: IBD-dependent
- Diarrhea (non-bloody) Skin: Erythema Nodosum Mucosa/Wall Superficial (sandpaper-like) – Deep/Transmural
A- Ulcerative Colitis: SUPERFICIAL inflammation - Abdominal pain à RLQ pain (on, off - esp. after eating) leading Joints: Arthritis (PERIPHERAL) Involvement mucosal + submucosal ulcers
to loss of appetite + weight loss Eyes: Scleritis, Episcleritis
Distribution: always involves the rectum in a continuous - Peri-anal disease (abscess + fistulae formation around rectum) Fistulae/ Rare Very common
fashion, never involves the small intestine. IBD-independent (even if IBD dormant/not flaring up) Stricures (since superficial) (since invasive)
- Acute inflammation (with fever)
1. Proctitis (inflammation of the rectum) Skin: Pyoderma Gangrenosum (especially if stoma bag gets
2. Procto-sigmoiditis (inflammation of the rectum + sigmoid infected after colostomy, treat with anti-TNF) Diarrhea Blood + Mucus Non-bloody
Complications:
colon) Joints: Ankylosing Spondylitis, Sacroiliitis (AXIAL) (since colon affected) (affected area is high up)
1) Strictures (after inflammation, fibrosis results in stricture –
3. Left-sided Colitis (inflammation of rectum + sigmoid colon string sign on TI) Eyes: Uveitis
+ descending colon) -- inflammation of anterior chamber Abdominal LLQ pain (Rectum) RLQ pain (ileum)
2) Obstruction (from edema or fibrosis – blocking bowel,
4. Total (pan) Colitis (anything that goes beyond the splenic -- you get ocular pain, photophobia, redness Pain Mimics appendicitis
dilatation – abdominal distention)
flexure) 3) Abscesses (due to CD’s deep fissures in the mucosa, lead to -- slit lamp exam for diagnosis
-- start on treatment (steroids) Inflammation Crypt Abscesses with neutrophils Lymphoid aggregates with
the collection of pus within GI tract due to inflammation) – can
granulomas
Presentation: Relapsing + Remitting either drain: Other: Primary Sclerosing Cholangitis
- Diarrhea (bloody, mucus) -- into lumen of GI tract (easy) -- inflammation of bile duct
Complications Toxic Megacolon Malabsorption
- Abdominal pain à LLQ pain (Rectum) -- back into fissure, leading to fistula formation -- end up getting strictures and obstruction
Carcinoma Nutritional Deficiency
- Tenesmus 4) Malnutrition -- need liver transplant)
Calcium Oxalate Nephrolithiasis
- Systemic (fatigue, malaise, lethargy, nausea) 5) Fistulas (severe and DEEP inflammation burrows through the à shows a beading pattern, dilation before strictures
Fistulas/Strictures
GI tract layers – tunnel forms) Carcinoma (if colonic)
Complications: -- Perianal (with stool inside) Treatment of IBD
1) Colonic Stricture (inflammation, fibrosis, stricture) -- Abdominal Fistula (with stool and bile) Extra-intestinal Primary sclerosing cholangitis Ankylosing Spondylitis
2) Toxic Megacolon (colon is inflamed + dilated, indication for Goals of Treatment
Findings Positive p-ANCA Sacroiliitis
surgery Differential Diagnosis of IBD: 1. To induce remission
Recurrent mouth ulcers Uveitis
3) Dysplasia or Colonic Carcinoma -- Appendicitis 2. To maintain remission
Migratory Polyarthritis
4) Colonic perforation (severe bleeding in ~1%) -- Diverticulitis 3. To maintain adequate nutrition (or else more inflammation)
Erythema Nodosum
5) Growth Failure (if diagnosed as a kid - short, thin…) -- Carcinoma (if colon affected) 4. To minimize disease- and treatment-related complications
6) Extra-intestinal disorders (arthritis, ocular, renal…) -- Ischemic Colitis 5. To improve the patient’s quality of life
6. With the least quantity of medications possible Effect of Improves Worsens
-- Celiac Disease (Malabsorption, Diarrhea) Smoking (protects against UC) (Increases risk for Crohn’s)
Disease Presentation: symptoms can be divided into:
1) Sx targeted to UC (bowel movement, blood in stool) Etiology and Pathogenesis Ulcerative Colitis
Gross Pseudo-polyps Cobblestone mucosa
2) Sx targeted to systemic inflammation (fever, tachycardia, IBD is caused by an interaction between those three factors: -- Surgery is curative but most of the times we try with medical Appearance Loss of Haustra Creeping Fat
anemia – sign of chronicity, ESR -- inflammatory marker, not 1) Genetic Susceptibility: (most people don’t have family history) therapy before proceeding to surgery
Strictures
used that much anymore – we use CRP these days) -- Race: White >> Black > Asian -- Exceptions: Colon dysplasia/cancer or medically refractive
3) Endoscopy -- Ethnicity: Jew (Ashkenazi) > Jew (Sephardic) > Non-Jew colitis (these are people we directly refer to surgery, risks of
Medications for IBD
-- Twins: Monozygotic (67% CD, 20% UC) > Dizygotic keeping colon)
1) 5-aminosalicylic acid (5-ASA)
Mild Moderate Severe -- Genes: NOD2 explains 20% of CD -- UC (mild-moderate): induce and maintain remission in 50-70% of mild to moderate UC
-- Family History: (positive) increases risk Crohn’s Disease
-- CD: not using them much
Bowel <4 per day 4–6 per day >6 per day -- Neither medical nor surgical therapy provides a cure
2) Glucocorticoids: IV or oral prednisone used in moderate to severe UC and CD. Induce remission.
movements
2) Immune Dysregulation: -- Surgery (to remove inflamed area) is NOT a failure – they
NO role in maintaining remission. Not liked/used due to side effects (bone loss…)
Blood in stool Small Moderate Severe -- Normally: the mucosal immune system controls/down- will feel much better!! 3) Purine Analogues: Azathioprine and mercaptopurine used in glucocorticoid dependent IBD.
regulates gut inflammation in response to luminal contents 4) Methotrexate/Cyclosporine
Fever None <37.5°C mean >37.5°C mean
-- IBD patients: there is an inappropriate and exaggerated Surgical Therapy 5) Biologic agents: (VERY good) anti-TNF agents, anti-IL12/23, anti-integrins
Tachycardia None <90 mean pulse >90 mean pulse mucosal immune response to environmental factors (most Indications for surgery include complications such as:
probably the bacteria) due to failure to down-regulate. • intra-abdominal abscess IBD Surgeries
Anemia Mild <75% of cases > 75% of cases
• medically intractable fistula UC Surgery: Total Colectomy (TAC/IPAA)
Sedimentatio <30 mm >30 mm
3) Environmental Triggers • fibrotic stricture with obstructive symptoms
n rate -- infections • toxic megacolon CD Surgery:
-- anti-biotics (esp. in kids; changes flora, predisposing factor) • intestinal perforation, hemorrhage 1. Ileocecal/Ileocolonic Resection (ICR) then connect via primary anastomosis
Endoscopic Erythema, Marked erythema, Spontaneous
appearance decreased coarse bleeding, -- NSAIDs (horrible because they clamp down blood vessels, lead • dysplasia/cancer 2. Segmental Resection (cut inflamed segment, connect it via anastomosis)
vascular granularity, ulcerations to ulcerations, severe inflammation ) • Patients refractory to/dependent on glucocorticoids 3. Stricturoplasty (to preserve as much of the gut as possible)
pattern, fine contact bleeding,
granularity no ulcerations
-- Diet, SMOKING 4. Diverting Ileostomy (2 stages, 1st – cut colon from cecum, cut sigmoid colon, keep rectum and
-- Stress (very important factor) add ileostomy bag; 2nd – J-pouch 6 months later)
Diverticular Disease
-- Prognosis: Treatment of IBS:
Diverticulosis: (TRUE) outpouching/herniation (1+) of the colonic
- After acute syndrome resolves, patient should have a colonoscopy - Education/Reassurance
mucosa and submucosa through weak spots in the muscular layer of the
(after 8 weeks, to exclude malignancy in case obstruction by tumor) - Dietary Modification:
colonic wall.
- risk of diverticulitis increases after each episode -- avoid short chain CHO b/c osmotically active + poorly absorbed
- Most patients improve over 2-3 days (after antibiotics) -- avoid gas-producing foods
Location: Along any hollow organ (small intestine, stomach…) –
- Surgery recommended if 2-3 episodes of diverticulitis -- avoid gluten and lactose
especially affecting the sigmoid colon (due to higher pressure).
- Physical Activity
à In Asians, right sided more common
-- Treatment: - Probiotics
1. Mild Uncomplicated Attack (1st): - Anti-spasmodics (if patient has abdominal pain)
Pathophysiology: due to high intraluminal pressure weak spots in the
- Outpatient unit, discharged on clear liquid diet and ADAT - Rifaximin (Normix, antibacterial – especially for IBS-D)
muscular layer (especially where vasa recta penetrates the bowel wall)
- use broad-spectrum antibiotics (ciprofloxacin, metronidazole) - Celium Fiber (especially IBS-C, to get water into lumen, and IBS-D to
- colonoscopy done to rule out cancer in that area bulk up their stool)
Epidemiology: affects western societies more, secondary to diet (more
constipation, more pressure, sigmoid has to contract more)
2. Sensitive: if patient cant tolerate PO antibiotics/doesn’t improve:
-- uncommon in patients < 40 years
- Hospitalization w/ CT scan to rule out abscess/perforation Colorectal Cancer Epidemiology (3rd most common cancer in US, 2nd
-- 80% of people > 80 years have diverticulosis
- broad-spectrum antibiotics IV leading cause of neoplastic death)
-- Risk factors:
- percutaneous drainage of abscess + CT/surgery after 6 weeks
1. Increasing age
• Mean Age: 73 years
2. Obesity
3. Peritonitis/Uncontrolled Sepsis/Perforation: Emergency Surgery
3. Constipation
• Pattern:
4. Diet (low fiber, high meat)
4. Fistula repair/stricture surgery/Recurrent diverticulitis: Elective -- Overall incidence decreasing, young people incidence increasing
5. Connective Tissue disorder like Marfan or Ehlers Danlos
-- Men develop CRC 5-10 years earlier than women
syndrome (colon very stretchy)
-- Black people develop CRC 5-10 years earlier than white people
6. Genetic Predisposition
2. Painful Diverticular Disease – abdominal pain with altered bowel
movements with diverticulosis without any other explanation • Risk Factors:
Clinical Findings:
-- IBD (Ulcerative Colitis or Crohn’s Disease)
-- PAINLESS condition without any symptoms or chronic infection
~ related to DURATION of disease and AMOUNT of bowel inflamed
3. Bleeding (most common): PAINLESS, NOT related to diverticulitis ~ related to concomitant primary sclerosing cholangitis (PSC)
Complications:
- patients with diverticulosis have acute PAINLESS lower GI bleeding -- Family History (always screen kid 10 years younger than age of
1. Diverticulitis (more common) – PAINFUL inflammation or infection of
- these bleeds are SELF-LIMITING (but still give blood transfusion) relative affected with CRC, or at least by age 40)
1+ diverticula – could be uncomplicated or complicated (w/abscess,
- perform a COLONOSCOPY to rule out other causes of GI bleeding -- Strep bovis bacteriemia or endocarditis (colonoscopy)
fistula, perforation)
1st – exclude malignancy -- Defined inherited syndromes (small percentage of CRC)
2nd – exclude celiac disease
-- Pathophysiology: due to obstruction of diverticulum by:
3rd – exclude angiodysplasia
~ Fecalith
( diverticulosis itself does not cause anemia unless too much bleeding)
~ Bacterial Flora
~ Micro/Macro-perforation
à if the neck is obstructed, it distends, leads to bacterial overgrowth,
and possible micro-perforation and inflammation. Irritable Bowel Syndrome
It is a functional GI syndrome characterized by chronic abdominal pain
-- Clinical Findings: and change in bowel habits in the absence of any organic cause.
- LLQ abdominal PAIN (which may radiate)
- rebound tenderness (+ over surrounding area) + local guarding Diagnosis: Rome IV criteria = recurrent abdominal pain at least 1
- altered bowel habits (diarrhea usually) day/week in the last 3 months associated with 2+ of the following:
- Anorexia, fever (systemic symptoms) 1. Pain related to defecation
- NO bleeding! 2. Pain associated with a change in stool FREQUENCY
3. Pain associated with a change in stool FORM/APPEARANCE
-- Complications: Should exclude presence of a more serious illness (anemia, occult…)
1. Abscess formation (collection of pus + neutrophilic inflammation)
2. Rupture of diverticulum (leads to perforation + peritonitis – Epidemiology: females are diagnosed more than 2x as often as males
especially in the elderly/immunosuppressed)
3. Colonic Obstruction (in case of repeated episodes) Subtypes:
4. Pyelophlebitis (in patients with jaundice + hepatic abscesses) 1- IBS with predominant constipation (IBS-C)
5. Fistulas (when abscess opens next to an organ) 2- IBS with diarrhea (IBS-D) – associated with increased serotonin
3- Mixed IBS
-- Diagnostic Studies: (no endoscopy – can perforate) 4- Unclassified IBS
1. CBC shows leukocytosis
2. Urine analysis shows pyuria Clinical Features: MUCUS with stools, PERIODIC + abdominal pain
3. Ultrasonography shows inflammation (not really good, operator (not bloody, no large volume, they do NOT wake up at night, no weight
dependent, guarding and rebound pain make it hard) loss, no greasy stools, no anemia…)
4. CT scan can be useful to detect abscess (20% false –ve)
5. Enema studies identify diverticulosis but not diverticulitis
I- Functions of the liver: Cannot survive without liver; it is involved in: Hepatocyte Structure: hepatocytes have three membranes in three Hepatic Stellate (Ito) Cell Function: (occupy space of Disse) Hepatic Microcirculation: (it’s a LOW PRESSURE system)
1- Metabolism, detoxification, and inactivation of endogenous (bilirubin, different planes (not touching) They are cells that store fat and vitamin A. Flow at low pressure is essential for the exchange that takes place
ammonia) AND exogenous (drugs) substances 1- BASOLATERAL Sinusoidal Memrbane (contains microvilli for They play an active role in: continuously between hepatocytes and blood.
2- Kupffer cells of liver involved in filtering blood of foreign substances (virus exchange with plasma, in direct contact with sinusoids) • Regulation of microvascular tone and blood flow, hence portal
infected cells, tumor cells…) 2- APICAL Cannalicular Membrane (where cell secretes bile into the pressure The normal portal pressure is < 7 mmHg.
3- Conversions of important hormones and vitamins into active forms, e.g., biliary canaliculus) • Regeneration of hepatocytes
hydroxylation of vitamin D, and de-iodination of T4 into T3 3- LATERAL Desmosomal Membrane (faces other hepatocytes) • Fibrogenesis (transformation into myofibroblasts) when Portal Hypertension: (pressure goes > 10 mmHg)
4- Procession of lipophilic chemicals into water soluble forms (cannot be activated by inflammation, alcohol…
processed in kidney) Hepatocyte Function: (organelles) Portal hypertension may have a number of different causes:
5- Synthesis of bile salts and bile secretion Activation of Ito cells is at the center of liver fibrosis -- Anytime 1) Pre-hepatic:
6- Storage of proteins, carbohydrates, lipids and minerals Mitochondria – energy generation hepatocytes die (apoptosis or necrosis), Ito cells and Kuppfer cells • Schistosomiasis
7- Synthesis of essential proteins (like albumin), carbohydrates, metabolites • oxidative phosphorylation are activated leading to TGF-beta release and fibrosis (deposition of • Portal Vein Thrombosis
8- Release of nutrients to other organs, in the free (e.g., glucose – important • b-oxidation of fatty acid collagen in liver sinusoids) => CENTRAL mechanism to keep in • Malignant Tumors
for brain) or bound form (e.g., triglyceride) • heme synthesis mind
• enzymes for citric acid cycle 2) Intra-hepatic
Strategic location of the liver as the only organ b/w splanchnic and Liver Regeneration: (begins in zone I, oxygenated, richer) • Cirrhosis
systemic circulation enables functions RER The liver is capable of regeneration; its an organ of conditional à Alcohol
• Protein synthesis (albumin – maintains oncotic pressure, renewal: à Chronic Hepatitis
II- Functional Anatomy: the liver is functionally divided into segments, each carries endogenous and exogenous molecules like lipids, -- at baseline, hepatocytes and cholangeocytes die but are replaced • Congenital Hepatic Fibrosis
with their own independent blood supply (hepatic artery, portal vein) and coagulation factors) slowly
independent biliary drainage. • Triglyceride synthesis, complexing to lipoproteins -- during ongoing liver injury (rapid tissue loss) it’s a very high level 3) Post-hepatic
• Glucose-6-phosphatase synthesis – vital to generate glucose replacement (from Stem cells: oval cells + bone marrow cells) • Hepatic Vein Thrombosis (Budd-Chiary Syndrome)
How is this division made? like when fasting • Right-sided heart failure
1- Draw a line b/w right and left lobes (connect IVC and gallbladder) so the Liver Injury: They require adequate amount of growth factors and • Constrictive Pericarditis
left lobe would consist of the caudate + quadrate lobes. SER primers high/fast replacement UPON need. In case destruction rate
2- Divide each lobe into medial and lateral sectors • Bilirubin conjugation overpowers them, they begin proliferating in a disorderly fashion Consequences of portal HTN include:
3- Divide each sector into anterior and posterior subsector • P-450 systems (detoxification) (associated with fibrosis, and eventually liver cirrhosis). 1) Collaterals between the portal and the systemic circulation (leading to
Thus, a functional unit may be surgically removed (segmentectomy, for • Steroid, cholesterol, bile acid synthesis increased blood flow in these veins):
example, if it has a cancer) without affecting the function of other units. • Induced by phenobarbital Genetic Regulators: Proliferation involves c-fos, c-jun, c-myc, NO • Azygos à Gastro-esophageal varices (+/I hemorrhage)
synthase, HGF, EGF, TGF-α and β • Umbilical à Caput medusae (reopening of umbilical vein) –
III- Functional Unit of Liver: Rappaport’s (portal) Acinus Lysosomes converges on the umbilicus, not like IVC thrombosis
It consists of a 3D mass of hepatocytes with two axes: • Hydrolytic enzymes for cell destruction (filtering) Minimum Amount: What is the minimum amount of liver you need • Retroperitoneal system à retroperitoneal varices
- Axis going through two portal triads • Deposition of ferritin and copper • Rectal system à huge hemorrhoids and rectal varices
for regeneration (sufficient critical mass of hepatocytes for
- Axis going through two central veins regeneration)? 2) Formation of ascites
Golgi: Packaging and excretion of proteins/waste products into bile • Minimum amount is 20% (normal) 3) Splenomegaly
Hepatocytes from different zones are genetically, structurally, and functionally or into circulation • Minimum amount is 30% (mild/controlled disease) 4) Hepatic encephalopathy (liver not functional, ammonia cannot be
different. • Minimum amount is 40% (cirrhotic liver) processed to urea, travels to brain)
Zone I Hepatocytes = next to periportal area (hepatic artery, portal vein) Endothelial Cell Structure: the endothelial cells lining the sinosoids
-- better oxygenated (less susceptible to hypoxia) are organized in a discontinuous manner (not continuous/tight, like Hepatic Blood Flow: The most serious associated condition is liver cirrhosis.
-- larger + more numerous mitochondria (more Kreb’s cycle enzymes) in capillaries) with multiple fenestrations (pores) in between
-- more active in bile secretion allowing for the exchange of material between hepatocytes and Liver receives about 1.5 L/min of blood flow (almost a ¼ of CO, and Pressure of Vascular Bed: determined by two main factors:
-- more fenestrations of surrounding endothelial cells plasma (no basement membrane). blood content constitutes a third of the liver’s total weight) 1) Resistance
-- less numerous smooth ER, less P450 (more susceptible to toxins) -- 2/3 is from portal vein 2) Flow Rate
-- more susceptible to viral hepatitis (due to close proximity to portal blood) Pressure in Sinosoids: 2-3 mmHg -- 1/3 is from hepatic artery
(Gluconeogenesis, Cholesterol Synthesis, Ureagenesis, Beta Oxidation) Pressure in Capillaries: 18-19 mmHg (bile duct receives blood from branches of right hepatic artery)

Zone III Hepatocytes = closest to hepatic vein Endothelial Cell Function: Hepatic Arterial Buffer Response:
-- less oxygenated (more susceptible to hypoxia) -- Lipid, Vitamin A, and cholesterol homeostasis If portal vein blood flow is reduced (portal vein thrombosis due to
-- smaller + less numerous mitochondria -- Filtration of blood (wastes, clear pathogens and harmful prolonged OCP use), hepatic artery is dilated to compensate. This
-- less fenestrations of surrounding endothelial cells enzymes) process is mediated by adenosine.
-- more numerous smooth ER, more P450 (less susceptible to toxins)
-- fat accumulation begins here What’s the difference between liver sinusoids and systemic Liver Congestion: In conditions where systemic venous pressure is
-- processes taking place: capillaries? high (congestive right sided heart failure), both hepatic venous and
(Glycogen Synthesis, Glycolysis, Lipogenesis, Ketogenesis, Glutamine The liver sinusoids have: portal venous radicles dilate, a process that leads to “liver
Formation (to remove ammonia), Biotransformation of drugs (detox)) 1. No tight junctions congestion”, and ultimately might lead to cardiac cirrhosis (cardiac
2. No basement membranes hepatopathy).
3. Fenestrations (to allow exchange with hepatocytes)
Blood Flow
Ischemic Hepatitis: A sudden drop in blood pressure, leads to
Portal Hypertension: In liver disease, Ito cells are activated and constriction of both hepatic venous and portal venous radicles. This
Hepatic Bile Portal Zone I Zone II Zone I Hepatic turn into fibroblasts that deposit collagen in the sinosoids. The leads to marked diversion of blood flow away from the liver, with
à à (Periportal) (Midzone)
Artery Duct Vein (Centrilobular) Vein vessels are thus obliterated and capillarated. They become an area resultant liver ischemia, necrosis.
of high pressure (since resistance increased, and pressure = flow x
resistance). This forms the root of portal hypertension.
Bile Secretion