677 Gi

Lecture 30_Disorders of Esophagus 2
Lecture 31_Disorders of Stomach 62

Lecture 32_Malabsorption _ Diarrheas 112
Lecture 33_IBD _ Disorders of Colon 179
DLA NOTES ON GI BLEEDING 237
DLA Notes on LIVER DISORDERS-Part1 267
DLA Notes on LIVER DISORDERS-Part2 318
DLA Notes on PANCREAS _ BILIARY DISORDERS 357
Lecture 30
Pathophysiology Of
Gastrointestinal system:
Disorders of Esophagus
By
Dr Tey
1
Disorders of the esophagus
Esophageal Function
• Insertion by hypopharynx & relaxation of the upper
esophageal sphincter (UES)
• Transport by esophageal peristalsis
• Delivery by peristalsis and relaxation of the lower esophageal
sphincter (LES)
2
Case -1:
55-year old male who has a history of progressive
dysphagia to both liquids and solids
• 15 lbs loss of weight over the last 6 months

• Notes regurgitation but not heartburn. He tried Prilosec
but it was not helpful
• The patient was somewhat thin but the examination was
otherwise normal
• Labs including a CBC were normal
POSSIBLE CAUSES OF THIS PATIENT’S DYSPHAGIA?
3
Dysphagia: Diagnostic algorithm
Solids Solids + liquids
Intermittent Progressive
weight Heartburn
Schatzki’s loss Achalasia
ring Scleroderma
Eosinophilic
Peptic Diffuse esophageal
Esophagitis carcinoma
stricture spasm 4
ESOPHAGEAL NEUROMUSCULAR
(MOTILITY) DISORDERS
• Achalasia
• Scleroderma
• Motility disorders
• Distal (diffuse) esophageal spasm
• Hypomotility
5
ACHALASIA
“FAILURE TO RELAX” (LES pressure is
about 15 mmHg above intragastric pressure)
Disorders are mainly related to motor function:

1.Disordered peristalsis in lower 2/3 of esophagus.
2.Hypertensive lower esophagial sphincter (LES) tone,
sphincter tone increases.
Pathophysiology: Defective innervation of smooth muscles in the

esophageal body and in LES; Loss of normal peristalsis (myenteric
plexus degeneration)
Degeneration of neurons (myenteric plexus)

• Nitric oxide neurons (inhibition)
• VIP neurons
6
7
Etiology:
1. Idiopathic disorder
2. Malignancy – eg. pancreatic cancer, prostate cancer,
lymphomas etc.
3. Further diseases- eg. amyloidosis, MEN, glucocorticoid
deficiency syndrome.
4. Secondary Achalasia may arise from Chagas disease.
Clinical manifestation: dysphagia, regurgitation, chest pain

 Dysphagia to both liquids and solids
 Weight loss
LES dysfunction : tremendous enlargement of the esopha-

gus (It can hold as much as 1 L of putrid, infected material
high risk of aspiration pneumonia) Increased risk of
squamous carcinoma after age 50 if untreated.
8
ACHALASIA
• Diagnosis
• Upper endoscopy
• Esophageal motility study
• Treatment
• Pneumatic balloon dilation
• Surgical myotomy
• Endoscopic myotomy
• Botox injection
• Medication – not very useful
• Nitrates
• Calcium channel blocker
• Viagra
9
ACHALASIA
BIRDʼS BEAK ENDOSCOPIC VIEW
10
Achalasia Manometry
11
ACHALASIA
PNEUMATIC BALLOON DILATION
12
Scleroderma
13
Pathophysiology of Esophageal
Problems in Scleroderma
• Primarily a motility disturbance affecting the smooth
muscle esophagus
• 3 stages (neuropathy, myopathy and fibrosis)
• Symptoms mainly a consequence of severe GERD and
its complications.
14
Scleroderma and GERD
• The “Perfect Storm”
• Impaired lower esophageal sphincter
• Impaired esophageal clearance
• Decreased gastric emptying
• Sometimes complicated by decreased saliva
production with impaired neutralization and clearance
of refluxed acid
15
Scleroderma
Esophageal involvement
Radiology Endoscopy
16
Scleroderma
Manometry
17
Non-cardiac chest pain (NCCP)
• 50% of NCCP has an esophageal component
• 50% of esophageal NCCP induced by reflux
• Esophageal manometry (EMS)
• Nutcracker (high pressure propagated contractions)
• DES (simultaneous prolonged contractions)
• Other investigations
• Esophageal motility
• 24 hour pH monitoring
• Esophageal impedance
18
Diffuse Esophageal Spasm
• Atypical chest pain
• Intermittent dysphagia
• Simultaneous prolonged contractions
• Reassurance
• Smooth muscle relaxants (calcium channel blockers,
nitrates)
19
20
Manometry
21
Nutcracker Esophagus
• High amplitude, peristaltic contractions
• Atypical chest pain plus odynophagia
• Nitrates or calcium channel blockers
• Reassurance
Boerhaave syndrome:
Transmural distal esophageal rupture due to violent
retching: Sx Emergency
Plummer-Vinson Syndrome:
Triad of Dysphagia(esophageal webs), Iron deficiency and
Glossitis. Seen in elderly female classically.
22
ESOPHAGEAL INFLAMMATORY
LESIONS
• EOSINOPHILIC ESOPHAGITIS
• CANDIDA ESOPHAGITIS
• HERPETIC ESOPHAGITIS
• IDIOPATHIC ULCER - AIDS
• CANDIDA
• CMV
• HERPES
23
29 year old male with HIV infection
develops dysphagia and
odynophagia
candida esophagitis
24
22 year old university student
with acute odynophagia
herpes (HSV) esophagitis
25
IDIOPATHIC ULCER - AIDS
ODYNOPHAGIA
26
Case 2: 59-y.o. male
• History of chest pain
• Heartburn
• Intermittent dysphagia
• Normal exam
• Labs: normal
• Normal cardiac evaluation
27
59-y.o. male
• UPPER ENDOSCOPY:
• EROSIVE ESOPHAGITIS
• ESOPHAGEAL STRICTURE
28
Gastroesophageal reflux – reflux
esophagitis
Definitions
Reflux: passage of gastric juice into esophagus
GERD: symptoms or pathological alteration
Esophagitis: mucosal change
Etiology – conditions resulting in persistent/repetitive acid
exposure (also pepsin and bile) to the esophageal mucosa (any
disorder that diminishes LES pressure; increase gastric volume
or pressure and acid production)
29
Pathophysiology of GERD
• Lower esophageal sphincter (LES) dysfunction
• Persistent low pressure (+/- hiatus hernia)
• Transient inappropriate relaxations of the LES
• Poor esophageal clearance
• Delayed gastric emptying
• Impaired salivary neutralization
• Increased abdominal pressure
• Obesity
• Pregnancy
30
GERD Pathophysiology
• Incompetent LES / Decreased LES pressure
• drugs
• alcohol
• chocolate
• peppermint
• fatty foods
• smoking
31
Common GI Symptoms of GERD
‐Heartburn
-Regurgitation Burning sensation in
the chest and throat
-Acidic/bitter taste
-Hypersalivation
-Dysphagia
-NCCP (non-cardiac chest pain)
-Dyspepsia
-Globus
32
GERD
Extra-esophageal Symptoms
Pulmonary
• chronic cough
• asthma
ENT
• pharyngitis Complications – stricture in
• laryngitis/hoarse voice the distal esophagus
Oral dysphagia; hemorrhage,
• dental erosions perforation; aspiration of
gastric content ; pneumonia.
33
Hiatal Hernia
Hiatus
Paraesophageal
Sliding Hiatal Hernia
Hiatal Hernia
34
HIATAL HERNIA
SLIDING
35
HIATAL HERNIA
PARAESOPHAGEAL
Most (small) are
Asymptomatic
Larger paraesophageal
hernia can cause:
-Epigastric pain
-Nausea/vomiting
-Gastric obstruction
-Bleeding
-Perforation
-Gastric volvulus
Require surgical
Repair
36
DIAGNOSIS : GERD
• History – symptoms
• Heartburn, regurgitation, chest pain
• UGI series (barium)
• Demonstrate reflux
• Insensitive
• Upper endoscopy
• Normal (nerd)
• Esophagitis
• Barrettʼs esophagus
• Evaluate and treat complications
37
GERD: Investigation
“Red flags” mandating endoscopy
• weight loss (decreased intake or malignancy)
• dysphagia (obstruction or motility disorder)
• melena / anemia (ulceration or tumor)
• Inadequate response to treatment
• possible Barrettʼs esophagus with long history of under
treated GERD, symptoms > 5 – 10 yrs
38
Barium x‐ray
EsophagoGastroDuodenoscopy
(EGD)
-Peptic Stricture Dilated
39
Barrett’s Esophagus
Metaplastic process
Replacement of normal squamous mucosa by columnar
epithelium lined mucosa
Columnar epithelium contains goblet cells (intestinal metaplasia)
Up to 10% of patients with symptomatic GERD
Barrett’s
esophagitis Adenocarcinoma
Esophagus 0.3%/year
40
Barrett’s Esophagus
squamous columnar
41
Barrett’s Esophagus:
Clinical Significance
• BE : The predisposing factor for the development of
adenocarcinoma of the esophagus
• Risk factors for progression to cancer
• LARGE HIATAL HERNIA
• LONG BARRETT’S SEGMENT
• DYSPLASIA (high grade)
• MALES > FEMALES
• AGE > 70
• SMOKING
• BE patients – 30X increased risk of developing
adenocarcinoma
42
Normal Barrett’s Esophagus
43
Pathological features of Barrett’s
Esophagus
Spechler SJ, Souza RF. N Engl J Med 2014;371:836‐845.
OTHER DIAGNOSTIC TESTS
ESOPHAGEAL MOTILITY
• evaluate esophageal function before surgery
24‐hour pH STUDY
• position pH probe
• when diagnosis is in doubt
• non response to therapy
ESOPHAGEAL IMPEDANCE
• measures reflux; acid and nonacid reflux
45
Therapy
• Lifestyle modification – Clin. Gastro & Hep, January 2016

• discontinue aggravating meds (eg. anticholinergics)
• head elevation; weight reduction; smoking; limit late meals, fatty foods,
alcohol, caffeine, chocolate
• Pharmacotherapy
• H2 antagonists
• Proton pump inhibitors (PPI)
• Surgery - Fundoplication
46
Dysphagia : Difficulty swallowing
• Oropharyngeal dysphagia – difficulty with the
transfer of food from the mouth into the esophagus
• Esophageal dysphagia – difficulty with the transfer of
food down the esophagus to the stomach
Key questions
• Where does the food stick?
• Is it solids or liquids, or both, that stick?
• Is the swallowing difficulty progressive, is it intermittent?
• Is there associated heartburn – past or present?
• Weight loss?
47
Dysphagia
Diagnostic algorithm
weight heartburn
loss Achalasia
Schatzki’s
ring CREST syndrome
Eosinophilic carcinoma Peptic stricture Diffuse esophageal spasm
Esophagitis
48
Case 3:
63-year-old male presents with a history
of progressive dysphagia
• Dysphagia associated with a 15 lb weight loss over the
last 3 months
• Has to eat softer food to get it to go down
• History of heartburn, self-treated with antacids
• 40 year history of smoking 1 pack of cigarettes/day
• Exam: height was 70 inches and he weighed 155 lbs
(weight 6 months ago 170 lbs)
• The remainder of the examination was normal except for
reduced breath sounds on chest exam
WHAT IS THE MOST LIKELY CAUSE OF THIS
PATIENT’S DYSPHAGIA?
49
Dysphagia
Diagnostic algorithm
weight heartburn
loss Achalasia
Schatzki’s
ring CREST syndrome
Esophagitis
50
Esophageal Cancer
• Primary
• Adenocarinoma : Common in lower 1/3rd, M/c in US
• Reflux-induced Barrett’s
• Absolute risk is low < 10,000 cases/year in US
But the incidence Is Increasing
• Squamous: Common in upper 2/3rd, M/C in world
• Smoking, EtOH, caustic injury, tylosis
• Secondary
• Extrinsic (eg. lung cancer with nodes)
• Submucosal (eg. breast with “pseudoachalasia”)
51
ESOPHAGEAL ADENOCARCINOMA
PATHOGENESIS
GERD CHRONIC ESOPHAGITIS
INTESTINAL METAPLASIA (BARRETTʼS)
DYSPLASIA ADENOCARCINOMA
52
ESOPHAGEAL CANCER
ADENOCARCINOMA
53
ESOPHAGEAL CANCER
SQUAMOUS CELL
OBSTRUCTIVE DYSPHAGIA
ALCOHOL & SMOKING
54
Case- 4
26-year-old male dysphagia associated
with an esophageal food impaction
• Occurred while eating chicken
• History of intermittent heartburn and on occasion
dysphagia over the last 3 years.
• The heartburn has not been helped with the use of
ranitidine
• The patient was thin otherwise the examination was
normal
• Labs including a CBC were normal
What does “impaction” suggest?

What are the possible causes of the dysphagia?
How should this patient be evaluated?
55
Dysphagia: Diagnostic algorithm
weight heartburn
loss Achalasia
Schatzki’s
ring CREST syndrome
Esophagitis
56
EOSINOPHILIC ESOPHAGITIS (EoE)
• Prevalence: 6 to 30 /100,000
• AFFECTS ALL AGE GROUPS including children
• 65% have history of atopy in childhood; less common in adults
• Children > Men > Women
• SHARES CLINICAL and HISTOLOGIC FEATURES with GERD
• CHILDREN: vomiting, feeding intolerance, failure to thrive
• ADULTS: chest pain, heartburn, epigastric pain, dysphagia,
food impactions, ”refractory GERD”. Don’t respond to GERD
Tx.
• EoE AND GERD ARE NOT MUTUALLY EXCLUSIVE
• PPI-responsive EoE (PPIREE) do not have GERD, exhibit a
clinical response to PPIs
• PPI may have an anti-inflammatory effect
Omeprazole blocks IL-13 induced Eotaxin-3 secretion
57
Eosinophilic esophagitis
Activity = Inflammation + Tissue Remodeling
(Esophageal Eosinophilia) (Esophageal Fibrostenosis)
Pathology :≥ 15 eosinophils / hpf
Esophageal remodeling
• ↑ TGFβ1
• Subepithelial fibrosis /
stenosis
• mucosal fragility
• rings/furrows/exudates/strictu
res
• reduced luminal caliber due
to fibrostenosis, related to
duration of untreated EoE
58
MEAT (CHICKEN) IMPACTION IMPACTION REMOVED
EOSINOPHILIC ESOPHAGTITIS
59
Thank you
Clicker question
60
Lecture 31
Disorders of the Stomach
By
Dr Tey
1
Stomach
Motor and Secretory function
Motor function
-gastric relaxation
-contraction both of the gastric body and antrum
own peristalsis (slow waves – basic electric rhytm :
3 cycles / min)
Secretory function
-glands in cardia mucus (it contains HCO3-)
-parietal cells HCL, intrinsic factor
-chief cells pepsinogen A and C, HCO3-,
acid lipase.
2
Disturbance of the gastric motility
• Deceleration
- Organic causes : carcinoma, chronic peptic ulcer,
pylorostenosis
- Functional : abdominal trauma, hypokalemia,

disturbance of vagal innervation
hypothyroidism, diabetes mellitus
• Acceleration : less frequent, usually at hyperthyroidism
3
• Vomiting control: from the centrum for vomiting in medulla activation of
autonomic nerves (palpitations, tachypnoe, tachycardia, arrhytmias,
mydriasis – sometimes bradycardia, hypotension)
• Nausea – sometimes before vomiting

• Long-term vomiting: loss of H+, ions and water
metabolic alkalosis, dehydration
4
GASTRIC MUCOSAL BARRIER
THREE LINES OF DEFENSE
5
Disturbance of gastric secretion
• Gastric secretion – decline in course of ageing; at diseases of stomach
• Acc. to volume of released gastric juice hyper-, hyposecretion
• Acc. to HCl production
hyperacidity (hyperchlorhydria)
hyp(o)acidity (hypochlorhydria)
achylia gastrica no HCl, no enzymes
6
• Increase of secretion:
short-term – acute inflammatory process, excitation of
mucosa – food, infection, Et-OH
Long-term + proteinases + hyperacidity – peptic ulcer,

liver disease, hypercalcemia
• Decrease of the secretion :
Either volume, or HCl, proteinases, intrinsic factor or all.

Achlorhydria and achylia – accompanied with atrophic
gastritis ex. Due to pernicious anemia
7
GASTRIC MUCOSAL DISEASE
“GASTRITIS” (Classification based
on etiology)
• NSAID’s
• INFECTIOUS - H. pylori most common, ~50% of people on the Planet
• DECREASE acid production (in most infected people - 85%; BUT in
15% of infected people may have INCREASED acid production)
• ATROPHIC : Chronic gastritis
• CORPUS (BODY AND FUNDUS or TYPE A) AUTOIMMUNE DISEASE
– pernicious anemia (B-12 deficiency)
• CORPUS (BODY AND FUNDUS) H. pylori
• GASTRIC CANCER PHENOTYPE
• DUODENAL ULCER PHENOTYPE – ANTRAL INFECTION (TYPE
B) H. pylori
• OTHERS
• ESOSINOPHILIC, CROHN’S, SARCOID, SYPHILIS
8
Acute Gastritis (Erosive)
Pathogenesis – Acid hypersecretion, gastric hypoxia
Alteration of defense mechanisms,espec. diminished
mucus secretion, prostaglandin production ,reduced
intramucosal pH.
Includes
1. Inflammation due to superficial mucosal injury
2. Mucosal erosion
Curlings ulcer: dec plasma volume--- sloughing of

gastric mucosa in Burns.
Cushings ulcer: inc. vagal stimulation---- inc. Ach--

-inc. H+ production in Head injury.
9
Chronic athrophic gastritis
Characterization:
-inflammatory cell infiltration
-gastric mucosal atrophy
-loss of glands
-reduced capacity to secrete gastric acid
10
• Infectious = in app. 90% - Helicobacter pylori infection consequence:
adenocarcinoma.
• Autoimmune disease; Ab against intrinsic factor; against complex intrinsic

factor + vit. B12 also against parietal cells.
CD8+ are activated consequnce = megaloblastic anemia, adenocarcinoma
11
12
Helicobacter pylori
• Gram negative, spiral
organism
• Slow growing
• Microaerophilic
• Highly motile
• Abundant producer of
urease (including cell
surface)
13
Helicobacter pylori
Prevalence in US 30 to 40%
Usually acquired in early childhood (oral-oral, fecal-oral)
1 in 3 may clear the infection
More common
Older individuals
Less developed countries
Lower socioeconomic classes
• Associated diseases
• Chronic gastritis
• Peptic ulcer
• Gastric adenocarcinoma
• MALT lymphoma
• ? Non-ulcer dyspepsia
14
85% 1%
14%
15
Helicobacter testing
Test Sensitivity Specificity
Culture* variable 100%
Pathology* 90-95% 95-98%
UBT* 97% 95%
Rapid urease* 80-90% 95-99%
Stool antigen* 91% 88%
Serology** 85% 79%
* Affected by PPI use (preferably avoid for two weeks)
** Not useful after eradication therapy
UBT = urea breath test
16
GASTRITIS - H.pylori
17
CASE 6 : 37-year-old female presents with a one month
history of dyspepsia
• Epigastric pain occurring 2 to 3 hours after meals
• Eating reduces the pain for a while
• No history of weight loss, nausea or vomiting, nor
evidence of gastrointestinal bleeding
• History of rheumatoid arthritis which has been treated
with embrel. Due to a change in insurance the embrel
was stopped and naproxen was started at 500 mg twice
daily
• Exam was normal except for mild epigastric tenderness
WHAT IS THE CAUSE OF THIS PATIENT’S EPIGASTRIC
PAIN?
18
PROSTAGLANDINS
DEFENSE AND REPAIR
ASA AND NSAIDs

Membrane
COX-2 INHIBITORS phospholipids
Phospholipase A2
Arachidonic Acid
Stomach Macrophages
Kidney COX‐1 COX‐2 Leukocytes
Platelets housekeeping Fibroblasts
Endothelium
inflammation
Synovial cells
PGE2, TXA2, PGI2
PGI2, PGE2
GI mucosal integrity
inflammation
renal function
mitogenesis
platelet aggregation bone formation
19
NSAIDs GASTROPATHY (NOT
“GASTRITIS”)
20
NSAID Use
• NSAIDs among most frequently used drugs1
• Use  with age
• 10-30% of patient 65 yrs have current/recent NSAID prescription1
NSAIDs increase risk 3-5x : Even low-dose aspirin  risk by 2-

4x
14-31% of NSAID users develop ulceration
15-35% of peptic ulcer complications due to NSAIDs
21
Peptic ulcer ( Gastic & Duodenal Ulcers)
• Davenport (1932): HCl in stomach = ulcer, no HCl = no ulcer
• Discordance among protective and aggresive factors
• Protective factors:
mucose layer (mucus, HCO3-, phospholipids, water),HCO3-, prostaglandins (inhibition of
H+, creation of HCO3-), intact perfusion
• Aggresive factors:
HCl – activation of the proteinases
pepsin, gastrin
decreased production of prostaglandins (!!! non-steroid antiinflammatory drugs)
helicobacter pylori infection
(releasing of proteases, gastrin overproduction, stop of granulocyte migration, arrest of
phagocytosis)
22
23
PEPTIC ULCER DISEASE ETIOLOGIES
• HELICOBACTER PYLORI 60-75%

• Duodenal ulcer 80%
• Gastric ulcer 60%
• ASPIRIN AND NSAIDs 20-50%
• IDIOPATHIC (DU) 15-20%(USA)
• GENETIC (HYPERSECRETION)
• 2 to 5% in other countries
• ZES - RARE
• MASSIVE HYPERSECRETION
24
OTHER FACTORS
PEPTIC ULCER DISEASE
• Emotional stress
• Heredity
• Pre-existing medical disorders
• Smoking (reduces healing)
• Not a factor in peptic ulcers

• Alcohol
• Diet, caffeine
25
Gastric ulcer
Some GU are related to impaired mucosal defense
(acid and pepsin secretory capacity is normal or even below
normal)
Motility defects – duodeno-gastric reflux (esp. bile can lead

to diminished mucosal barrier against acid and pepsin)
Delayed gastric emptying (food retention) results in increased

gastrin secretion and acid production
Mucosal ischemia – prostaglandins increase mucosal blood

flow, bicarbonate and mucus secretion stimulation of
mucosal cell repair and renewal
26
Gastric ulcer
Clinical signs:
Abdominal and epigastric pain(Timing of the symptom is
important),nausea, vomiting. weight loss (only in GU).
Classically, gastric ulcer pain is aggravated by meals, whereas

the pain of duodenal ulcers is relieved by meals and recurrs 2-3
hours after post-prandial with duodenal ulcer.
It is important to remember that although these patterns are
typical, they are not pathognomonic.
Complications: Bleeding( Lesser curvature bleeds from

Left gastric Art) ,inc. risk of Gastric cancer.
27
BENIGN GASTRIC ULCER
UPPER GI SERIES UPPER GI ENDOSCOPY
28
Duodenal ulcer
Extends through the mucosa and muscularis mucosa into
submucosa occurs more frequently in men and in patients
with blood group O.
Pathogenesis
1. increased acid and peptic secretory capacity
2. increased basal acid secretion
3. increased postprandial acid secretory response due to
increased sensitivity parietal cells to gastrin
4. rapid gastric emptying
29
• Etiology – genetic factors, psychologic stress, diet, smoking, ethanol consumption,
Helicobacter pylori infection (high production of gastrin) – eradication of H.p. reduces
relapse in 70%, non-steroid inflammatory drugs.
ZE synd. commonly presents with duodenal ulcers.

• Clinical presentation – Ulcer may erode into blood vessels bleeding( m/c posterior
surface bleed, Gastroduodenal art.), through duodenum perforation(Ant. > Post.) , air
under diaphragm on X-ray, peritonitis; it can penetrate into surrounding tissues and
organs (pancreatic pain), severe abdominal pain, hypovolemic shock, obstruction.
30
DUODENAL ULCER
31
DIAGNOSIS
• History
• Upper endoscopy
• UGI series (barium x-ray)
• H. Pylori
• Noninvasive
• Stool antigen test
• Urea breath test (UBT)
• Serology (? active infection)
• Endoscopic (invasive)
• Antral bx with urease test
32
PROBLEM ULCERS
• Recurrent ulcer
• ASA, NSAIDS continued use
• Non-HP, non-NSAID ulcer
• Refractory ulcer r/o
• Z-E syndrome
• Cancer
• Crohn’s disease
• Lymphoma
33
CASE 7: 32-year-old female presents with a
six week history of dyspepsia
• Patient has noted bloating occurring after meals. This has

been associated with anorexia, nausea and vomiting,
weight loss of 10 lbs.
• Exam was normal except for mild epigastric tenderness
WHAT IS THE POSSIBLE CAUSE OF THIS PATIENT’S

DYSPEPSIA?
HOW SHOULD THESE PATIENT BE EVALUATED?
34
MOTILITY DISORDERS of the STOMACH
• Gastroparesis (delayed emptying)
• Acute
• Gastritis (viral)
• Drugs (narcotics)
• Surgery
• Hyperglycemia
• Electrolyte abnormality
• Chronic
• Idiopathic
• Diabetes
• Scleroderma, vagotomy, hypothyroidism
• Female: male; 4:1
35
DIABETIC GASTROPARESIS
• Pathophysiology : Autonomic neuropathy
• Reduced reflexive relaxation - fundus
• Antral hypomotility
• Hyperglycemia (acute)
• Dysrhythmia
• Increased pyloric pressure
36
SYMPTOMS
• Nausea, vomiting
• Bloating
• Anorexia
• Weight loss
• Dehydration
• Difficult glucose control
• Not much pain
37
EVALUATION
• HISTORY - DIABETES type 1 or 2 OTHER
PREDISPOSING CONDITION
• Upper endoscopy (rule out obst.)
• UGI series (barium)
• SOLID PHASE GASTRIC EMPTYING - at 2 or 4 hours
• GASTRODUODENAL MANOMETRY (research study)
38
POST-OPERATIVE DISORDERS
• Dumping syndrome
• Rapid emptying of hyperosmolar, cho-rich food
• Early
• Late (hypoglycemia)
• Nausea, cramping, bloating, diarrhea, weakness,
sweating, flushing
• Postvagotomy diarrhea
• Iron and calcium malabsorption
Billroth ii
39
CASE 8 : 72-year-old male presents with a six week history
of dyspepsia
• Bloating occurring after meals
• Anorexia, nausea and vomiting
• Weight loss of 20 lbs
• On exam the patient was pale
• There was epigastric tenderness
• The hct 34% with a mcv of 78 (normal 80-100)
HOW SHOULD THIS PATIENT BE EVALUATED?
40
CANCER OF THE STOMACH
41
RISK FACTORS : GASTRIC CANCER
• Diet (nitroso compounds)

• Processed meats, fried food
• High salt diet
• Smoking
• Infection
• H. Pylori
• EB virus
• Previous gastric surgery
• Genetics
• Germline mutation cdh1 (e-cadherin)
• PERNICIOUS ANEMIA (autoimmune atrophic gastritis)
• Gastric adenomas
• Hypertrophic gastropathy
42
NEOPLASIA OF THE STOMACH
• PRE-NEOPLASTIC LESIONS (from which cancer may
develop)
• ATROPHIC GASTRITIS (autoimmune gastritis,
h.pylori)
• H. Pylori intestinal metaplasia
• Intestinal metaplasia
• Cardia (GERD)
• Body/antrum (h. Pylori)
* Adenomatous polyps
* Menetrier Disease: Gastric hypertrophy with
protein loss, Perietal cell atrophy, and inc. mucosal
cells. Stomach rugae appear like brain gyri.
Precancerous 43
Gastric cancer: Pathogenesis
Acute Hp gastritis
Chronic gastritis Gastric ulcer
Antral predominant gastritis Multifocal atrophic gastritis
Intestinal metaplasia
Duodenal ulcer
Dysplasia
Adenocarcinoma
44
CANCER OF THE STOMACH
• ADENOCARCINOMA (H. pylori -incidence is
decreasing in the US but less so in developing
countries); acanthosis nigricans may be seen along
with early mets to liver and LNs.
• Intestinal type: common on lesser curvature.
Appears like ulcer with raised margins.
• Diffuse type: Not associated with H.Pylori, Signet
ring cell seen, stomach thickened and leathery;
Linitis plastica.
• GASTRIC LYMPHOMA
• some are secondary to H. pylori - “MALT”
LYMPHOMA
45
SYMPTOMS & SIGNS OF
STOMACH CANCER
• Epigastric pain (dyspepsia)
• Early satiety
• Weight loss
• Fatigue
• Virchow nodes: Left supraclavicular node
involved.
• Krukenberg tumor: Bilateral metastasis to
ovaries. Classic “signet ring cells” and
mucous on biopsy.
• Sister Mary Joseph Nodule:
Subcutaneous Periumbilical Metastasis.
46
GASTRIC LYMPHOMA
Less common
47
Zollinger-Ellison syndrome
Gastrinoma – gastrin producing tumor of δ(D)-cells in

Langerhans islets in pancreas, can also arise form duodenum.
Plasma gastrin level – extremely high, basal acid secretion –

markedly elevated = hyperacidity
High frequency of duodenal ulcers, ulcers can be evident

in esophagus, stomach, as well as in the proximal parts of
small bowel
48
GIST TUMORS
• Gastrointestinal stromal tumors (GIST)
• Mesenchymal tumor (interstitial cells of
cajal)
• Size and number of mitoses
• Leiomyomas to leiomyoma sarcoma (smooth
muscle tumors
49
Thank you
Clicker question
50
Lecture 32
Diarrheas &
Malabsorption
By
Dr Tey
1
Diarrhoea
Definition: bowel movements, which are excessive in volume,

frequency, liquidity (acc. clinicals: > 200g of the stool / day)
Pseudodiarrhea – production frequent loss of stool (150 g/

day) without changes in consistency
Small intestine – predominant site for fluid absorption – stool

is voluminous
Colonic pathology small volume diarrhea
2
Diarrhoea
• Acute Vs Chronic
• Osmotic diarhea – nonabsorbable substrates cause
increased osmotic load, draw water into the lumen.
Osmotic diarhea is dependent upon presence of
osmotically active substances (eg. sugars).
• Secretory diarhea (large volum dia.) excessive
mucosal secretion of fluid + electrolytes. Regulatory
peptides (eg. VIP) stimulate chloride + water secretion.
secretory diarhea is improved in a fasting state.
• Malabsorptive diarhea – ability of digest or absorb a

particular nutrient is defective
3
Acute Diarrhea
4
Diarrhoea
• Inflammatory diarrhea – associated with mucosal

damage stool contains great number of granulocytes, may
contain blood, systemic symptoms may be present
• Non-inflammatory diarrhea – as a result of influence

mainly toxicogenic Escherichia coli, viruses, cathartic,
neuroendocrine tumors
5
Types + etiologic factors of the
diarrhea
• Acute infectious diarrhea – Non-inflammatory
(decreased fluid absorption + increased secretion) –
rotavirus, Norwalk like virus.
Inflammatory – variety bacterial, viral, parasitic, fungal
agents
• Chronic infectious diarrhea
1. Postenteric diarrhea – infection is resolved,
residual effect is still present
2. Chronic persistence of infection
Acute on chronic presentations.
6
• Cholera – Vibrio cholerae – waterborne diarrheal ilness
– mild to life threatening in severity. Most patients respond
well to re-hydration consisting of glucose, electrolytes
and water (glucose cotransport with sodium remains
intact)
• Inflammatory diseases mucosal damage + altered

cell permeability histamine, leukotriens, prostaglandins,
some of neurotransmiters (subst. P) also lead to diarrhea
healing by fibrosis and strictures intestinal
obstruction.
7
Diarrhea - consequences
• Acute diarrhea
dehydration, loss of electrolytes,metabolic acidosis
(due to loss of HCO3-), if infectious; shock
• Chronic diarrhea
steatorrhea, deficit of fat soluble vitamins (disturbance
in calcium and phosphate balance, bleeding etc)
8
CHRONIC DIARRHEA
LOOSE STOOLS > 4 WEEKS
9
CASE 4: An 72-year-old female is referred for
evaluation of a 6-month history of loose,
watery stools
• Had no previous gastrointestinal symptoms
• There has been no weight loss, any significant abdominal
pain, nausea, or vomiting
• She has started no new medications during the immediate
months preceding the onset of her diarrhea
• Physical examination was normal
• Labs: hematocrit 40%, wbc 5,400
• The chemistry panel including liver function tests, tissue
transglutaminase IgA, and thyroid-stimulating hormone were
normal
• Fecal WBC, ova and parasite, giardia ag, clostridium difficile
toxin were negative
• Qualitative fecal fat was negative. Stool electrolytes: Na+
45, K+ 65 osm gap = 70 (290 − 2 ([Na+] + [K+])
10
NEXT STEP IN THIS PATIENT’S
EVALUATION?
A. Stool culture
B. Colonoscopy and biopsies of the colonic mucosa
C. Empiric treatment with an anti-diarrheal medication
D. Upper endoscopy with small bowel biopsies
11
PATHOPHYSIOLOGY
• Secretory (watery)
• NO significant OSMOTIC GAP (< 100)
• Net increase in secretion
• Osmotic (watery)
• Large osmotic gap (>125)
• Ingestion of poorly absorbed carbohydrates or mg
SALTS
• Decrease in absorption
• Malabsorption (fatty stools)
• INFLAMMATORY (wbcs, BLOODY)
12
HISTORY
• Duration
• Onset (abrupt, gradual)
• Stool characteriestics
• Watery
• Bloody
• Fatty
• Pattern of the diarrhea
• Continuous
• Intermittent
13
HISTORY
• Diet history
• Previous surgical history
• Weight loss, how much?
• Malabsorption
• Neoplasm
• Ischemia
• Aggravating and mitigating factors
• Previous evaluations
14
HISTORY
• History of eating disorders
• Secondary gain
• Systemic disease
• Hyperthyroidism
• Diabetes
• Collagen-vascular diseases
• Aids
15
PHYSICAL EXAM
• Weight loss
• Nutritional status
• Oral ulcers
• Thyroid mass
• Wheezing
• Heart mummer
• Hepatomegaly
-Ascites
-Edema
-Wasting
-Anal sphincter tone
16
ROUTINE LAB TESTS
• CBC
• Serum chemistry
• Liver tests
• ESR
• C-reactive protein
17
LAB TESTS
• Anti-TISSUE TRANSGLUTAMINASE IgA
• TSH
• GASTRIN
• CALCITONIN
• VIP
• SOMATOSTAIN
• ACTH STIMULATION
18
STOOL STUDIES
• Fecal occult blood
• FECAL wbc’s
• Culture
• Ova and parasite exam
• Giardia (stool antigen)
• CRYPTOSPORIDIUM (stool antigen)
• AMOEBA (stool antigen)
• C. DIFF TOXIN ASSAY (whether recent antibiotic
exposure or not)
19
INFECTIOUS DISEASE OF THE
GI TRACT
GIARDIA UPPER SMALL INTESTINE
May be associated with acute or chronic diarrhea
20
DIAGNOSTIC STUDIES
STRUCTURAL DISEASES
• Flexible sigmoidoscopy + biopsies (younger patient,
no weight loss or blood)
• COLONOSCOPY + BIOPSIES (older patient, with or
w/o wt loss, FECAL OCCULT BLOOD and/or WBC)
• Barium studies (small bowel, barium enema)
• Upper endoscopic biopsies, culture
• Ct-scan of the pancreas
21
POSITIVE DIAGNOSTIC
STUDIES
• Inflammatory bowel disease
• Malignancy
• Microscopic colitis
• Collagenous colitis
• Lymphocytic colitis
• Pseudomembranous colitis
• Celiac disease
22
SECRETORY DIARRHEA
• Pancreatic cholera
• Non-beta islet cell tumor of pancreas
• VIP mediated
• May have multiple endocrine tumors
• CARCINOID SYNDROME :
Vasoactive mediators: 5-hydroxytryptophan,
histamine
• Paroxysmal flushing, cramping, explosive diarrhea,
tachycardia and decreased blood pressure
• Elevated urine 5-HYDROXYINDOLEACETIC ACID (5-
HIAA)
23
BILE ACID MALABSORPTION
• Caused by ileal resection or disease
• Limited resection (<100 cm)
• Malabsorbed bile acids enter colon and stimulate
secretion
• No steatorrhea; fat <24 g/24hr
• Rx: cholestyramine
• Extensive resection (>100 cm)
• Bile acids severely malabsorbed with impaired
enterohepatic circulation
• Inadequate liver synthesis with Impaired micelles,
causing fat malabsorption and secretion in colon
• Rx: low fat diet and medium chain triglycerides
24
ADDITIONAL STOOL STUDIES
(72 HOUR STOOL)
• Stool weight/24 hours
• Quantitative stool fat
• Stool osmolality
• Measured*
• Laxative studies
• Mg++
• Bisacodyl, anthroquinone
• Room search*
25
ADDITIONAL STOOL STUDIES
• STOOL ph < 5.3
• Qualitative stool fat
• OSMOTIC GAP (stool na, K)
• Laxative screening
• Urea, creatinine (urine in the stool)
26
OSMOTIC GAP
290 - 2(Na + K)stool
• GAP > 125 mOsm/kg = OSMOTIC DIARRHEA

• GAP OF < 50 mOsm/kg = SECRETORY DIARRHEA
• GAP OF 50 - 125 = MIXED DIARRHEA
27
INCREASED OSMOTIC GAP
• Gap > 125
• STOOL FAT > 14g/100g stool
• Malabsorption syndromes
• Pancreatic insufficiency
• Bacterial overgrowth
28
INCREASED OSMOTIC GAP
• Gap > 125
• STOOL FAT < 14 grams / 100g stool
• LACTOSE INTOLERANCE: genetic or elderly.
• Fodmaps
• Fructose (corn syrup)
• Fructans (wheat)
• Galactans (beans
• Polyols (sorbitol, stone fruits)
• Laxative abuse
29
NORMAL OSMOTIC GAP
• Normal gap < 50
• Normal stool weight
< 300 g/ 24 hours
• Irritable bowel syndrome
• Factitious diarrhea
30
NORMAL OSMOTIC GAP
• Normal osmotic gap < 50

• Normal stool fat
• Increased stool wt >300 g/ 24 h
• > 1000 g Secretory diarrhea
• Laxative abuse
31
CASE 1: 46-year-old female
• Weight loss
• No rectal bleeding
• Bloating & cramping
• Hungry but afraid to eat
Exam:
• Ecchymosis
• Ascites
• Edema
• Wasting with obvious weight loss
32
WHAT IS CAUSING THE
PATIENT’S SYMPTOMS?
a. Malabsorption
B. Cirrhosis of the liver
C. Irritable bowel syndrome
D. Cancer of the stomach
E. Ulcerative colitis
33
Malabsorption
34
Malabsorption
Malabsorption may involve one or many substances;
consequent patterns of nutritional deficiency are often similar
regardless of the primary pathological lesion
On the other hand : Excesive absorption
Iron (in hemochromatosis)
Copper (in hepatolenticular degeneration – Wilson´s disease)
35
Mechanisms of malabsorption
• Primary diseases of intestinal mucosa (disturbance in

enterocyte enzymes)
• Systemic diseases (involvement of mucosa or
mesenteric lymphatic vessels)
• Faulty digestion of food due to secretory disorders
• Abbreviated contact between nutrients and mucosa
• Inadequate mucosal surface available for absorption
• Competition of bacteria and nutrients
• Infective, toxic and nutritional factors
36
MALABSORPTION SYNDROME
MOST COMMON CAUSES
‐PANCREATIC INSUFFICIENCY
-CELIAC DISEASE
-TROPICAL SPRUE
-SHORT BOWEL SYNDROME
-BACTERIAL OVERGROWTH
-GIARDIASIS
-CROHN’S DISEASE* (Sm. Bowel)
37
EVALUATION: General Approach
History & exam
• Alcohol (chr. Pancreatitis)
• Family hx (celiac sprue)
• Travel (tropical sprue)
• Surgery (sbo, gastrectomy)
Laboratory
• D-XYLOSE : done to differentiate between
• Small intestine vs pancreatic insufficiency
• GENERAL TESTS (CBC, metabolic)
• SPECIFIC TESTS (TTG-IgA , fe, B12)
• Stool fat, pancreatic elastase
38
EVALUATION
X-RAYS
PLAIN FILM
UGIS, SMALL BOWEL SERIES
CT SCAN
ERCP
MRCP
SMALL BOWEL BIOPSY
39
CELIAC DISEASE
GLUTEN-SENSITIVE ENTEROPATHY
CELIAC SPRUE
DIARRHEA CHYLOSA
CONSUMPTION OF THE BOWELS
Prevalence ~ 1:100 (vs 1:3000 in 1994)
1950 0.2% had positive TTG (9,000 healthy adults)
2000 0.9% had positive TTG (12,768 healthy adults)
4 times more common than 50 years earlier
Improved diagnosis
40
Wheat, Barley, Rye
PATHOGENESIS
Gluten / gliadin
1.Ingested
2.Survives digestion
3.Crosses gut epithelium
4.Better fit made by TTG
5.Taken up by “antigen
presenting cells”
6.Genetically encoded
DQ2 or DQ8 receptor
binding site
7.Presented on the DQ2/8
8.T cell activated

- Inflammation
- Antibody production
41
- Tissue damage
PATHOGENESIS
Gluten-derived gliadin peptides
Genetic predisposition
HLA-DQ2 and/or DQ8 loci genes + other non-HLA loci gene(s)
Virus or Bacteria (?trigger)
• Infection allows gliadin to pass into the lamina propria
• Amino acid sequence homology between gliadin and a
protein in adenovirus type 12; infection sensitizes T-cells
to antigenic determinant shared with gliadin up regulating
the gut immune system
GLIADIN (drives the inflammation) with TTG deaminating the

glutamine at positions 4,6,7 on the gliadin peptide causing an
increased T-cell response
42
GENETIC PREDISPOSITION
ONE 1st DEGREE RELATIVE = 10%,

TWO 1st DEGREE RELATIVES = 25%
ONE 2nd DEGREE RELATIVE = 8%
IDENTICAL TWINS - 70% CONCORDANCE
43
CLINICAL FEATURES
WIDE SPECTRUM OF SYMPTOMS:
Diarrhea, weight loss
BRUSING, SKIN RASH (dermatitis herpetiformis)
Fe deficiency, anemia,
Abdominal pain
Osteopenia, bone pain
Swelling, ascites, joint pain,
Epilepsy, infertility, short stature
32% are overweight or obese at diagnosis
44
GI SYMPTOMS
• Anorexia
• Dyspepsia
• Bloating/Distention
• Recurrent abdominal pain
• Recurrent diarrhea
• microscopic colitis
• Constipation (~ 3%)
• Aphthous stomatitis
• Dental abnormalities
45
Extraintestinal Symptoms
• Skin
• Dermatitis herpetiformis
• 100% have celiac disease Itchy and blistery patches of
skin on knees, elbows,
buttocks
• Growth and Development
• Short stature
• Delayed puberty, Infertility
• Metabolic Bone Disease
• Osteopenia, Osteoporosis
• Arthritic pain
46
Extraintestinal Symptoms
• Liver Disease
• Elevated transaminases
• Autoimmune hepatitis
• Primary Biliary Cirrhosis
• Ascites (hypoalbuminemia)
• Weight Loss
• Anemia (Iron / Folate deficiencies;
rarely B-12)
• Bruising: Vit K deficiency, Prothrombin time
47
Complications of Untreated CD
• Autoimmune • Malignant
• DH
• Nutritional
• Small bowel lymphoma
• Type 1 DM • Protein (122X)
• Addison’s • Small bowel carcinoma
• Iron (83X)
• Thyroid
• Arthritis • Folic acid • Pharyngo-esophageal
(10X)
• Neurologic
• Calcium
There is a 4 fold increased risk of death with undiagnosed CD

Over a 50 year time period
48
SEROLOGY
ANTI-tissue TRANSGLUTAMINASE IgA (TTG IgA)

or ANTIENDOMYSEAL IgA (EMA)
TOTAL IgA determination (2-5% of Celiac patients are IgA
deficient)
ANTI-Deamidated Gliadin Peptide (DGP) IgA, IgG
(do not use: ANTI-GLIADIN IgA & IgG)
49
PATHOLOGY (SMALL BOWEL)
Villi are blunted
Crypts are elongated
Inflammatory infiltration
Changes are compatible with celiac disease (not
specific)
50
ENDOSCOPIC AND HISTOLOGICAL
CHANGES
CELIAC DISEASE NORMAL
51
ENDOSCOPIC FEATURES OF CELIAC
SPRUE
“MUCOSAL CRACKS” “MUCOSAL CRACKS” - methylene blue
52
DIAGNOSIS
‐Small bowel biopsies (six)
-Response to gluten-free diet
53
Causes of Villous Atrophy Other Than Celiac
Disease
54
Diagnostic strategies when on GFD
• HLA typing excludes CD if negative

> 95% of patients are DQ2 and/or DQ8 positive
• Gluten challenge then serology +/- biopsy
• 1-2 pieces of bread for 2-4 weeks
• Endoscopy/biopsy to look for subtle change
• Over 50% of patients with severe disease can have residual changes
for up to two years
55
Gluten-Free Diet (GFD)
• Highly effective in celiac disease
5% non-responsive
1-2% refractory
• Improvement of the abnormality in the small bowel with
normalization of absorption
~ 30% of adults have ongoing partial villous atrophy on biopsy
• 5 year survival = general population
• Strict GFD is difficult to maintain
Need for non-dietary treatments of celiac disease
56
Wheat, Barley, Rye
Gluten free diet PATHOGENESIS
Gluten / gliadin
1.Ingested
2.Digest with Glutenases
3.Tight junction modulator

Larazotide 0.5 mg TID
4. Better fit made by TTG
5. Taken up by “antigen
presenting cells”
6.Genetically encoded
DQ2 or DQ8 receptor
7.Presented on the DQ2/8 Induce immune

tolerance
8.T cell activated Anti-inflammatory
- Inflammation
- Antibody production
57
- Tissue damage
Case 2: 37-YEAR OLD FEMALE
15 year history of symptoms
• Abdominal bloating
• Fatigue
• Headaches
• NORMAL BLOOD TESTS including TTG-IgA and
normal stool studies
• Diagnosis = IBS
• Gluten free diet suggested by a friend with celiac
disease: all symptoms abated
Non-celiac gluten sensitivity
58
NON-CELIAC GLUTEN SENSITIVITY
IBS-like symptoms with the ingestion of gluten and
improvement after gluten withdrawal with no evidence of
celiac disease or wheat allergy
BETWEEN CELIAC DISEASE AND IBS
“NO MAN’S LAND”
ESTIMATED PREVALENCE OF NON-CELIAC GLUTEN
SENSITIVITY ~ 7% or ~20 MILLION?
CELIAC DISEASE = 0.9% or 3 MILLION
WHEAT ALLERGY (IgE mediated) < 500,000
59
NON-CELIAC GLUTEN or WHEAT
SENSITIVITY (NCGS)
Non-celiac gluten intolerance > celiac disease
More people aware of NCGS than celiac disease
Symptoms
Diarrhea
Abdominal pain, bloating
Fatigue
Poor concentration
130 other symptoms suggested to be associated with
NCGS
60
NON-CELIAC GLUTEN SENSITIVITY
GLUTEN or WHEAT SENSITIVITY?
Myriad of symptoms
No diagnostic markers
Symptoms subside when stop ingesting gluten
(wheat)
No inflammation on duodenal biopsies
Negative serology for celiac disease
61
Tropical sprue
Cause: persistent contamination of mucosa by coliform bacteria
(Klebsiella, Enterobacter cloacae, Escherichia coli) – toxins
make structural abnormality of mucosa.
Signs: megaloblastic anemia (folate deficiency), watery diarrhea

abdominal cramps, increased flatulence
62
BACTERIAL OVERGROWTH
SMALL INTESTINE
Loss of gastric acidity
Decreased motility
Scleroderma
Diabetes
Anatomical abnormalities
Diverticula
STRICTURES (crohn’s disease)
FISTULA (crohn’s disease)
Advancing age
63
BACTERIAL OVERGROWTH
SMALL INTESTINE
Chronic diarrhea, abdominal cramps, weight loss,
nausea
Evidence of malabsorption
Small bowel barium x-ray
13c-xylose breath test
Lactulose hydrogen breath test

Good story with predisposing condition
64
WHIPPLE’S DISEASE
• First described by whipple in 1907. Since then there has been
about 1000 cases reported (incidence of 10/year)
• Systemic infection caused by gram+ bacilli: tropheryma
whippelii
• Involves small bowel, CNS, heart, kidneys, joints
• SUSPECT with ARTHRALGIAS, ABDOMINAL PAIN, WEIGHT
LOSS, DIARRHEA, and CNS tissue or CSF)
• Often with marked inc ALBUMIN, EDEMA
• Small bowel biopsy shows PAS + granules in macrophages (+
PCR for T. Whippeii)
• Treatment: CEFTRIAXONE then BACTRIUM
65
PAS Positive Granules
WHIPPLE’S DISEASE
66
Thank you
Clicker question
67
Lecture 33
Pathophysiology of GIT:
IBD & Disorders of the Large
Intestine
By
Dr Tey
1
INFLAMMATORY BOWEL DISEASE
ULCERATIVE COLITIS CROHN’S DISEASE
2
CASE 6 : A 32-year-old woman is
referred with a 4-month history of
diarrhea
• Multiple small volume diarrheal stools with blood and
mucous; 4-6/day
• Physical examination: 125 lbs with normal vital signs.
There was tenderness in the LLQ
• Labs: hematocrit 35%, wbc 11,500, mcv 79 (normal > 80,
<100)
• Evaluation to date has consisted of recently negative
stool studies for bacteria, parasites, and clostridium
difficile toxin
3
WHAT IS THE MOST LIKELY CAUSE OF THIS PATIENT’S
CHRONIC DIARRHEA?
a. LACTOSE INTOLERANCE
b. GIARDIASIS
c. ULCERATIVE COLITIS
d. CELIAC DISEASE
e. CANCER OF THE RECTUM
4
CLINCAL FEATURES:
ULCERATIVE COLITIS VS. CROHN’S DISEASE
FLARES AND REMISSIONS
• UC – ACUTE to SUBACUTE ONSET with FREQUENT

BLOODY DIARRHEAL STOOLS, ABDOMINAL CRAMPS,
+/- FEVER, +/- SYSTEMIC TOXICITY
• CD – INSIDIOUS ONSET with DIARRHEA WITH OCCULT

BLEEDING, OBSTRUCTIVE SXS (STRICTURES),
ABDOMINAL PAIN CRAMPS, +/- FEVER, SYSTEMIC
TOXICITY
• FISTULAE (penetrating disease),fissures.
5
INFLAMMATORY BOWEL
DISEASES
• ULCERATIVE COLITIS • CROHN’S DISEASES
S
S (CONFLUENT • INFLAMMATORY E
E INVOLVEMENT) V
V
E • PROCTITIS 1/3 • FIBROSTENOSING E
R
R • RECTOSIGMOIDITIS I
I
T • LEFT COLITIS 1/3 • FISTULIZING T
Y
Y • PANCOLITIS 1/4
AFTER 20 YEARS 50% WILL

HAVE PANCOLITIS
6
PATHOGENESIS
• GENETIC FACTORS (> 163 genes associated with
IBD) 30 specific for CD; 23 specific for UC; 110
seen in both
• TWIN CONCORDANCE STUDIES
• 30% in CD
• 15% in UC
• NOD2 mutation – greatest risk
• Remainder convey minor risks
• Immune factors (mucosal)
• Innate gut immune system
• Adaptive gut immune system
• Gut immune system interaction to the gut
microbiota / bacterial flora, viruses
• Dysfunctional microbial recognition
• Loss of tolerance
7
8
Figure 1
9
PATHOGENESIS
• GENETICS CONFERS SUSCEPTIBILITY
• NOD 2 GENE MUTATION (CHRMOSOME 16)
• Heterozygosity – 2 to 4 x increased risk for CD
• Homozygosity – 11 to 27 x increased risk for CD
• BARRIER DISRUPTION (eg. GELATINASE)
• TRANSLOCATION of BACTERIA / BACTERIAL PRODUCTS
• DISTURBED INFLAMMATORY RESPONSE TO GUT BACTERIA
(NO FLORA - NO INFLAMMATION)
• INNATE IMMUNE SYSTEM
• ADAPTIVE IMMUNE SYSTEM
• DYSREGULATION (up-regulation of inflammatory response to
intestinal bacteria / bacterial products)
• Th-1 + Th-17 expansion – Crohn’s disease
• Th-2 expansion – Ulcerative colitis
10
ENVIROMENTAL FACTORS
• GEOGRAPHIC FACTORS – northern latitudes
• HYGIENE HYPOTHESIS
• Extremely hygienic environments negatively affects immune development
and predisposes to immunologic disease such as ibd
• DIET
• SUGARS, FATS
• SMOKING
• Exacerbates crohn’s disease (affects NOD2 function)
• Protective in ulcerative colitis
• APPENDECTOMY
• Reduces the risk of ulcerative colitis (if less than 20 years of age at the
time of surgery)
• NSAIDs - MUCOSAL INJURY
• ORAL CONTRACEPTIVES
• STRESS – modifier rather an inducing factor
11
ULCERATIVE COLITIS
MILD SEVERE
12
ULCERATIVE COLITIS CROHN’S DISEASE
13
CROHN’S DISEASE TERMINAL ILEUM
14
CLINICAL LANDSCAPE OF INFLAMMATORY BOWEL DISEASES
ULCERATIVE COLITIS I. COLITIS CROHN’S DISEASE
15
ULCERATIVE CROHN’S COLITITS
DISEASE • TRANSMURAL infl.
• MUCOSAL, Sub infl • ENTIRE GI TRACT
• COLON ONLY • AT RISK
• CONFLUENT • SKIP AREAS
• CRYPT ABSCESS • GRANULOMAS 1/3(Th1

mediated); (cobble stone
• No Granuloma ( Th2 appearance, String sign on
mediated) Barium swallow)
• RECTUM INVOLVED • RECTAL SPARING
• Loss Of Haustra: Lead • IN SOME CASES
Pipe appearance
SURGERY 30% • FISTULAE 1/4
INDETERMINATE COLITIS • ABSCESS
< 5% cases; when both • STRICTURES 1/2
ASCA and pANCA are + • ABDOMINAL MASS
ASCA trumps pANCA
SURGERY 75% with
• INFLAMMATORY
recurrence 85%
16
EXTRAINTESTINAL MANIFESTIONS
• OCULAR (UVEITIS, IRITIS); APTHOUS ULCERS
• SKIN (ERYTHEMA NODOSUM ON SHINS,
PYODERMA GANGRENOSUM)
• STONES (GALLSTONES, KIDNEY STONES in CD)
• MIGRATORY POLYARTHRITIS (CD)
• ANKYLOSING SPONDILITIS (ASSOCIATES WITH
DISEASE ACTIVITY)
• BILIARY TRACT (PRIMARY SCLEROSING
CHOLANGITIS in male patients with UC)
Increased risk of colorectal cancer
Increased risk of biliary tract cancer
17
PATIENT EVALUATION
• History and physical
• Lab: CBC, ESR, CRP, biochemical eval.
• Stools for WBCs, lactoferrtin, calprotectin
• Cultures, C. diff toxin,
• Serology for amoebasis
• COLONOSCOPY + biopsies
• Flexible sigmoidoscopy + biopsies
• CT scans
• CT enterography
• MR enterography
• Pelvic MRI
• Capsule endoscopy
• Small bowel barium x-rays
• Serologic markers
• ASCA – CD
• pANCA – UC
18
BIOMARKERS
ESR CD > UC, slow to
CRP CD 95%, UC 50%
symptoms + CRP 86%
mucosal inflammation
ASCA CD spec 96, sens
50%
pANCA UC > CD
FECAL CALPROTECTIN
FECAL LACTOFERRIN
19
EVALUATION OF EXACERBATIONS
• Inflammatory vs noninflamatory
• Irritable bowel syndrome
• Lactose intolerance
• Infectious colitis
• C. Diff COLITIS
• NSAID usage
• Continued smoking (crohn’s)
• Stopped smoking (ulcerative colitis)
20
THE TREATMENT “STEPS”
• 5-ASA (MESALAMINE)
• STEROIDS
• THIOPURINE (IMMUNOMODULATORS)
• AZATHIOPRINE metabolized to 6-MP
• 6-MERCAPTOPRINE (6-MP)
• METHOTREXATE
• ANTI-TNF ANTI - INTEGRIN
• Infliximab (Remicade) Vedolizumab (Entyvio)
• Adalimumab (Humira)
• Certolizumab (Cimzia)
• Golimumab (Simponi)
• SURGERY – decreasing for both CD and UC
21
CASE 8: 26 y.o. Male
• 4 year history of lower abdominal cramps,
abdominal bloating and intermittent diarrhea
• Increased symptoms for the last 6 months
• No fever or weight loss
• No rectal bleeding
• Exam normal except for mild LLQ tenderness
• Stool negative for blood
• CBC, C-reactive protein were normal
22
THE MOST LIKELY DIAGNOSIS IN THIS CASE?
a. CANCER OF THE COLON

b. GIARDIASIS
c. CROHN’S DISEASE
d. IRRITABLE BOWEL SYNDROME
e. CELIAC SPRUE
23
Irritable Bowel Syndrome (IBS)
• 50% of healthy people experience brief “IBS-like

symptoms” when stressed
• 10-13% of the population experience frequent
symptoms (female to male 2:1)
• Incidence 1.4%
• 10-20% of symptomatic people seek help
• 25% who seek help are referred
24
SYMPTOMS
• Abdominal pain
• Bloating
• Altered bowel pattern
• Frequency
• Consistency
• Dyspepsia (45%)
• No weight loss, fever, bleeding
25
IBS - D (Diarrhea Predominant)
IBS - C (Constipation Predominant)
IBS - M (Mixed or Alternating D C)
ROME IV Criteria – May 2016

Symptom onset at least 6 months before diagnosis (chronicity). Recurrent
abdominal pain at least 1 day per week in the last 3 months that has 2 or
more of the following features:
1. Related to defecation (pain either relieved or worsened)

2. Associated with a change in frequency of stool
3. Associated with a change in form (appearance) of stool
26
Differential diagnosis
• Malabsorption (celiac disease)
• Dietary factors
• Infection (giardiasis)
• Microscopic colitis
• Neoplasia
• Gynecological disorders
• Psychological disorders
27
IRRITABLE BOWEL SYNDROME
• An anatomically “normal” GI tract behaving badly

• Disease entity, recognizable triggers, pathophysiological
pathways, therapeutic targets
• IBS...a diagnosis of exclusion.
28
Potential Contributing Factors
Genetics
Early social learning
Hormonal factors
Chronic stress
Food intolerances
29
Figure 1
BIOPSYCHOSOCIAL DISORDER
FOLLOWING INTESTINAL
INFECTIONS
EMOTIONAL MOTOR SYSTEM
ANXIETY
DEPRESSION
VESCERAL
HYPERSENSITIVITY
PAIN
BLOATING
DYSMOTILITY
DIARRHEA
CONSTIPATION
EXAGERATED INTESTINAL
MOTOR RESPONSE TO
MODULATORS
30
Copyright © 2011 AGA Institute
MODULATORS
• STESSORS • FOOD
• PSYCHOSOCIAL INTOLERANCES (NOT
DISORDERS ALLERGIES)
• ANXIETY • Gluten ?
• DEPRESSION • Lactose, Fructose
• FODMAPs
• PSYCHOSOCIAL
TRAUMA • FAT CONTENT IN
FOOD
• ACT OF EATING
• SLEEP
• DRUGS
31
ROLE OF STRESS IN THE DEVELOPMENT
and
MODULATION OF IBS SYMPTOMS
32
EVALUATION
• Physical exam - excludes other diagnoses
• Laboratory
• CBC, C-reactive protein, Liver tests
• Serology for celiac disease (tissue
Transglutaminase IgA)
• Upper endoscopy and duodenal biopsies if +
• IBSChek (Anti-CdtB, anti-vinculin), IBS-D
33
-Stool for occult blood
-Stool studies (diarrhea)
Fecal Calprotectin
WBCs
Antigen for giardiasis
C. difficle toxin
Bacterial culture - usually not helpful
• If 50 years of age consider screening colonoscopy
34
COLORECTAL ADENOMAS AND CANCER
35
CASE 9 : 58-year-old Male
• 9 month h/o diarrhea
• 6 to 10 movements
• Small volume
• Notes some bleeding
• Symptoms are increasing
• Weight loss - 15 pounds
• Abdominal cramps and pain
• Except for the obvious weight loss the exam is
normal.
• Lab: hct of 38% with an MCV of 75
36
WHICH IS THE MOST LIKELY DIAGNOSIS IS
THIS CASE?
a. GIARDIASIS
b. CROHN’S DISEASE
c. IRRITABLE BOWEL SYNDROME
d. CELIAC DISEASE (SPRUE)
e. CANCER OF THE RECTUM
37
COLORECTAL CANCER
• 140,000 NEW CASES OF CANCER

• Death reduction of 46% since peak in the 1990s
• RISK FACTORS
• Age ( > 50 years)
• Previous colonic neoplasia
• Family cancer syndromes
• First degree relatives
• Ulcerative colitis
• Crohn’s colitis
38
CLINICAL BEHAVIOR OF COLORECTAL CANCER IS
DETERMINED BY THE MULTIPLE FACTORS OF
COLORECTAL CARCINOGENESIS
Age
Obesity
Smoking
Alcohol
Diet
Inflammatory bowel disease
Hx of cholecystectomy
Physical activity
Aspirin / NSAIDs*
*30% reduction in risk in

Daily Aspirin uses in 3 large case-
control studies reported in 2015;
COX-2 inhibition
39
SYMPTOMS
• EARLY SYMPTOMS
• SILENCE with OCCULT and/or
INTERMITTENT BLEEDING
• LATER SYMPTOMS
• OBSTRUCTIVE (left colon)
• ANEMIA (right colon)
• WEIGHT LOSS
40
COLONIC POLYPS
PRECANCEROUS LESION
• Non-neoplastic
• Hyperplastic
• Inflammatory
• Neoplastic (40% of people > 60 yrs)
• Adenomatous (~70%)(Villous,Tubular &
Tubulovillous)
• Serrated (Premalignant, BRAF mutation
seen)
• Depending on the polyp the estimated time to
cancer is between 4 to 15 + years
• Risk of malignancy
• Size
• Villous element
• Dysplasia
41
COLON CANCER
MUTATED GENES
• Tumor suppressor genes (tsg) – inhibit cell proliferation or

promote cell death (apoptosis)
• Mutation leads to loss of apoptosis, clonal evolution, clonal
expansion:
Adenomatous polyposis coli gene (APC)
Gatekeeper – mutated in 85% crc (tumor initiation)
Mismatch repair genes (mmr)
Caretaker genes – mutated in 10-15% (tumor progression)
GUARDIAN of the GENOME p53 GENE – LATE MUTATION
• Proto-oncogenes - induce cells to proliferate (cell growth / clonal
expansion)
• Mutation to oncogenes lead to uncontrolled growth: k-ras, cox-2
(celecoxib*)
42
GENETIC RISK
• General risk ~ 6% lifetime
• 70% sporadic colon cancer
• Dietary / environmental factors
• Step-wise acculumation of somatic mutations
• 30% of population has one or more susceptiblity genes
• Inherited predisposition < 5%
• Familial adenomatous polyposis (fap) 100% risk
• Hereditary non-polyposis colon cancer
• 80% risk for cancer
• Younger age
• Right colon > left colon
• Hamartomatous polyposis syndromes(PJS ,JPS)
• Familial – 25%
• One 1st degree relative 1.7x = 10%
• RELATIVE < 55 yrs 5X = 30% 43
• TWO 1st DEGREE RELATIVES 5X = 30%
Genetic associations with genetic syndromes:
• Familial adenosis Polyposis (AD)
• Gardner syndrome
• Turcot syndrome
• HNPCC/Lynch syndrome(AD)
• Additional risk factors: Juvenile polyposis syndrome, Peutz-
jeghers syndrome, large villous adenoma, IBD, tobacco.
44
GENES AND GROWTH FACTOR PATHWAYS THAT DRIVE
THE PROGRESSION OF COLORECTAL CANCER
15% 80%
5%
10-15 YEARS
BEFORE CANCER
45
MICROSATELLITE INSTABILITY IN COLORECTAL CANCER
46
47
TREATMENT AND PREVENTION
• Removal of all neoplastic lesions (polyps) by

colonoscopy
• Synchronous lesions 40%
• Metachronous lesions 20-50%
• Colorectal cancer - surgical resection
• Any TNM STAGING or DUKES A to D
• Chemotherapy for stage III OR IV
• Chemoradiation therapy then surgery for rectal
cancer
48
SCREENING OPTIONS
• Annual FOBT 32% reduction in mortality from cancer of
the colon.
• Stool DNA Testing detects 92% of CRC and 42% adv.
Polyps.
• FOBT + FLEX. SIG. EVERY 5 YEARS - Sens 75%
• COLONOSCOPY EVERY 10 YEARS
• sensitivity ~ 95%
• incidence of “interval cancer” ~ 6% (risk reduction
not risk elimination)
• thorough (high quality) with very low complication
rate (near zero)
benefit must be >>> harm
• VIRTUAL COLONOSCOPY
49
BARIUM ENEMA
50
CECUM WITH A SMALL POLYP
51
COLONIC POLYP
52
LARGE POLYP
53
CANCER OF THE SIGMOID COLON
54
CANCER OF THE ASCENDING COLON
55
Constipation
Pathophysiologic mechanisms most often involve poor colonic
propulsive activity.
It may be due to:
1. Structural causes – benign or malignant tumors, strictures

(due to fibrosis, inflammation, diverticular disease, irradiation,
IBD)
2. Anorectal causes – painful defecation (inflamed hemorrhoids,
anal fissures, rectal inflammation, trauma)
3. Long term immobilization
4. Metabolic causes – smooth-muscle disorders, collagen
vascular disorders, drug-associated conditions, diabetic
neuropathy, hypothyroidism
5. Dehydration 56
Thank you
57
Clicker Question
58
DLA on Upper and Lower GI
Bleeding
Objectives
• Describe the difference in presentation of
Upper vs Lower GI bleeding.
• Enumerate the examples of UGI & LGI
bleeding.
• Describe the principles of initial evaluation
and management in GI bleed.
MELENA and HEMATEMESIS
UPPER GI BLEEDING
HEMATOCHEZIA IN A FEW CASES
Example:46
year-old
Example: 56 year-old Male Female
Duodenal Ulcer esophageal
“Visible Vessel” – Ulcer eroded varices -
onto an artery banded
300,000 admissions /year and 125,000/year inpatients in US
MORTALITY OF 3-10%
ASSESSMENT - GI BLEEDING
• Recognition & Resuscitation
– MINOR BLEEDING or MAJOR HEMORRHAGE
• History, Vital Signs, Orthostatic changes
Vital Signs Acute Volume Loss
Stable <500cc
Ortho h HR 500 - 700 cc
Ortho i BP 700 – 1000 cc
Resting h HR 20% or >1 Liter
Resting i BP 30 – 40%
Death >50%
ASSESSMENT - GI BLEEDING
• Recognition & Resuscitation
– MINOR BLEEDING or MAJOR HEMORRHAGE
• History, Vital Signs, Orthostatic changes
• INITIAL SUPPORTIVE THERAPY
– IV FLUIDS (2 IV LINES IF MAJOR BLEED)
– TYPE AND CROSS (2 to 6 UNITS OF BLOOD)
FOR POSSIBLE TRANSFUSION (HCT < 27% Hgb
< 9 in high risk patients; < 21% or Hgb 7 most cases
including variceal bleeding)*
• ESTIMATE OF BLOOD LOSS (HISTORY)
• VITAL SIGNS: RESTING HEART RATE AND BP
• ONGOING BLEEDING
• COMORBID CONDITIONS
– AGE, LIVER FUNCTION, COAGULOPATHY,
CARDIAC, PULMONARY, RENAL FUNCTION
ASSESSMENT - BLEEDING SITE
– UPPER vs LOWER vs MID GI TRACT
• History - hematemesis; black unformed stool (melena)
vs. red stool (hematochezia)
melenic stool ~ 200 cc of blood
• N-G tube 10% false negative result
– NO ACTIVE BLEEDING OR DUODENAL ULCER
WITHOUT BLOOD REFLUXING BACK INTO
STOMACH
• BUN/Cr ratio > 25 (>35 more accurate)
– CASE 1: 40/0.9 = 44,
– CASE 2: 36/0.5 = 72
UGI bleeding site is suggested in the first and
obvious in the second patient (hematemesis)
AN ELEVATED BUN/Cr RATIO SUGGESTS AN
UGI BLEED (RATIO OF > 35)
– BLOOD IN THE UPPER GI TRACT

• LARGE NITROGEN LOAD (BLOOD) IN THE
UPPER SMALL INTESTINE LEADS TO AN
INCREASE IN THE BLOOD UREA NITROGEN
(BUN)
– PRE-RENAL AZOTEMIA DUE TO HYPOVOLEMIA
AFTER CONTROL OF THE BLEEDING AND CLEARING

OF THE BLOOD FROM THE SMALL INTESTINE THE
BUN FALLS TO NORMAL
HEMATOCRIT AND BLOOD VOLUME
INITIALLY HCT UNDER ESTIMATES

ACTUAL BLOOD LOSS
1. FLUID SHIFT FROM EXTRAVASCULAR SPACE to CIRCULATORY SPACE

2. IV FLUIDS W/O RED CELLS
SUSPECTED UGI BLEEDING
INITIAL INITIAL
CLINICAL RESUSCITATION and
ASSESSMENT STABILIZATION
INITIAL PRE-ENDOSCOPY RISK

ASSESSMENT
HIGH RISK LOW RISK

ICU ADMISSION WARD ADMISSION
HOLD IN ER
EARLY
ENDOSCOPY
EARLY/ELECTIVE
ENDOSCOPY
CAUSES OF UPPER GI BLEEDING
• Gastric ulcer ~ 45%
– Gastric erosions
• Duodenal ulcer ~ 30%
– Erosive duodenitis
• Esophageal varices ~ 10%
• Mallory-weiss tears ~ 7%
• Esophagitis / esoph. Ulcers ~ 5%
• Uncommon causes ~ 3%
– Dieulafoy lesion
– Vascular malformations
– Aortoenteric fistulas
– Tumors
PATHOGENESIS
• MUCOSAL BREAKS - EROSIONS, ULCERS, TEARS,
ISCHEMIA, NEOPLASM DISRUPTION OF VESSEL
• VASCULAR LESIONS - VARICES, HEMORRHOIDS, ANEURYSMS,
VASCULAR ECTASIAS, FISTULA
– PRESSURE AND/OR WEAKNESS IN THE VESSEL WALL
MALLORY-WEISS TEAR ESOPHAGEAL VARICES

DISRUPTION OF VESSEL PRESSURE OR WEAKNESS IN WALL
IMPORTANT CLUES FROM
PATIENT HISTORY
• Peptic ulcer disease
• Liver disease
• ASPIRIN AND NSAIDS
• Anticoagulation therapy
• Previous surgery
– Gastric surgery
– Abdominal aortic aneurysm repair
• CHEST PAIN (increase risk for a cardiac event
in older patients)
EVALUATION & THERAPEUTIC
TOOLS
• UGI endoscopy
• Colonoscopy
• Capsule endoscopy
• Single or double balloon assisted small
intestine endoscopy
• Bleeding scans
• Angiography
• Barium x-rays are not used when evaluating
a patient with gi bleeding
MALLORY-WEISS TEARS
(3 TEARS)
DUODENAL ULCER
“VISIBLE VESSEL”
ESOPHAGEAL VARICES
BLEEDING RISK IS RELATED TO SIZE OF THE VARIX

AND PORTAL PRESSURE
Rationale for acute acid
suppression in UGIB
• Improved platelet aggregation
– Platelets aggregate poorly at pH< 6
• Inhibition of pepsin-mediated fibrin digestion
– Pepsinogen requires a pH< 4 to be activated to
pepsin
NON-BLEEDING VISIBLE
VESSEL
DUODENAL ULCER
LOWER GI BLEEDING
COLON / ANUS
MINOR
1. HEMMORRHOIDS
2. FISSURES
3. NEOPLASIA
4. INFECTIOUS COLITIS
5. INFLAMMATORY BOWEL DISEASE
6. ISCHEMIC COLITIS
LOWER GI HEMORRAGE
– Diverticulosis + hemorrhage
~ 50% from the diverticulosis
~ 50% other causes
– Angiodysplasia
• Angioma
• Vascular ectasia
– Hemorrhoids (less common)
NEOPLASIA (rarely)
ISCHEMIC COLITIS (typically minor)
POLYPECTOMY SITE
PROSTATE BIOPSY SITE (rarely)
MASSIVE DIVERTICULAR BLEEDING
EVALUATION AND TREATMENT
• Same initial treatment as with UGI bleed
– Stop aspirin, nsaids, anticoagulants
• Stopped; low-grade bleeding
– “EARLY” COLONOSCOPY (within 12 to 24 hours)
• Bleeding vessel, adherent clot, nonbleeding visible vessel
– Epinephrine injection
– Bipolar coagulation
– Hemoclip (right colon)
– Band ligation
• Massive
– UGI panendoscopy
– Bleeding scans, angiography
– Surgery
Undetected UGI and Colonic Bleeding
Upper GI Lesions ~ 25% Mid GI Tract ~ 75%
Cameron’s erosions Younger than 40 years of age
Fundic varices Tumors
Peptic ulcer Meckel’s diverticulum
Angioectasia Dieulafoy’s lesion
Dieulafoy’s lesion Crohn’s disease
Gastric antral vascular ectasia Older than 40 years of age
Lower GI Lesions Angioectasia
Angioectasia NSAID enteropathy
Neoplasms Diverticulosis, Celiac disease
Uncommon
Hemobilia
Hemosuccus pancreaticus
Aortoenteric fistula
SMALL INTESTINAL BLEEDING
AGE MATTERS
• PATIENTS < 50 years • PATIENTS > 50 years
– Small bowel tumors – Vascular lesions
– Nsaid ulcers – NSAID ulcers
– Meckel’s diverticulum – Diverticulosis
• 2% of population – Dieulafoy’s lesion
• Male:Female 2:1 – Small bowel tumors (2%
• 2 ft (60 cm) proximal to of all GI cancers)
the ileocecal valve • Adenocarcinoma
• 2 inches (5 cm) • Carcinoid tumors
• 2% have a complication • Stromal tumors (gist)
• 2 types of ectopic tissue
– gastric/pancreatic
– Dieulafoy’s lesion
– Crohn’s disease
SMALL INTESTINAL BLEEDING
EVALUATION
• BLEEDING TAGGED RBC SCAN (if

actively bleeding ~ 0.5 ml/min
• Meckel’s scan may be helpful in younger
patients
• Angiography
– Active bleeding 50% yield
– Not bleeding 25% yield
• CT scan enterography
• MR enterography
SMALL INTESTINAL
TREATMENT
• Angiodysplasia - 80%
– Cauterization
– HORMONAL tx (ORTHONOVUM 1/50 BID?)
Ulcers - stop NSAIDs (8% of small intestines at
autopsy have ulcers when nsaids have been
used within 6 months)
• Tumors - surgery
• Meckel’s Diverticulum (age < 20) SURGERY
OCCULT BLEEDING
Bleeding not apparent to the patient but a positive
fecal occult blood test
• No anemia
– Colonoscopy only, if asymptomatic
– Upper endoscopy if there are upper GI tract symptoms
present
• Iron deficiency anemia - upper endoscopy / colonoscopy
– Lesions found in 70% of cases
• 30% upper source esophagitis, ulcer, gastritis especially
true when there is upper GI symptoms
• 30% colonic source (polyp, cancer, AVM, IBD)
• 10% lesions found in both the upper and lower GI tract
– 30% of cases no lesion found – small bowel cause
SMALL INTESTINAL EVALUATION
• CAPSULE ENDOSCOPY
– No therapeutic capability
– Confirms active bleeding and location, guide to further
evaluation and treatment.
– Small intestinal bleeding; improved diagnosis with
capsule endoscopy
• DEEP ENTEROSCOPY (small intestine endoscopy)

– Can apply therapy guided by capsule endoscopy
Clicker question
A 34-year-old male patient comes with complains of
intermittent pain in upper part of his belly since 3 months.
The pain is aggravated within 30 minutes of food. He has
lost 5 pound since the pain started. He is a smoker for 10
pack year, drinks 3-4 beers/day and has a very stressful
job. Which of the following complication is most likely
expected in this case?
A. Duodenal perforation
B. Stomach ulcer bleeding
C. Pyloric stricture
D. Peritonitis
E. GERD
DLA on LIVER DISORDERS
Part- 1
1
This DLA covers pathophysiology of:
ACUTE LIVER FAILURE

and
CHRONIC NONVIRAL HEPATITIS
2
Acute liver failure (ALF)
❖ A disease that produces rapid deterioration of liver functions that
results in development of :
1) Coagulopathy, (prothrombin time >20 sec or prolonged by 4-

6 seconds or INR > 1.5)
2) Encephalopathy – (any degree of mental alteration )
3) Previously healthy individual patient without preexisting
cirrhosis and with an illness of less than 6 months duration.
❑ Fulminant liver failure – encephalopathy develops within 2 weeks

❑ Subfulminant liver failure – develops within 3 months
3
Classifications of presentations
• Hyperacute - associated with acute acetaminophen toxicity, acute
Hepatitis A or E
▪ progression from jaundice to encephalopathy < 1 week
▪ severe coagulopathy
▪ moderate intracranial hypertension
• Acute - associated with hepatitis B

▪ progression from jaundice to encephalopathy 1-4 weeks
▪ moderately severe coagulopathy
▪ mild to moderate intracranial hypertension
• Subacute - associated with nonacetaminophen drug toxicity

▪ progression from jaundice to encephalopathy 4-12 weeks
▪ mild coagulopathy
▪ severe jaundice
▪ absent or mild intracranial hypertension 4
5
Pathophysiology of ALF
❖Mechanisms of acute liver injury

1. Direct hepatocyte damage
2. Innate immune-mediated response

➢ Immune cells express receptors that are able to recognize type-
specific molecular changes
▪ Pathogen-associated molecular patterns (PAMPs) as in viral
hepatitis
▪ Damage-associated molecular patterns (DAMPs) in toxin-
mediated liver injury
❖Mechanisms of hepatocyte death in ALF

– Necrosis (e. g. acetaminophen)
– Apoptosis
6
Metabolism of Acetaminophen
7
Mechanism of Acetaminophen Induced Liver Damage
❖ N-acetyl-p -benzoquinoneimine (NAPQI) has an extremely short

half-life and is rapidly conjugated with glutathione, and is then
renally excreted.
❖ Under conditions of excessive NAPQI formation or a reduction in
glutathione stores by approximately 70%, NAPQI covalently
binds to hepatocellular proteins, forming NAPQI-protein
adducts.
❖ This causes an ensuing cascade of oxidative damage and
mitochondrial dysfunction.
❖ The subsequent inflammatory response propagates
hepatocellular injury and death.
❖ Necrosis primarily occurs in the centrilobular (zone III) region,
owing to the greater production of NAPQI by these cells
8
9
Clinical Presentation In ALF
History
▪ Jaundice
▪ History of: Alcohol use, Medication use (prescription and
illicit or recreational), Herbal or traditional medicine use
▪ Family history of liver disease (Wilson disease)
▪ Exposure to risk factors for viral hepatitis (travel,
transfusions, sexual contacts, occupation, body piercing)
▪ History of exposure to hepatic toxins (mushrooms, organic
solvents, phosphorus contained in fireworks).
▪ Evidence of complications (eg, renal failure, seizures,
bleeding, encephalopathy)
10
Physical Findings in ALF
• Encephalopathy signs and symptoms

• Cerebral edema ( papilledema, hypertension,
bradycardia)
• Jaundice (maybe absent in early acetaminophen
poisoning)
• Ascites
• Right upper quadrant tenderness
• Change in liver span
• Hematemesis or melena
• Hypotension and tachycardia
11
Lab Investigations in ALF
▪ Coagulation studies
▪ LFT, RFT & ABG
▪ Complete blood count
▪ Viral serology
▪ Blood Studies: Ammonia, Ceruloplasmin level, Amylase
and lipase, Autoimmune markers
▪ Toxicology screen
▪ Liver biopsy
12
Liver biopsy
• Indicated if suspicion of:
❖Autoimmune hepatitis
❖Metastatic liver disease
❖Lymphoma
❖Herpes simplex hepatitis
❖Wilson disease
13
Lab Findings in ALF
Typical Lab Findings
• Prolonged prothrombin time/INR (5-6 seconds/>1.5)

• Elevated aminotransferases (>1000)
• Elevated bilirubin Findings
• Elevated serum creatinine and blood urea nitrogen
• Elevated ammonia level
• Decreased platelets
• Hypoglycemia
14
Diagnosis of ALF
Based on constellation of the following clinical
findings:
➢ *Jaundice in a previously healthy person
➢ Preceding history of malaise or nausea
➢ Rapid onset of altered mental status and coma
➢ Laboratory evidence of coagulopathy and acute
hepatic injury
❑Consider acetaminophen toxicity in all patients,

even without a history of toxic ingestion
▪ AST levels are very high (3500 units/L) suggest acetaminophen
hepatotoxicity)
▪ Normal acetaminophen levels do not rule out overdose
15
Complications of ALF
▪ Seizures
▪ Hemorrhage (as a result of impaired coagulation,
from esophageal, gastric, or ectopic varices)
▪ Cerebral edema and intracranial hypertension
▪ Sepsis
▪ Acute renal failure (30-50%) (due to dehydration,
hepatorenal syndrome)
16
17
➢ A group of conditions that result in chronic

inflammation of the liver
➢ Ultimately lead to fibrosis, cirrhosis, and liver failure
Includes:
1) Autoimmune Hepatitis
2) Wilson Disease
3) α1-Antitrypsin Deficiency
4) Hereditary Hemochromatosis
18
Wilson Disease (WD)
[Hepatolenticular Degeneration]
• Autosomal recessive inherited disorder of copper
metabolism
• characterized by excessive deposition of copper in the
liver, brain, and other tissues .
• Genetic defect is a mutation in ATP7B gene (Chr. 13q)

• Onset of symptoms from 3 to 40 years (usually late
childhood)
• Liver disease progress from acute hepatitis to cirrhosis
19
Pathogenesis of WD
The transport of copper by the copper-transporting P-type ATPase is
defective secondary to one of several mutations in the ATP7B gene
Gene Mutation:
• More than 40 different mutations
• The most common: a change from a histidine to a glutamine

(H1069Q).
Results in:
1) Defective hepatocytes transport of copper into bile for excretion
2) Defective incorporation of copper into apo-ceruloplasmin to form
ceruloplasmin ( binding protein for copper in blood)
• The excess copper promotes free radical formation that results in

oxidation of lipids and proteins. 20
21
Pathogenesis cont.
22
Clinical Findings
Kayser-Fleischer rings
▪ deposition of copper in the descemet membrane in the limbus of
the cornea
▪ greenish gold to brown color
▪ consist of electron-dense granules rich in copper and sulfur
▪ 90% of individuals with symptomatic Wilson disease
❑ Not pathognomonic of Wilson’s

disease; seen in patient with
chronic cholestatic disorders
(primary biliary cirrhosis)
23
❖ Central Nervous system disease
➢ Copper deposits in the basal ganglia
❑ produce movement disorder resembling Parkinsonism
❑ Hemibalismus
❑ Dysphagia; Dystonia; Incoordination
❑ difficulty with fine motor tasks
❑ gait disturbance
➢ Cerebral cortex copper deposit is toxic to neurons, causing

dementia
❖Psychiatric features (Behavioral,Affective,Cognitive,

Schizophrenic-like changes )
▪ Emotional lability
▪ Impulsiveness
▪ Disinhibition, and self-injurious behavior. 24
❖Hepatic symptoms
Sign and symptoms of hepatic insufficiency and cirrhosis may slowly
develop and can result in fulminant hepatic failure
❑ Hepatosplenomegaly; Steatosis
❑ Acute, Fulminant hepatitis; chronic hepatitis
❑ Cirrhosis
❖Hemolytic anemia - due to oxidative injury of the cell membrane

caused by excess copper
❖Renal Disease – Proximal tubule damage produces Fanconi

syndrome
❖ Musculoskeletal manifestations – chondrocalcinosis,

osteomalacia, osteoarthritis and osteoporosis 25
Lab Findings in WD
❖Decreased total serum copper

▪ Due to decreased ceruloplasmin
❖Decreased serum ceruloplasmin

▪ Useful in diagnosing Wilson’s disease in its early
stages
❖Increased serum and urine free copper

▪ Useful in diagnosing Wilson’s disease in the later
stages
26
Diagnosis of WD
❑ Suspect WD in any young person with
▪ Chronic hepatitis or cirrhosis
▪ Low ceruloplasmin levels (<50 mg/d)
❑ With low ceruloplasmin levels or high clinical suspicion:

▪ Kayser-Fleischer rings on slit-lamp examinations
▪ Increased urinary excretion of Cu (>100 mcg/24 h)
▪ Liver biopsy
✓Histological evidence of Cu deposition
✓Hepatic tissue Cu content >250 mcg Cu/g dry liver (N: ≈55 mcg)
❑ Identification of family-specific mutation

– The most common mutation is H1069Q (His/Gln) 27
Treatment
➢D-Penicillamine or Trientine(copper chelator)

➢Zinc-based therapy (inhibits copper reabsorption in
intestines)
➢Ammonium tetrathiomolybdate
competes for copper reabsorption in bowel
Increase copper excretion in the urine
➢Liver Transplant (if hepatitis or cirrhosis)
28
Alpha 1-Antitrypsin (α1-AT) Deficiency
▪ An autosomal co-dominant disease resulting from
defects in the SERPINA1 gene (Chr. 14q)
▪ Most common in people of North European descents
▪ Manifests with a spectrum of disease affecting the liver,

lung, and skin
▪ People with AATD are predisposed to obstructive
pulmonary disease and liver disease
▪ Most common cause of cirrhosis in children

▪ Its primary manifestation is early-onset panacinar
emphysema
29
Alpha 1-Antitrypsin (α1-AT)
➢ Small plasma glycoprotein
➢ Major function - is inhibition of neutrophil-derived proteases
(eg, elastase)
➢ Very polymorphic - 75 α1-AT variants
➢ Normal allele is M (MM is normal genotype with α1-AT in the

normal range- 150-350 mg/dL)
➢ Deficient variants: Z allele and S allele
❑ Severe deficiency most commonly occurs in the homozygous

ZZ variant (PiZZ), with decreased (<10 % of normal) AAT level in
serum
30
31
Pathogenesis
➢ In α1AT deficiency, variants (eg.PiZZ) in the proteinase inhibitor
(Pi) gene alter α1AT structure
➢ The PiZZ polypeptide is prone to misfolding and aggregation due

to amino acid substitution, glutamine to lysine
➢ Aggregated, deformed polymers of α1AT accumulate in the

hepatocyte endoplasmic reticulum
➢ This triggers the unfolded protein response, which leads to

apoptosis.
➢ Liver disease results from accumulation of the insoluble and non-

degradable mutant protein
➢ The emphysema stems from loss of α1AT function and excessive

protease activity 32
Clinical Findings in α1-AT Deficiency
❖ Initial symptoms include:
▪ cough, sputum production, and wheezing
▪ Dyspnea is the symptom that eventually dominates AATD (84%)
❖ A spectrum of liver abnormalities

➢Neonatal hepatitis with cholestatic jaundice 10 to 20%
newborns
➢Chronic hepatitis, cirrhosis, and hepatocellular
carcinoma– adolescence and adults
❖ Panacinar emphysema
❖ Panniculitis
Painful cutaneous nodules at sites of trauma
33
Laboratory Findings in α1-AT Deficiency
Low serum levels of α1-AT
Decreased serum levels (<80 mg/dL) or decreased activity
Liver biopsy
✓ determine stage of hepatic fibrosis
✓ shows characteristic PAS-positive, diastase-resistant
globules in the periphery of the hepatic lobule
Most patients with liver disease have either PiZZ or PiSZ
Treatment
– IV α1-AT
– Liver transplant
34
HEREDITARY HEMOCHROMATOSIS (HHC)
➢Abnormal accumulation of iron in
parenchymal organs, leading to organ toxicity.
➢Autosomal recessive inheritance

➢Mutation of the HFE gene
➢Highest prevalence Northern European

descent
➢Excessive iron deposition in tissues lead to
end-organ damage
35
Iron Metabolism
36
Iron Metabolism cont..
❑Hepcidin is a key regulator of iron absorption
❑Hepcidin binds to ferroportin at the basolateral cell

surface of the duodenal enterocytes :
➢Ferroportin is internalized and degraded
➢Fe transport out of the enterocytes is impaired
➢Iron accumulation in enterocytes leads decreased Fe
absorption
❑Hepcidin also exert similar effects on ferroportin receptors

on reticuloendothelial macrophages
❑HFE mutations lead to reduced hepatic secretion of

hepcidin
37
Pathogenesis of HHC
❑Inheritance of one or more genetic

mutations in HFE gene
❑HFE gene is localized to

chromosome 6p
38
Pathogenesis of HHC
39
Pathogenesis of HHC
1. Reduced hepatic secretion of hepcidin in HHC leads to
2. Unrestricted release of Fe from enterocytes and macrophages
3. Uncontrolled Fe absorption
➢ Iron deposition involves the liver initially, and later, endocrine

organs (pancreas, pituitary), heart and other organs
➢ Patients are commonly asymptomatic until 20 g of stored Fe have

accumulated
➢ Mechanism of liver injury:

➢ Lipid peroxidation
➢ Stimulation of collagen formation
➢ DNA damage by reactive oxygen species
40
Clinical Manifestations
41
Clinical Findings in HHC
❑ Liver cirrhosis
▪ in 60% of the patients
▪ Risk of hepatocellular carcinoma (HCC) is 200x
❑ Skin Pigmentation (75%)

o Metallic or slate-gray hue to the skin (bronzing) due to:
▪ Increased epidermal melanin production
▪ Hemosiderin deposition in dermal macrophage and
fibroblast
❑ Diabetes mellitus (Bronze diabetes) (60%)

➢Destruction of beta-islets cells – by fibrosis and
atrophy
➢Increase Insulin resistance 42
❑ Hypogonadism
▪ Fe deposition in the pituitary gland
▪ Features include impotence, amenorrhea (25%) , reduced
libido (50%), and testicular atrophy
❑ Malabsorption
▪ destruction of exocrine pancreas
❑Rhythm disturbances (atrial fibrillation)
❑ Arthropathy (>40%)
▪ due to hemosiderin and calcium pyrophosphate deposits in
joints
▪ (pseudogout)
43
Laboratory Findings
❖ Increased:
✓ Serum iron
✓ % Transferrin saturation (best screening test - cutoff level of
45%)
✓ Ferritin
❖ Decreased
▪ Total iron-binding capacity (TIBC)
▪ Serum LH and FSH
❑ Serum ferritin is mainly used to follow therapy
44
▪ Liver biopsy - confirmatory test
• Permits histochemical estimation of tissue iron and
measurement of hepatic iron concentration
Screening Test
✓% percent transferrin saturation + serum ferritin
level
✓ If either of these tests is abnormal, then
✓HFE gene testing for C282Y mutation
45
Autoimmune Hepatitis (AIH)
❖ A chronic, progressive hepatitis with all the features of
autoimmune diseases
(Common Features of AI Diseases:

▪ Genetic predisposition
▪ Association with other autoimmune diseases
▪ Presence of autoantibodies
▪ Therapeutic response to immunosuppression)
❑ Present in all ethnic groups and all age groups

❑ Highest incidence among white northern Europeans
❑ Female predominance (78%)
46
Pathogenesis of AIH
❖ Type 1 AIH
▪ most common; middle age and older individuals
▪ Positive for antinuclear antibody (ANA) test (>60%), anti-
smooth muscle antibody (ASMA) test (>85%), and anti-soluble
liver antigen /liver-pancreas antigen (anti-SLA/LP) antibodies
▪ Linked to HLA DR3 and DR4
❖ Type 2 AIH
▪ Children and teenagers
▪ Positive for anti-liver kidney microsome-1 (ALKM) antibody
▪ Linked to HLA DR7
47
Clinical Features of AIH
From an acute illness (common presentation - 40%) with increased
transaminase, Fulminant hepatitis, or cirrhosis
Symptoms
• Fatigue (87%)
• Dark urine and light stools (77%)
• Right upper quadrant pain ; Anorexia
Signs
• Fever; Hepatomegaly (78%);
• Scleral icterus (46%)
• Encephalopathy
48
Patient with AIH may have one or more
of following autoimmune diseases:
Associated Autoimmune diseases
• Hashimoto thyroiditis
• Graves disease
• Rheumatoid arthritis
• Ulcerative colitis
• Insulin-dependent diabetes mellitus
• Sjogren’s syndrome
• Dermatitis herpetiformis 49
Investigation Findings in AIH
LABORATORY FINDINGS
▪ Marked elevation of ALT,
AST (10x uln)
▪ Serum γ-globulin (3x uln)
▪ Multiple liver function
tests derangement
HISTOLOGIC FINDINGS
• Interface hepatitis Note: Lymphoplasmacytic interface
• Bridging necrosis hepatitis - plasma cells and
• Lymphoplasmacytic lymphocytes at the interface between
infiltrate in the portal area the portal tract and liver lobule
50
51
DLA on LIVER DISORDERS Part 2
1
This DLA covers pathophysiology of:
-Alcoholic liver disease

-Nonalcoholic Fatty Liver Disease (NAFLD)
-Primary Biliary cirrhosis
-Cirrhosis of the liver.
2
ALCOHOLIC LIVER DISEASE (ALD)
Risk factors for ALD
▪ Ingestion of >35 drinks per week (one drink = 10 g of ethanol)
▪ Female gender (decrease level of alcohol dehydrogenase and lower

total body fluid )
▪ Chronic hepatitis C infection

▪ Acetaminophen overdose
▪ Hereditary hemochromatosis
3
Metabolism of Alcohol
Within the liver, 3 enzyme systems can oxidize ethanol:
1. Cytosolic alcohol dehydrogenase (ADH) - uses nicotinamide adenine

dinucleotide (NAD) as an oxidizing agent
2. The microsomal ethanol-oxidizing system (MEOS) - uses (NADPH) and

O2. The central enzyme of MEOS is cytochrome P-450 2E1 (CYP2E1).
3. Peroxisomal catalase - uses hydrogen peroxide as an oxidizing agent.
➢ The product of all 3 reactions is acetaldehyde.

➢ Acetaldehyde is a reactive metabolite that can produce injury in a variety of ways.
4
5
ALD Interrelationship
 Not all those who consume alcohol will develop ALD and liver cirrhosis
6
Pathogenesis of ALD
7
Pathogenesis of ALD cont…
❖Hepatocellular Steatosis
 the earliest response of the liver to alcohol abuse
 Alcohol metabolism leads to:

1. Redox imbalance (↓NAD+/NADH) - which disrupts mitochondrial β-
oxidation of fatty acids
2. Increases fatty acid synthesis in hepatocytes - via up-regulation of sterol
regulatory element-binding protein 1c (SREBP-1c)
3. Inhibits fatty acid oxidation in hepatocytes - via inactivation of the
peroxisome proliferator-activated receptor (PPAR)-α
4. Inhibits autophagy – (Long-term alcohol consumption)
5. Impairs the assembly and secretion of lipoprotein
8
❖ Alcoholic Hepatitis (AH)
▪ Characterized by infiltration of the liver by inflammatory cells and hepatocellular
injury
▪ The cause of AH is uncertain, but may be due to:
1 ) Accumulation of the highly toxic acetaldehyde, which results in:
➢ Lipid peroxidation
➢ Increased oxidative stress
➢ Glutathione (GSH) depletion
➢ Mitochondrial damage
2) Free radicals (from microsomal alcohol oxidation) damage proteins and

membranes
3) Free radicals also produce by the neutrophils, which infiltrate areas of

hepatocyte necrosis, add more injury to the above.
9
❖ Alcoholic Cirrhosis
Final stage in ALD.
Mechanism:
1. Chronic alcohol consumption induced gut inflammation,
resulting in Translocation of gut bacteria and bacterial LPS into the
portal system
2. Gut-derived endotoxin in the liver activates Kupffer cells
3. Release of pro-inflammatory cytokines such as TNF-α, and TNF-β
4. Activation of hepatic stellate cells to produce collagen, leading to fibrosis.
10
Clinical Features of ALD
➢ Asymptomatic Alcoholic fatty liver
(steatosis)
➢ Incidental finding of
elevated liver enzymes ❑ Right upper quadrant
discomfort
❑ Tender hepatomegaly
➢ Microvesicular and
❑ Nausea
macrovesicular steatosis
with inflammation on ❑ Jaundice (rarely)
liver biopsy
11
Acute alcoholic hepatitis Alcoholic Cirrhosis
o Malaise Stigmata of chronic liver disease

o Anorexia
o Fever ▪ Hepatomegaly
o Jaundice ▪ Splenomegaly
o Upper abdominal ▪ Palmar erythema
discomfort ▪ Spider angioma
o Tender hepatomegaly ▪ Gynecomastia
▪ Dupuytren’s contracture
▪ Impotence
▪ Testicular atrophy
▪ Decreased body hair
▪ Peripheral muscle wasting
12
Laboratory Findings in ALD
➢ Elevated serum AST and ALT level <500 (AST >ALT)
➢ Elevated γ-glutamyl transferase (GGT) levels (GGT is an SER enzyme)
➢ Reduced folate level in alcoholics (macrocytosis, MCV >100 fL) due to:
▪ Decreased intestinal absorption
▪ Increased bone marrow requirement of folate
▪ Increased urinary loss
➢ Neutrophilic leukocytosis
➢ Hypertriglyceridemia
➢ Hypoglycemia
13
Liver Biopsy in ALD
❖Hepatic Steatosis
Macrovesicular fat accumulation
Initially centrilobular (perivenular)
❖Alcoholic Hepatiitis
▪ Perivenular fibrosis,
progressing to pericellular
fibrosis
▪ Ballooned hepatocytes with
Mallory’s hyaline
▪ Fatty change
▪ Foci of necrotic cells with
neutrophilic reaction
14
NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)
▪ A group of disorders characterized by hepatic accumulation of triglycerides in the
absence of significant alcohol consumption
▪ Affects about 3% of children and 20-50% of obese children
▪ Spectrum covers
➢ ) Simple steatosis (fat accumulation with no background inflammation)
➢ Nonalcoholic steatohepatitis (NASH) (fat accumulation in the presence of
inflammation and fibrosis
▪ NAFLD is commonly associated with :

▪ Metabolic syndrome, obesity, diabetes, and hyperlipidemia
▪ NAFLD is a diagnosis of exclusion

15
Risk Factors for NAFLD
❖Insulin resistance ❖Diabetes mellitus
➢ A hallmark of metabolic ➢ Prevalence of NAFLD in type 2 DM
syndrome is 50%
➢ Risk increase by 4-11-fold ➢ Prevalence of type 2 DM in NAFLD
➢ 80% of patients with metabolic patients range from 10% to 75%
syndrome have NAFLD
❖Hyperlipidemia
❖Obesity  confer a 5-fold increased risk
➢ BMI ≥30 kg/M2
❖Certain drugs
➢ Prevalence of NAFLD is
➢ Amiodarone
increased to 4-6-fold
➢ Estrogen
➢ corticosteroids
16
Pathogenesis of NAFLD cont.
17
Pathogenesis of NAFLD: First Hit
❖Insulin resistance is the primary metabolic defect leading to NAFLD
1) Absence of insulin action leads to:

▪ Failure of suppression of hormone-sensitive lipase
▪ An influx of free fatty acids liberated from adipose tissues into the liver
2) Elevated insulin levels promote:

▪ continued synthesis of triglycerides in the liver
➢ The above two processes result in lipid-laden hepatocytes (macrovesicular

hepatic steatosis)
18
Pathogenesis of NAFLD cont.
19
Pathogenesis of NAFLD (cont.): Second Hit
❖The second “hit” is believed to result from:

1) Oxidative stress
2) Effect of specific cytokines plus lipopolysaccharides
➢ Free fatty acids and hyperinsulinemia potentiate lipid peroxidation and

the release of hydroxyl (OH-) free radicals
➢ Chronic liver injury leads to activation of hepatic stellate cells thereby

resulting in fibrosis
➢ Tumor necrosis factor-α (TNF- α) and interleukins may play a role.
20
Clinical Findings in NAFLD
➢ Asymptomatic
➢ Nonspecific and constitutional symptoms

❑Fatigue; malaise
❑Right upper quadrant discomfort
❑Hepatomegaly
➢ Absence of historical findings suggestive of other causes of liver damage

▪ Limited alcohol use
➢ Presence of risk factors: age (>45) , obesity, type 2 DM
➢ Family history of obesity, DM, or liver disease

21
Investigation Findings in NAFLD
❖Moderate elevations of ALT and AST (2-3-fold uln)
❑ AST/ALT ratio is typically less than 1.0 (>2: 1 in ALD)
❖Fasting lipid profile and plasma glucose levels

❑ Deranged in NAFLD
➢Liver biopsy is required to identify NASH and distinguish it from

uncomplicated NAFLD
22
The Diagnosis of Nonalcoholic Steatohepatitis (NASH)
❑ Minimal criteria for the diagnosis (NASH) are:
➢Steatosis (macrovesicular)
➢Lobular inflammation
➢ Ballooned hepatocytes
(swelling and enlargement of the hepatocytes, resulting in
loss of their normal hexagonal shape, along with
cytoplasmic alterations)
23
Liver Biopsy in NAFLD
Perivenular/pericellular
("chicken wire") fibrosis
steatosis (macrovesicular)
and inflammatory foci
(lymphocytes and Kupffer
cells) in the hepatic lobules ballooned hepatocytes that also
contain Mallory bodies 24
Autoimmune Cholangiopathies
❑Two distinct immunologically-mediated disorders that involve

intrahepatic bile ducts:
1) Primary Biliary Cholangitis/Cirrhosis (PBC)-discussed next

2) Primary Sclerosing Cholangitis-discussed in DLA on Hepatobiliary
disorders
Pathogenesis of PBC
Genetically susceptibility → Exposure to specific environmental triggers →

Molecular mimicry → Antimitochondrial antibodies against pyruvate
dehydrogenase E2 complex (PDC-E2) → Persistent T-cell–mediated
destruction of the intrahepatic bile ducts → Progressive loss of bile ducts
→ Secondary liver injury → Biliary cirrhosis. (ALP, alkaline phosphatase; AMA,
antimitochondrial antibody; GGT, γ-glutamyl transferase; LFTs, liver function tests)
26
27
Pathogenesis of PBC
➢ Suspected environmental factors trigger onset of
disease
▪ Infectious agents
▪ Chemicals (in cigarette smoke, exogenous estrogens)
➢ Molecular mimicry is possibly the mechanism for

initiation of autoimmunity
➢ CD 8 T cells that are specific for PDC-E2 autoepitope

infiltrate the portal triad and damage biliary epithelium.
28
Pathological changes in liver in PBC
▪ PBC is characterized histologically by damage to, and

eventual loss of, the biliary epithelial cells (BEC) lining
small intrahepatic bile ducts.
▪ BEC loss is typically accompanied by a significant portal

tract inflammatory infiltrate that is mixed in phenotype
(T cells (CD4 and CD8,), B cells, macrophages,
eosinophils and natural killer cells).
▪ Once destroyed regeneration of bile ducts is either not

possible or inefficient.
29
Clinical Features of PBC
➢Fatigue (65%)
▪ First reported symptom,
▪ Does not correlate with severity of the disease.
➢Pruritus (55%)
▪ Not related to the deposition of bile acids in the
skin.
Possible mechanism : Increased opioidergic tone
▪ Pruritus is worse at night and exacerbated by heat
➢Unexplained right upper quadrant discomfort.

30
Clinical Features of PBC
Examination Findings
➢ Early-stage findings
▪ Skin hyperpigmentation
▪ Excoriation from itching
▪ Steatorrhea
➢ Late-stage findings
▪ Jaundice
▪ Xanthelasmas/xanthomas
▪ Kayser-Fleischer ring in cornea
▪ Stigma of cirrhosis
Extrahepatic manifestations of autoimmunity – sicca

complex of dry eyes and dry mouth, systemic sclerosis etc.
31
Investigation Findings in PBC
Chemistry
Elevated serum
▪ Alkaline phosphatase (ALP) (ALP>>>ALT & AST)
▪ Gamma-glutamyl transferase (GGT)
▪ Cholesterol
Serology
➢ Antimitochondrial antibodies (AMA > 90% of cases)
➢ AMA titer does not correlate with activity of disease
➢ Elevated serum immunoglobulin M (IgM)
32
Comparison between PBC and PSC
Primary Biliary Cirrhosis (PBC) Primary Sclerosing Cholangitis (PSC)
Clinical 90% females 70% males

Features Middle age -50 20-40’s
Fatigue & pruritus Progressive obstructive jaundice
Site of Intrahepatic Intrahepatic & Extrahepatic
Involvement
Cause of Granulomatous inflammation destroying Fibrosis destroying bile ducts

Obstruction bile ducts
Associated Sjogren (70%), RA, Thyroid disease, etc Inflammatory bowel disease ( UC- 70%),
Conditions pancreatitis
Serology 95% AMA positive 65% ANCA positive
40% ANCA positive 0-5% AMA positive
Microscopic Florid duct lesions (granulomas) and loss of Concentric “onion-skin” fibrosis around bile ducts.
Features small ducts only Inflammatory destruction of extrahepatic and large
intrahepatic ducts
CIRRHOSIS of the Liver
 Represents the final common morphologic change for a
wide variety of chronic liver diseases.
 is defined histologically as a diffuse hepatic process

characterized by:
1) Fibrosis
2) The transformation of normal liver architecture into
regenerative parenchymal nodules surrounded by
fibrous band.
 Many forms of liver injury are marked by fibrosis(excess

collagens, glycoproteins, proteoglycans)
34
Causes of Cirrhosis
❖ Alcoholic liver disease (most common )
❖ Postnecrotic cirrhosis: HCV, HBV infections
❖Autoimmune diseases: Autoimmune hepatitis &

Primary biliary cirrhosis
❖ Metabolic/genetic diseases: Hemochromatosis, Wilson

disease & Alpha-1 antitrypsin deficiency
❖Cryptogenic causes: End stage of a chronic liver disease

in which its underlying etiology remains unknown after
extensive evaluation.
35
Pathophysiology of Cirrhosis
36
Changes in Liver: Normal liver
Regenerative nodules
▪ Hepatocytes reaction to injury

▪ Lack normal liver architecture
▪ Surrounds by bands of fibrosis
▪ Compress sinusoids and central veins
 Intrasinusoidal hypertension Cirrhosis
 Increase in hydrostatic pressure in
portal vein
37
Clinical Features of Cirrhosis
 General: Anorexia, Weight loss & Weakness
 Signs and symptoms of liver failure such as jaundice,

encephalopathy and coagulopathy.
 Additional features
▪ Pruritus
▪ Portal Hypertension
▪ Hyperestrogenemia
38
Complication Associated With Cirrhosis
 Hepatic Failure
 Portal hypertension
 Ascites
 Hepatorenal syndrome
 Hyperestrinism/ Hyperestrogenemia
 Hepatopulmonary syndrome
 Hepatocellular carcinoma
39
DLA ON PANCREATIC & BILIARY
DISORDERS
1
This DLA covers:
-Acute Pancreatitis
-Chronic Pancreatitis
-Cancer Pancreas
-Cholelithiasis
-Acute Cholecystitis
-Choledocholithiasis
-Primary sclerosing cholangitis
2
ACUTE PANCREATITIS
Common causes:
 Gallstones (30-60%)
 Alcohol (15-30%)
 Hypertriglyceridemia
 ERCP (Endoscopic Retrograde Cholangio-
Pancreatography)
 Trauma
Uncommon Causes
Infections (Mumps, CMV, parasites); Cancer of the Pancreas;
Cystic fibrosis; Hypercalcemia
Pathogenesis of Acute Pancreatitis
Mechanism involved:
Premature activation of pancreatic zymogens → Subsequent
autodigestion and release of chemokines and cytokines → Inflammatory
process.
Causes for premature activation:

 Mechanical obstruction of the pancreatic duct by gallstones
 Prolonged stasis of pancreaticsecretions
 Reflux of bile into the pancreatic duct
 Failure of inhibition of activated trypsin
 Mutant trypsin in inheritedpancreatitis
 Mutation in SPINK 1 gene (SPINK 1 proteinnormally
inhibits activated trypsin)
 Alcohol-induced activation
4
Pathogenesis of Acute Pancreatitis by
Alcohol
❖ Alcohol-induced premature activation and release of
digestive enzymes in thepancreas is due to:
•Increase in the protein content of pancreatic juice
and decreases bicarbonate levels → formation
of protein plugs that block pancreaticoutflow
• Decrease in trypsin inhibitor concentration inthe
pancreas.
❖ Alcohol also increases permeability of ductules, allowing
enzymes to reach the parenchyma and cause pancreatic
damage.
5
Clinical Findings in Acute Pancreatitis
 Epigastric pain
 Nausea and vomiting
 Abdominal distension from paralytic ileus
 Tender rigid abdomen withguarding
 Low grade fever
 Tachycardia
 Hypotension
 Jaundice
 Cullen’s sign
 Grey Turner’ssign
 Hypovolemic shock
6
Laboratory Findings in Acute Pancreatitis
 Increased serum levels of amylase and lipase
 >3X uln typically suggest acute pancreatitis
 Lipase has higher sensitivity and higher specificity
 Prolonged elevation following episode
 Other sources of elevated pancreatic enzymes are perforated
peptic ulcer, intestinal obstruction, and mesentericinfarction
 Elevated serum ALT
 >100 U/L (3X uln) strongly suggests a biliary origin
 Leukocytosis
 Hyperglycemia
 May signal the destruction of islet cells
 Hypocalcemia
7
Complications Acute Pancreatitis
 Pulmonary edema and ARDS
 Multi-organ dysfunction syndrome & Shock
 Stress-induced GI ulcers
 Pseudocysts: Infected necrosis/abscess
 Pancreatic ascites
 Bleeding from: a)Gastric varices secondary to
splenic vein thrombosis, b)Pseudoaneurysms of
vessels in areas of necrosis or c)Duodenal ulcer due
to duodenal compression by inflamed pancreas
 Splenic and portal vein thrombosis
 Diabetes
8
CHRONIC PANCREATITIS
 A condition of irreversible damage of the pancreas due to
 Pancreatic cell loss
 Inflammation
 Fibrosis
 Etiology: -Alcohol (90%)

-Tobaccosmoking
-Hypercalcemia (hyperparathyroidism)
-Chronic renal failure
-Cystic fibrosis
9
Pathogenesis of Chronic Pancreatitis
 Direct damage to pancreatic acinar cells by alcohol and other
noxious stimuli
 Resultant cytokine release stimulates pancreatic stellate cells
(PSC) to form collagen. Proinflammatory cytokines that induce
PSC activity include i) Tumor necrosis factor-α (TNFα) and ii)
Interleukins, IL-1 and IL-6.
 Decreased secretion of pancreatic stone protein (lithostathine*)
leads to precipitation of calcium within pancreatic duct resulting in
duct and gland destruction.
 Cellular damage affects exocrine glands initially and
endocrine glands later.
 Chronic pancreatitis may be a continuum that is initiated early
by an attack of acute pancreatitis
(*Lithostathine aka pancreatic stone protein, which also is produced by the acinar cells, keeps calium in
soluble form and inhibits the growth of calcium carbonate crystals.) 10
Clinical Findings in Chronic Pancreatitis
 Abdominal pain
 Recurrent episodes of severe epigastric pain
 Pain may be postprandial, associated with nausea and vomiting
 Features of pancreatic insufficiency
 Malabsorption syndrome (>90% of pancreatic function is
lost)
 Diabetes
 Pancreatic calcifications
 Weight loss
 Pseudocyst
 Ascites
 GI bleed
• Abdominal pain, Diabetes, and Steatorrhea typically
define chronicpancreatitis!
11
Investigation Findings in Chronic Pancreatitis
 Laboratory
 Elevated serum glucose levels
 Increase in serum ALP
 Normal serum amylase and lipase
 Abdominal X-ray
 Pancreatic calcifications
 Ultrasound & CTscan
 Calcification, dilated pancreatic ducts, pseudocyst
 Magnetic Resonance Cholangiopancreatography (MRCP)
 Abnormal pancreatic duct narrowing and dilation
12
Investigation Findings in Chronic Pancreatitis
 Fecal pancreatic elastase-1 (FPE-1) assay
 A marker of exocrine pancreatic function
 Low levels correlate with severe exocrine pancreatic
insufficiency
 72-h fecal fat test
 Secretin test
 Gold standard, combined with MRCP (SMRCP)
 Measures exocrine function
 Difficult to perform & unpleasant for patient
 Expensive
13
CT Scan: Chronic Pancreatitis
A. Calcifications B. Pseudocyst
14
Secretin Enhanced MRCP (SMRCP)
Secretin enhanced MRCP (SMRCP): Chronic pancreatitis. MRCP/SMRCP with abnormal pancreatic duct with visible side
branches (white arrows) and fluid-filled duodenum (gray arrow) after secretin stimulation.
15
PANCREATIC CANCER
 Fourth leading cause of cancer death in the U.S.

 5-year survival is 6%
 More common in males (M: F = 1.3: 1)
 Average age: 50 - 70
16
Risk Factors for Pancreatic Cancer
 Family history of pancreatic cancer
 Smoking (2 to 5-fold increased risk)
 Heavy alcohol intake
 Diabetes mellitus
 Chronic pancreatitis
 Chemicals: betanaphthylamine, benzidine
 African-American descent
17
Clinical Features of Pancreatic Cancer
Head of the pancreas
 Relatively earlypresentation
 Weight loss, obstructive jaundice, vague epigastric sign
 Courvoisier’s sign (common bile ductobstruction)
 Palpable tumor mass in the epigastric region
 Trousseau’s syndrome (migratory thrombophlebitis)
Body or tail of thepancreas

 Late presentation with widespreadmetastasis
 Weight loss, vague epigastricpain
 ± Jaundice
 Sudden onsetdiabetes
18
Investigation Findings in Pancreatic Cancer
 Blood Chemistry
 Elevated alkaline phosphatase level (4Xuln)
 Elevated serum bilirubin >300 µmol/L
 Tumor markers
 CA 19-9 & CEA
 For diagnosis and monitoring of the
treatmentresponse
19
GALLSTONES (CHOLELITHIASIS)
>90% of gallstones consist mainly of cholesterol
 Humans eliminate cholesterol from the body
mostly as cholesterol itself rather than as bile
acids
 Cholelithiasis is considered a disturbanceof
cholesterol secretion
20
Risk Factors for Gallstone disease
 Age >50 years
 Female sex (F: M = 2: 1)
 Mexican or Native Americanethnicity
 Genetic predisposition
 Defect in hepatic cholesterol transporter
ABCG5/G8, UGT1A1 Gilbert syndrome, and
canalicular phospholipid transporter(ABCB4)
genes
 Family history
21
Risk Factors for Gallstone disease (Contd)
 Pregnancy and parity

 Effect of progesterone and estrogen
 Estrogens (e. g. Oral contraceptive pills )
 Increases cholesterol hypersecretion
 Obesity
 Overproduction of cholesterol causes
cholesterol hypersecretion into bile
 The metabolic syndrome
22
Organic Composition of Bile
BAs = Bile acids

PL = Phospholipids
Chol = Cholesterol
BP = Biliary pigments
23
Classification of Gallstones
 Cholesterol stones (>90%)

 Contains >50% cholesterol
 Variable admixtures of calcium salts, bilepigments,
proteins, and fattyacids
 Pigment stones (<10%)
 Composed primarily of calcium bilirubinate
 Contains <20% cholesterol
24
Pathogenesis of Cholesterol Gallstones
Cholesterol gallstones usually originate in the
gallbladder.
Mechanism: Supersaturation of bile with cholesterol is
essential for the formation of cholesterol gallstones.
Cholesterol exceeds the solubilizing capacity of bile
acids and phospholipids.
This occurs because of:
a) Hypersecretion of cholesterol (most common)
b) Hyposecretion of bile acids or phospholipids
c) A combination of hypersecretion of cholesterol and
hyposecretion of bile acids or phospholipids.
25
Pathogenesis of Cholesterol Gallstones (contd)
Hypersecretion of cholesterol is due to:

 Increased synthesis of cholesterol
 Increased uptake of cholesterol by the liver
(endogenous, LDL or exogenous,
chylomicrons)
 Increased hepatocanalicular transport of cholesterol
 Obesity (increased intake and synthesis)
26
Pathogenesis of Pigment Gallstones
Classified into black and brown pigmentstones.
Black pigment stones:
 Composed of calcium bilirubinate formed from excess
unconjugated bilirubin. Formed in gallbladder.
 Risk factors include chronic hemolytic states, liver
cirrhosis, Gilbert syndrome.
Brown pigment stones:
 Stones which are soft and have claylike consistency.
 Formed by bacterial action on lecithin to release fatty acids that
bind with calcium and precipitate.
 Formed in infected intrahepatic or extrahepatic ducts.
27
Clinical Findings in Cholelithiasis
 Symptomatic gallstone disease without complications
 Biliary colic
 Obstruction of the cystic duct or common bile duct by a stone
 Severe visceral pain (epigastrium or right hypochondrium)
 Radiates to the interscapular area, right scapula, or shoulder
 Usually begins and subsides suddenly, lasts less than 5 hours
 Concomitant nausea with or without vomiting
 Many patients develop pain usually after a fatty meal
 Symptomatic gallstone disease with complications

 Pain generally lasts >5hours
 Presentation with complications (10%)
 Complications include cholecystitis, obstructive jaundice, or
pancreatitis
28
Investigation Findings in Cholelithiasis
Abdominal ultrasound
 Method of choice for the diagnosis of
gallbladderstones
 >95% sensitivity is for the detection of
gallstones ≥1.5 mm in diameter
 Mobility in a gravity-dependent fashionwith
the patient's position
 Gravity-dependent mobility of theechogenic
foci differentiates gallbladder stones from
polyps orcarcinoma
29
ACUTE CHOLECYSTITIS
 Acute cholecystitis is the most frequent
complication of gallstone disease
 Causes of acutecholecystitis
 Transient or permanent obstruction of the cystic
duct by a stone
 Bacterial inflammation
 Most frequently isolated organisms include
Escherichia coli, Klebsiella species, Streptococcus
species, and Clostridium species
30
Pathogenesis of Acute Cholecystitis
 An inflammatory response to mechanical,
chemical, or bacterial causes
 The increased intraluminal pressure and distention
of the gallbladder result in ischemia of the mucosa
and the wall of thegallbladder
 Inflammatory agents, such as lysolecithin, and local
tissue factors may bereleased
 Peritoneal signs of inflammation is responsible for
marked tenderness and inhibition of inspirationon
deep palpation under the right subcostal margin
(Murphy sign)
31
Clinical Features of Acute Cholecystitis
 An attack of biliary pain

 History of previous episodes of biliarypain
 Initially pain is more diffuse, laterbecomes
localized in the right upperquadrant
 Peritoneal signs of inflammation
 Increased pain with jarring or on deep
inspiration
 Nausea and vomiting are frequent
32
Clinical Features of Acute Cholecystitis
 Right upper quadrant tenderness

 Marked tenderness and inhibition of inspiration
on deep palpation under the right subcostal
margin (Murphy sign)
 An enlarged, tense gallbladder is palpable in about
one third of patients
 Low-grade fever is usually present, butshaking
chills or rigors is notusual
33
Lab Findings in Acute cholecystitis
 Mild to moderate leucocytosis

 Serum bilirubin and serum liver enzymes maybe
mildly elevated
 Marked elevations suggest bile duct
obstruction concomitant with acute
cholecystitis.
 Serum amylase levels usually arenormal
 Substantial elevation suggest pancreatitis
34
Complications of Acute cholecystitis
 Chronic cholecystisis
 Gallbladder gangrene, empyema, or perforation
 Fistulization and biliodigestive fistula
 Can manifest itself by ascending cholangitis or a
bile acid malabsorption syndrome
 Aerobilia is an important sign of a biliodigestive
fistula
 Gallstone ileus, especially in the terminal ileum
 Obstructive jaundice
 A gallstone becomes impacted in the neck of the
gallbladder or cystic duct, causing compression of
the common bileduct
35
CHOLEDOCHOLITHIASIS
 Refers to passage of gallstones into the common bile

duct
 Occurs in 10–15% of patients with gallbladder stones
 Majority of them are cholesterol stones that
originate in thegallbladder
 Stones that primarily form in the bile ducts are
usually pigment stones
36
Choledocholithiasis
CLINICAL FINDINGS
 Biliary pain accompanied with or withoutjaundice
LABORATORY FINDINGS
 Elevated liver enzymes ALT, AST in the acute phase of
obstruction
 Later ALT and AST decrease toward normal even if the
obstruction persists
 Whereas alkaline phosphatase rises, followedby
bilirubin elevation and eventually jaundice
37
Choledocholithiasis
IMAGING STUDIES
 Ultrasound scan
 Dilated common bile duct >6mm
 Higher diagnostic probability(if bilirubin, elevated
GGT, alkaline phosphatase and/or ALT are elevated)
 Endoscopic ultrasound (Endosonography)
 Has the highest sensitivity for the detection of stones
in the commonduct
COMPLICATIONS
 Obstructive jaundice, cholangitis, pancreatitis, and
secondary biliary cirrhosis
38
PRIMARY SCLEROSING CHOLANGITIS (PSC)
 Characterized by a progressive, inflammatory,

sclerosing, and obliterative process
 Affects medium-sized and large extrahepatic or
intrahepatic bile ducts, orboth
 A vast majority of patients (70%-90%) have
underling inflammatory bowel disease,
especially ulcerativecolitis
39
Clinical findings of PSC
 Asymptomatic at the time of diagnosis

 Persistent and otherwise unexplained abnormal elevation
in serum alkaline phosphatase >6 months in patients with
inflammatory bowel disease
 Persistent elevations of serum alkaline phosphatase
 Symptomatic
 Symptoms of chronic biliaryobstruction
 Fatigue
 Right upper quadrant abdominal pain
 Jaundice
 Pruritus
40
Laboratory Findings in PSC
 Liver tests show a cholestatic pattern
 Serum alkaline phosphatasedisproportionately
elevated to levels 4–10 times normal
 Serum aminotransferase (ALT or AST) thatis
usually 300 IU/L or less
 Higher levels suggest PSC-AIHoverlap
 Serum albumin and globulin levels are usually
normal except with advanceddisease
41
Imaging Studies in PSC
 Cholangiography
 Multifocal annular stricturing within the intra-
and/or extrahepatic bile ducts, with alternating
normal or slightly dilated segments (beading of
the bileducts)
 Magnetic resonancecholangiopancreatography
(MRCP)
 Intrahepatic and extrahepatic bile duct strictures
 Preferred to ERCP as it is a noninvasive and does
not carry the risk of either pancreatitis or
cholangitis
42
Histologic Findings
 The most characteristic histologic finding isfibrous
obliteration of small bile ducts with concentric
replacement by connective tissue in an "onion skin"
pattern
 Histopathologic Staging of PSC-Indicates the severity
of the disease as:
 Stage 1: enlargement, mononuclear cell infiltration,
and scarring in the portal triads
 Stage 2: fibrosis extending into thesurrounding
parenchyma
 Stage 3: bridging fibrosis
 Stage 4: cirrhosis
43
Comparison between PBC and PSC
Primary Biliary Cirrhosis (PBC) Primary Sclerosing Cholangitis (PSC)
Clinical 90% females 70% males

Features Middle age -50 20-40’s
Fatigue & pruritus Progressive obstructive jaundice
Site of Intrahepatic Intrahepatic & Extrahepatic
Involvement
Cause of Granulomatous inflammation destroying Fibrosis destroying bile ducts

Obstruction bile ducts
Associated Sjogren (70%), RA, Thyroid disease, etc Inflammatory bowel disease ( UC- 70%),
Conditions pancreatitis
Serology 95% AMA positive 65% ANCA positive
40% ANCA positive 0-5% AMA positive
Microscopic Florid duct lesions (granulomas) and loss of Concentric “onion-skin” fibrosis around bile ducts.
Features small ducts only Inflammatory destruction of extrahepatic and large
intrahepatic ducts

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Lecture 30_Disorders of Esophagus 2

Lecture 31_Disorders of Stomach 62

• 15 lbs loss of weight over the last 6 months

POSSIBLE CAUSES OF THIS PATIENT’S DYSPHAGIA?

Solids Solids + liquids

Disorders are mainly related to motor function:

Pathophysiology: Defective innervation of smooth muscles in the

Degeneration of neurons (myenteric plexus)

Clinical manifestation: dysphagia, regurgitation, chest pain

LES dysfunction : tremendous enlargement of the esopha-

• Lifestyle modification – Clin. Gastro & Hep, January 2016

What does “impaction” suggest?

Solids Solids + liquids

Pathology :≥ 15 eosinophils / hpf

- Functional : abdominal trauma, hypokalemia,

• Acceleration : less frequent, usually at hyperthyroidism

• Nausea – sometimes before vomiting

Long-term + proteinases + hyperacidity – peptic ulcer,

• Decrease of the secretion :

Either volume, or HCl, proteinases, intrinsic factor or all.

Curlings ulcer: dec plasma volume--- sloughing of

Cushings ulcer: inc. vagal stimulation---- inc. Ach--

• Autoimmune disease; Ab against intrinsic factor; against complex intrinsic

ASA AND NSAIDs

NSAIDs increase risk 3-5x : Even low-dose aspirin  risk by 2-

14-31% of NSAID users develop ulceration

15-35% of peptic ulcer complications due to NSAIDs

• HELICOBACTER PYLORI 60-75%

• Not a factor in peptic ulcers

Motility defects – duodeno-gastric reflux (esp. bile can lead

Delayed gastric emptying (food retention) results in increased

Mucosal ischemia – prostaglandins increase mucosal blood

Classically, gastric ulcer pain is aggravated by meals, whereas

Complications: Bleeding( Lesser curvature bleeds from

ZE synd. commonly presents with duodenal ulcers.

• Patient has noted bloating occurring after meals. This has

WHAT IS THE POSSIBLE CAUSE OF THIS PATIENT’S

HOW SHOULD THIS PATIENT BE EVALUATED?

• Diet (nitroso compounds)

Chronic gastritis Gastric ulcer

Antral predominant gastritis Multifocal atrophic gastritis

Gastrinoma – gastrin producing tumor of δ(D)-cells in

Plasma gastrin level – extremely high, basal acid secretion –

High frequency of duodenal ulcers, ulcers can be evident

Definition: bowel movements, which are excessive in volume,

Pseudodiarrhea – production frequent loss of stool (150 g/

Small intestine – predominant site for fluid absorption – stool

Colonic pathology small volume diarrhea

• Malabsorptive diarhea – ability of digest or absorb a

• Inflammatory diarrhea – associated with mucosal

• Non-inflammatory diarrhea – as a result of influence

Acute on chronic presentations.

• Inflammatory diseases mucosal damage + altered

GIARDIA UPPER SMALL INTESTINE

May be associated with acute or chronic diarrhea

• GAP > 125 mOsm/kg = OSMOTIC DIARRHEA

• Normal osmotic gap < 50

On the other hand : Excesive absorption

Iron (in hemochromatosis)

Copper (in hepatolenticular degeneration – Wilson´s disease)

• Primary diseases of intestinal mucosa (disturbance in

3.Crosses gut epithelium

4.Better fit made by TTG