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GASTROINTESTINAL GASTROINTESTINAL DISORDERSDISORDERSFe A. Bartolome, MD, FPASMAP

Department of Pathology

Our Lady of Fatima University

CLASSIFICATION CLASSIFICATION OF GI DISEASESOF GI DISEASES

Impaired Digestion & Impaired Digestion & AbsorptionAbsorption• Diseases of the stomach, intestine, biliary

tree & pancreas disrupt nutrient digestion and absorption

• Examples:1. Gastric hypersecretory syndromes (e.g.

Zollinger-Ellison syndrome) Damage intestinal mucosa Impair pancreatic enzyme activation

2. Lactase deficiency Most common intestinal

maldigestion syndrome3. Biliary obstruction from stricture or

neoplasm4. Chronic pancreatitis or pancreatic CA

Altered SecretionAltered Secretion

1. Gastric acid hypersecretion• Zollinger-Ellison syndrome, G cell

hyperplasia, duodenal ulcer disease

2. Decreased or absent gastric acid secretion• Atrophic gastritis or pernicious anemia

3. Fluid loss through impaired absorption or enhanced secretion• Inflammatory and infectious small-

intestinal and colonic diseases• Laxative abuse• Endocrine neoplasias with secretion of

vasoactive intestinal polypeptide (VIP)

Altered Gut TransitAltered Gut Transit

1. Mechanical obstruction

• Esophagus – acid-induced stricture or neoplasm

• Stomach – PUD or gastric cancer• Small intestines

Adhesions – most common Crohn’s disease, radiation-induced

strictures, malignancy• Colon

Colon cancer – most common Inflammatory strictures in patients

with inflammatory bowel disease

Altered Gut TransitAltered Gut Transit

2. Disordered gut motor function

• Achalasia – impaired esophageal body peristalsis

• Gastroparesis – symptomatic delay in gastric emptying of solid or liquid meals due to impaired gastric motility

• Injury to enteric nerves or intestinal smooth muscle intestinal pseudo- obstruction

• Impaired colonic propulsion constipation

Immune DysregulationImmune Dysregulation

• Celiac disease – mucosal inflammation due to ingestion of gluten-containing grains

• Eosinophilic esophagitis and gastroenteritis

• Ulcerative colitis & Crohn’s disease

• Bacterial, viral, and protozoal ileitis and colitis in selected patients

Impaired Gut Blood FlowImpaired Gut Blood Flow

• Gastroparesis may result from blockage of the celiac and superior mesenteric arteries

• Intestinal and colonic ischemia – more common; may be due to: Arterial thrombosis or embolus Venous thrombosis Hypoperfusion from dehydration,

sepsis, hemorrhage or reduced cardiac output

Neoplastic DegenerationNeoplastic Degeneration

• All GI regions are susceptible to malignant degeneration to varying degrees

• Most GI cancers are carcinomas, but lymphomas & tumors of other cell types are also observed

• Colorectal CA – most common in U.S.

• Gastric CA – worldwide & esp. in certain regions in Asia

• Esophageal CA – associated with chronic acid reflux & extensive alcohol and tobacco use

Disorders without Obvious Organic Disorders without Obvious Organic AbnormalitiesAbnormalities

• Irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, functional heartburn no abnormalities on biochemical or structural testing

• With altered gut motor function

• Exaggerated visceral sensory responses to noxious stimulation may cause discomfort

• Patients may exhibit significant emotional disturbances on psychometric testing

Symptoms of Gastrointestinal DiseaseSymptoms of Gastrointestinal Disease

Common Causes of Common GI Symptoms

Abdominal Pain

Appendicitis

Gallstone disease

Pancreatitis

Diverticulitis

Ulcer disease

Esophagitis

GI obstruction

Nausea & Vomiting

Medications

GI obstruction

Motor disorders

Functional bower d.o.Enteric infectionPregnancy

Endocrine disease

Diarrhea

Infection

Poorly absorbed sugarsInflam. Bowel dse.

Microscopic colitisFxnal bowel disorderCeliac dse.

Pancreatic insuff.

GI Bleeding

Ulcer disease

Esophagitis

Varices

Vascular lesionsNeoplasm

Diverticula

Hemorrhoids

Obstructive Jaundice

Bile duct stonesCholangio- carcinoma

Cholangitis

Sclerosing cholangitisAmpullary stenosisAmpullary CAPancreatitis

Symptoms of Gastrointestinal DiseaseSymptoms of Gastrointestinal Disease

Common Causes of Common GI Symptoms

Abdominal Pain

Inflammatory bowel dse.

Functional bowel d.o.

Vascular disease

Gynecologic causes

Renal stone

Nausea & Vomiting

Motion sickness

CNS disease

Diarrhea

Hyper- thyroidism

Ischemia

Endocrine tumor

GI Bleeding

Fissures

Inflammatory bowel dse.

Infectious colitis

Obstructive Jaundice

Pancreatic tumor

Abdominal PainAbdominal Pain

• GI disease and extraintestinal conditions involving the GUT, abdominal wall, thorax or spine

• Visceral pain midline in location and vague in character

• Parietal pain localized and precisely described

• Most common causes are IBS and functional dyspepsia

Abdominal PainAbdominal Pain

• Other causes:

Inflammatory Peptic ulcer, appendicitis, IBD,

diverticulitis, infectious enterocolitis Gallstone disease, pancreatitis

Non-inflammatory Mesenteric ischemia Neoplasia

Heartburn Heartburn

• Burning sub-sternal sensation

• Result from excess gastroesophageal reflux of acid

Nausea and VomitingNausea and Vomiting

• Mechanical obstruction of upper gut

• Others: gastroparesis & intestinal pseudo-obstruction; IBS and functional disorders of upper gut

Altered Bowel HabitsAltered Bowel Habits

• Constipation Infrequent defecation Straining with defecation Passage of hard stools Sense of incomplete fecal evacuation Causes:

1. Obstruction2. Motor disorders of colon3. Medications4. Endocrine diseases (hypothyroidism

and hyperparathyroidism)

Altered Bowel HabitsAltered Bowel Habits

• Diarrhea Frequent defecation Passage of loose or watery stools Fecal urgency Sense of incomplete evacuation Causes:

1. Inflammatory – (+) pus in stool IBS – constipation, diarrhea, or

alternating bowel pattern; (+) fecal mucus

2. Infectious3. Malabsorption – (+) steatorrhea4. Medications

GI BleedingGI Bleeding

• Upper GI bleed – (+) melena or hematemesis Most common causes are: ulcer disease,

gastroduodenitis, and esophagitis

• Lower GI bleed – passage of bright red or maroon stools Most common causes are: hemorrhoids,

anal fissures, diverticula, ischemic colitis, and arteriovenous malformations

• Chronic slow GI bleed (+) iron deficiency anemia

Other SymptomsOther Symptoms

• Dysphagia, odinophagia & unexplained chest pain esophageal disease

• Weight loss, anorexia, fatigue neoplastic, inflammatory, gut motility, pancreatic, small bowel mucosal, and psychiatric conditions

• Extraintestinal symptoms IBD – hepatobiliary dysfunction, skin &

eye lesions, arthritis Celiac disease – dermatitis

herpetiformis

ESOPHAGEAL DISORDERS

Signs and Symptoms of Esophageal Signs and Symptoms of Esophageal Disease Disease

1. Heartburn• Most commonly due to GERD

2. Dysphagia for solids alone• Symptom of an obstructive lesion• Examples: esophageal cancer,

esophageal web, stricture3. Dysphagia for solids and liquids

• Signify motility disordera) Oropharyngeal (upper esophageal)

Striated muscle dysmotility Dermatomyositis, myasthenia

gravis, strokeb) Lower esophageal

Smooth muscle dysmotility Systemic sclerosis, achalasia

Esophageal AtresiaEsophageal Atresia

• Incomplete development

• Thin, non-canalized cord replaces a segment of esophagus, causing mechanical obstruction

• Proximal and distal blind pouches connect to the pharynx and stomach, respectively

• Occurs most commonly at or near the tracheal bifurcation usually associated with fistula connecting the upper or lower esophageal pouches to a bronchus or the trachea

Esophageal Atresia: TypesEsophageal Atresia: Types

EA with distal TEF

EA with proximal TEF

Isolated EA

EA with double TEF

Isolated TEF

Esophageal AtresiaEsophageal Atresia

• Fistulae can lead to aspiration, suffocation, pneumonia, and severe fluid and electrolyte imbalances Abdominal distention in NB

air in stomach from fistula Regurgitation of food

• EA associated with congenital heart defects, GU malformations, and neurologic disease

Esophageal StenosisEsophageal Stenosis

• Incomplete form of atresia

• Esophageal lumen markedly reduced in caliber due to fibrous thickening of the wall partial or complete obstruction

• May involve any part of the GIT esophagus & SI most commonly affected

Esophageal StenosisEsophageal Stenosis

• Associated with atrophy of the muscularis propria & secondary epithelial damage

• Causes:1. Congenital – occasional2. Inflammation and scarring

Most common Due to GERD, irradiation or

caustic injury

• Progressive dysphagia

Congenital esophageal stenosis in a young man with long-standing dysphagia and occasional superimposed food impactions. Double-contrast esophagogram shows an area of mild narrowing in the mid-esophagus with distinctive ring-like indentations (“ringed esophagus”) (arrows) in the region of the stricture.

Nutcracker EsophagusNutcracker Esophagus

• High-amplitude esophageal contractions

• Outer longitudinal layer of smooth muscle contracts before the inner circular layer of smooth muscles lack of coordination

• Cause periodic short-lived esophageal obstruction

Diffuse esophageal spasmDiffuse esophageal spasm

• Cause increased esophageal wall stress

• Result in functional obstruction

• Can cause small diverticulae to form

Diffuse esophageal spasm produces intermittent contractions of the mid and

distal esophageal smooth muscle, associated with chest symptoms. Patient

experienced chest pain during examination

Esophageal diverticulaeEsophageal diverticulae

• Small mucosal outpouchings

True diverticulae – with true muscularis

Pseudodiverticulae – lack true muscularis


Zenker’s Diverticulum

• Pharyngoesophageal diverticulum

• Occurs in older women

• Posteriorly at site of Killian's dehiscence = superior boundary is thyropharyngeal muscle and inferior boundary is cricopharyngeal muscle

• Pulsion diverticulum

• False diverticulum = herniation of mucosa and submucosa through muscular layer

Esophageal diverticulae: TypesEsophageal diverticulae: Types

Traction Diverticulum

•Mid-esophageal diverticulum

•May be formed in response to pull from fibrous adhesions following lymph node infection (usually TB)

•Or, may form from increased intraluminal pressure and be pulsion diverticula

•True diverticulum = contains all 3 esophageal layers

Epiphrenic Diverticulum

•Location is usually in distal esophagus on lateral esophageal wall, right > left

•Often associated with hiatal hernia

•Pulsion diverticulum

•False diverticulum

Esophageal mucosal websEsophageal mucosal webs

• Uncommon ledge-like protrusions of mucosa

• Women > 40 y/o

• Often associated with: 1. Gastroesophageal reflux2. Chronic graft-versus-host disease3. Blistering skin diseases

• Most common in upper esophagus (at level of cricopharyngeus or C5-C6)

• Main symptom is dysphagia associated with incompletely chewed food

Barium esophagram demonstrates a thin membrane arising from the anterior wall of

the cervicalesophagus at the level of C5-C6

without circumferential involvement of the lumen

characteristicfor an esophageal web

An upper esophageal web (arrow) in a patient with

Plummer-Vinson syndrome.

Esophageal mucosal websEsophageal mucosal webs

• Patterson-Brown-Kelly or Plummer-Vinson Syndrome

Iron deficiency anemia Stomatitis Glossitis Dysphagia Spoon-shaped nails Esophageal webs

Atrophic glossitisEsophageal

web

Hypochromic, microcytic anemia

Koilonychia (spoon-shaped fingernails)

Cheilitis (rhagades,

angular stomatitis)

Esophageal ringsEsophageal rings

• Similar to webs but circumferential and thicker

• Include mucosa, submucosa, and in some cases, hypertrophic muscularis propria

• If present in distal esophagus, above the gastroesophageal junction; covered by squamous mucosa A rings

• If located at squamocolumnar junction (Z line) of lower esophagus & with gastric cardia-type mucosa on undersurface B rings (Schatzki rings)

Esophageal A-ring due to muscular contraction. It varies during examination and may not

persist.

The esophageal B-ring is located at the squamocolumnar junction, also termed the 'Z' line. The appearance does not change during

the examination.

AchalasiaAchalasia

• Triad:1. Incomplete LES relaxation2. Increased LES tone3. Aperistalsis of the esophagus

• Impaired smooth muscle relaxation increased tone of LES

• Primary – idiopathic; failure of distal esophageal inhibitory neurons

• Secondary – Chaga’s disease, diabetic autonomic neuropathy, malignancy, amyloidosis, polio, surgical ablation

LEFT: Dilated esophagus (arrows) appears as long, well-defined structure paralleling heart RIGHT: Dilated esophagus usually deviates to right, narrowing (arrow) at hiatus.

Esophageal Causes of Esophageal Causes of HematemesisHematemesis

Mallory-Weiss SyndromeMallory-Weiss Syndrome

• Longitudinal tears near the gastro-esophageal junction; superficial lacerations

• Usually associated with severe retching or vomiting due to acute alcohol intoxication

Boerhaave SyndromeBoerhaave Syndrome

• Distal esophageal rupture and mediastinitis

• Occurs rarely; catastrophic• Causes:

1. Endoscopy (~75% of cases)2. Retching3. Bulimia

• Complications:1. Pneumomediastinum

Air dissects into subcutaneous tissue

Produces a crunching sound (Hamman’s crunch) on P.E.

2. Pleural effusion contains food, acid, amylase

Chemical EsophagitisChemical Esophagitis

• Alcohol, corrosive acids or alkalis, excessively hot fluids, heavy smoking

• Generally causes only self-limited pain, particularly with swallowing

• Complications: hemorrhage, stricture, perforation

Corrosive esophagitis. This is a vinegar-induced esophageal burn. The patient had a fish bone in her throat. She ingested vinegar in an attempt to dissolve the fish bone but to no avail; this led to corrosive esophagitis.

Pill-induced EsophagitisPill-induced Esophagitis

• Occurs when medicinal pills lodge and dissolve in the esophagus rather than passing into the stomach

• Frequently occurs at the site of strictures that prevent passage of luminal contents

Infectious EsophagitisInfectious Esophagitis

• Frequently in debilitated or immunocompromised individuals commonly HSV, CMV, or fungi (Candidiasis most common) HSV – punched-out ulcers CMV – shallower ulcerations +

char. nuclear and cytoplasmic inclusions

Candida – adherent, gray-white pseudomembranes

This is Candida esophagitis. Tan-yellow plaques are seen in the lower esophagus, along with mucosal hyperemia. The same lesions are also seen at the

upper right in the stomach.

Candidiasis (thrush) of the esophagus.

A ‘pseudomembrane’ is present (top) on the surface of the stratified squamous epithelium. It consists of desquamated epithelial cells and thin filament-like fungi. The fungi has penetrated the superficial layer of the squamous epithelium which is separated from relatively unaffected basal layer.

Here are two sharply demarcated "punched out" ulcerations of the mid esophagus in an

immunocompromised patient with herpes simplex infection.

A herpetic ulcer is seen microscopically to have a sharp margin. The ulcer base at the left shows loss of overlying squamous epithelium with only necrotic debris remaining. Biopsies of these lesions reveals intranuclear inclusions in squamous epithelial cells indicative of herpes simplex virus esophagitis. This patient was immune compromised from chemotherapy.

Cytomegalovirus Infection.Microscopic sections reveal typical intranuclear inclusions Viral particles confirmed by electron microscopy

Reflux EsophagitisReflux Esophagitis

• Reflux of gastric contents into the lower esophagus called gastroesophageal reflux disease (GERD)

• Due to conditions that increase abdominal pressure or decrease lower esophageal sphincter tone1. Alcohol and tobacco use2. Obesity3. CNS depressants4. Pregnancy5. Hiatal hernia6. Delayed gastric emptying7. Increased gastric volume


• Morphology:

Simple hyperemia may be the only alteration

Mild GERD histology unremarkable

Severe GERDo Eosinophils & neutrophils in

squamous mucosao Basal zone hyperplasia > 20% of

the total epithelial thicknesso Elongation of lamina propria

papillae


Gross appearance of a severe case of reflux esophagitis. Marked hyperemia with focal hemorrhage is present in the area of reflux.


Gastroesophageal Reflux with Ulceration.A common pattern of reflux are longitudinal ulcers

arising from the gastroesophageal junction


Intra-epithelial eosinophils


Degrees of Gastroesophageal Reflux.In response to acid reflux, the squamous epithelium

becomesthicker with basal cell hyperplasia and elongated rete

papillae.


• Clinical Features:

Most common in adults > 40

Most common clinical symptoms:1. Dysphagia2. Heartburn

Other symptoms may include: regurgitation of sour-tasting gastric content; attacks of severe chest pain (chronic)



Complications:1. Esophageal ulceration2. Hematemesis3. Melena4. Stricture development5. Barrett esophagus

• Treatment: proton pump inhibitors or H2 histamine receptor antagonists symptomatic relief

Eosinophilic EsophagitisEosinophilic Esophagitis

• Majority of affected individuals are atopic with atopic dermatitis, allergic rhinitis, asthma, or modest peripheral eosinophilia

• Symptoms: adults food impaction and dysphagia Children feeding intolerance and

GERD-like symptoms

• Essentials for diagnosis:1. Large numbers of intraepithelial

eosinophils2. Failure of high-dose proton pump

inhibitor treatment3. Absence of acid reflux

Eosinophilic EsophagitisEosinophilic Esophagitis

A, Reflux esophagitis shows papillary lengthening, basal hyperplasia, and rare intraepithelial eosinophils (IEEs) (hematoxylin-eosin, original magnification ×20). B, Eosinophilic esophagitis shows prominent IEEs, aggregates of eosinophils, and superficial eosinophils (hematoxylin-eosin, original magnification ×20)

Hiatal HerniaHiatal Hernia

• Characterized by separation of the diaphragmatic crura and protrusion of the stomach into the thorax through the resulting gap part of stomach protrudes through the diaphragm and up to the chest

• Symptomatic in < 10% of adults associated with other causes of LES incompetence

• Symptoms include heartburn and regurgitation of gastric juices, similar to GERD


• Other potential contributing factors:

1. Permanent shortening of esophagus due to inflammation and scarring from reflux of gastric acid pulls stomach up

2. Abnormally loose attachment of esophagus to diaphragm allow esophagus and stomach to slip upward


Hiatal Hernia: TypesHiatal Hernia: Types

Sliding Hernia

• Most common type• Gastroesophageal junction + part

of stomach protrude into the chest

Para-esophageal Hernia

• Gastroesophageal junction stays where it belongs (attached at level of diaphragm) but part of stomach protrudes into the chest beside the esophagus

With sliding or axial hiatal hernia there is thinning and elongation of the phrenoesophageal membrane leading to herniation of the stomach into the posterior mediastinum. As such, there is no potential for incarceration or strangulation. With paraesophageal herniation, visceral elements herniate through a focal weakness in the phrenoesophageal membrane with the potential to lead to the usual array of complications associated with visceral herniation through a constricted aperture. (Source: Modified from Skinner.15 with permission from American Gastroenterological Association.)

Barrett EsophagusBarrett Esophagus

• Complication of chronic GERD

• Characterized by intestinal metaplasia within the squamous mucosa (+) goblet cells necessary for diagnosis

• Most common in white males, between 40 – 60 yrs old

• Increased risk of esophageal adenoCA pre-malignant condition

Patients with Barrett's esophagus have a 30- to 125-fold increased risk of the development of esophageal cancer in

comparison with the general population. The disease is most common in white males.


• Gross: tongues or patches of red, velvety mucosa extending upward from gastro-esophageal junction alternating with residual smooth, pale squamous mucosa

• Classification:1. Long segment - > 3 cm of

esophagus involved2. Short segment - < 3 cm of

esophagus involved


• Microscopic:

(+) goblet cells

Gland architecture: budding, irregular shapes, and cellular crowding

Classification if with dysplasia:1. Low grade2. High grade



• Clinical Features: Identified only through

endoscopy and biopsy Usually prompted by GERD

symptoms

• Treatment options: surgical resection or esophagectomy

Esophageal VaricesEsophageal Varices

• Due to diseases that impede venous blood flow from GIT to the liver via portal vein before reaching IVC (first-pass effect) Alcoholic liver disease – 90% of

cirrhotic patients Schistosomiasis – second most

common cause worldwide

• Congested sub-epithelial and sub-mucosal venous plexus within the distal esophagus


• Tortuous dilated veins lying within the submucosa of the distal esophagus and proximal stomach

• Variceal rupture (+) hemorrhage into the lumen or esophageal wall overlying mucosa appears ulcerated and necrotic


Cirrhotic patient with portal hypertension, in whom upper endoscopy shows large esophageal varices with red spots on their surface - indicating a high risk of bleeding.



Often asymptomatic Rupture massive hematemesis

o Contributory factors include:1. Inflammatory erosion of thinned

overlying mucosa2. Increased tension in progressively

dilated veins3. Increased vascular hydrostatic

pressure associated with vomiting


• Treatment: medical emergency Sclerotherapy – endoscopic injection

of thrombotic agents Endoscopic balloon tamponade Endoscopic rubber band ligation

• 50% die from first bleeding episode either as (1) direct consequence of hemorrhage, or (2) following hepatic coma triggered by hypovolemic shock

Esophageal Tumors: AdenocarcinomaEsophageal Tumors: Adenocarcinoma

• Typically arises in a background of Barrett esophagus and long-standing GERD Risk further increased by:

1. Tobacco use2. Obesity3. Prior radiation therapy

Risk reduced by diets rich in fresh fruits and vegetables, and some H. pylori serotypes


• Epidemiology: Caucasians 7x more common in males 50% of esophageal cancers in the

U.S.

• Pathogenesis: Step-wise acquisition of genetic and

epigenetic changes Mutation or over-expression of p53 Amplification of c-ERB-B2 , cyclin D1 &

cyclin E genes Allelic loss of p16INK4α by hyper-

methylation Increased expression of TNF and

NFκβ


• Morphology:

Distal 3rd of esophagus may invade gastric cardia

Initially flat or raised patches large masses

May infiltrate diffusely or ulcerate and invade deeply

Barrett esophagus usually present adjacent to the tumor

Most commonly produce mucin and form glands with intestinal-type morphology


Endoscopic image of patient with esophageal adenocarcinoma seen at gastro-esophageal junction.


H & E stain, Top - Low magnification,

Bottom - High magnification, Esophageal

Adenocarcinoma.



More commonly presents with: pain or difficulty in swallowing, progressive weight loss, hematemesis, chest pain, or vomiting

Tumor spread to submucosal lymphatic vessels by the time symptoms appear 5-year survival < 25%

5-year survival ~ 80% if limited to mucosa or submucosa

Esophageal Tumors: Squamous Cell CAEsophageal Tumors: Squamous Cell CA

• Epidemiology: U.S. – adults > 45 yrs old; 6x more

common in African-Americans 4x more common in males Risk factors:

1. Alcohol and tobacco use2. Poverty – more common in rural and

under-developed areas3. Caustic esophageal injury4. Achalasia5. Plummer-Vinson syndrome6. Frequent consumption of very hot

beverages7. Previous radiation therapy to

mediastinum


• Pathogenesis:

Alcohol and tobacco synergize to increase risk

Nutritional deficiencies, polycyclic hydrocarbons, nitrosamines, fungus-contaminated foods, HPV infection in areas where alcohol and tobacco use is uncommon

Loss of tumor suppressor genes, including p53 and p16INK4α


• Morphology:

50% occur in middle third Begins as in situ lesion called squamous

dysplasia early lesions small, gray white, plaque-like tumor masses (polypoid or exophytic) over months to years protrude into and obstruct lumen

Most are moderately to well-differentiated

LN metastases vary with tumor location: Upper 3rd cervical LN Middle 3rd mediastinal, paratracheal,

and tracheobronchial nodes Lower 3rd gastric & celiac nodes


Ulcerating Squamous cell carcinoma of the lower end of the esophagus.

Malignant tumor of the esophageal squamous mucosa, most common in the middle and lower third of the esophagus, and strongly associated with tobacco and alcohol use.



Onset insidious

Dysphagia, odynophagia (pain on swallowing), and obstruction

Extreme weight loss & debilitation

Tumor ulceration (+) hemorrhage and sepsis

Overall 5-year survival = 9%

GASTRIC DISORDERS

Normal Normal

• pH of gastric lumen close to 1

• Normal defensive forces include:1. Mucin – secreted by gastric foveolar

cells a) Forms a thin layer of mucus

prevents large food particles from directly touching epithelium

b) Promotes formation of a layer of fluid over the epithelium protects mucosa & has neutral pH

2. Rich vascular supply delivers oxygen, bicarbonate, and nutrients while washing away acid that has back-diffused into the lamina propria

Signs & Symptoms of Stomach DiseaseSigns & Symptoms of Stomach Disease

1. Hematemesis• Vomiting of blood• Most commonly due to PUD• Other causes: esophageal varices,

hemorrhagic gastritis

2. Melena• Dark, tarry stool• Hemoglobin is converted into

hematin by gastric acid• Signifies bleed proximal to duodeno-

jejunal junction

Signs & Symptoms of Stomach DiseaseSigns & Symptoms of Stomach Disease

• Gastric analysis includes measurement of:1. Basal acid output (BAO)

Acid output of gastric juice collected via NGT over a 1-hour period on an empty stomach

Normal = < 5 mEq/hr

2. Maximal acid output (MAO) Acid output of gastric juice that is

collected over 1 hour after pentagastrin stimulation

Normal = 5 – 20 mEq/hr

3. BAO:MAO ratio - normally 0.20:1

Congenital Hypertrophic Pyloric StenosisCongenital Hypertrophic Pyloric Stenosis

• Also known as gastric outlet obstruction

• 3-4x more common in males; 1:300-900 live births

• Monozygotic twins with high rate of concordance (+) genetic basis

• Progressive hypertrophy of the circular muscles in the pyloric sphincter

• Associated with Turner syndrome and trisomy 18



• Presents in 2nd or 3rd week of life as new-onset regurgitation and persistent, projectile, non-bilious vomiting

• P.E.: hyperperistalsis + firm, ovoid abdominal mass

• May be acquired in adults due to antral gastritis or peptic ulcers near the pylorus, and CA of distal stomach and pancreas

GastroparesisGastroparesis

• Decreased stomach motility, usually due to autonomic neuropathy (e.g. DM)

• May also be due to previous vagotomy

• Manifestations include 1. Early satiety and bloating2. Vomiting of undigested food a

few hours after eating

Acute GastritisAcute Gastritis

• Transient mucosal inflammation brought about by disruption to protective mechanisms1. Elderly – reduced mucin synthesis2. NSAIDs – interfere with cytoprotection

provided by PGs or reduce secretion of bicarbonate

3. Uremic patients & those with H. pylori infection (+) inhibition of gastric bicarbonate transporters by ammonium ions

4. Ingestion of harsh chemicals (acids and alkalis), excessive alcohol consumption, NSAIDs, radiation therapy, and chemotherapy direct cellular injury

5. Decreased oxygen delivery


• Morphology:

Mild, acute gastritis:

Intact surface epithelium with scattered neutrophils among epithelial cells or within mucosal glands

Moderate edema and slight vascular congestion

Neutrophils above basement membrane in direct contact with epithelial cells active inflammation


• Morphology:

Severe acute gastritis: Development of

1. Erosions – loss of superficial epithelium (+) defect in the mucosa limited to lamina propria and accompanied by pronounced neutrophilic infiltrates + purulent exudate

2. Hemorrhage – dark punctae in a hyperemic mucosa

Hemorrhage + erosion acute erosive hemorrhagic gastritis


This is a more typical acute gastritis with a diffusely hyperemic gastric

mucosa.


At high power, gastric mucosa demonstrates infiltration by neutrophils. This is acute

gastritis.


Here are some larger areas of gastric hemorrhage that could best be termed "erosions" because the superficial

mucosa is eroded away.


Gross appearance of hemorrhagic gastritis as seen at autopsy. The entire gastric mucosa is involved by fresh hemorrhage.

Acute Gastric UlcerationAcute Gastric Ulceration

• Types:1. Stress ulcers

Most common in individuals with shock, sepsis, or severe trauma

2. Curling ulcers Proximal duodenum; severe

burns or trauma3. Cushing ulcers

Gastric, duodenal, and esophageal ulcers in patients with intracranial disease

High incidence of perforation


• Pathogenesis:

NSAID-induced cyclooxygenase inhibition prevent PG synthesis

Intracranial injury direct stimulation of vagal nuclei gastric acid hypersecretion

Systemic acidosis decreased intracellular pH of mucosal cells

Stress-induced splanchnic vasoconstriction hypoxia and reduced blood flow


• Morphology:

Acute stress ulcers• Rounded, < 1 cm in diameter• Found anywhere in the stomach• Gastric rugal folds normal• Margin and base of ulcers are

not indurated• Usually multiple• Microscopically: sharply

demarcated, with essentially normal adjacent mucosa


Acute stress ulcers

Multiple acute ulcers of the stomach, occurring in a chronically debilitated patient. Microscopically, there was very little fibrous reaction in the ulcer bed.


Curling's ulcer is an acute peptic ulcer of the duodenum resulting as a complication from severe

burns.


• Clinical:

1. Bleeding 10 – 20% of patients Most common complication 25% of ulcer deaths May be the first indication of an

ulcer

2. Perforation Up to 5% of patients 2/3 of ulcer deaths Rarely the first indication of an

ulcer


• Clinical:

3. Obstruction Mostly in chronic ulcers Secondary to edema or scarring Approx. 2% of patients Most often associated with pyloric

channel ulcers Incapacitating, crampy abdominal

pain Rarely cause total obstruction and

intractable vomiting


• Treatment:

Prophylactic H2 histamine receptor antagonist or proton pump inhibitors

Blood transfusion for severe bleeding

Correction of underlying cause

Chronic GastritisChronic Gastritis

• Symptoms less severe but more persistent Nausea and abdominal discomfort Hematemes is uncommon

• Most common cause: Helicobacter pylori infection

• Other causes:1. Chronic irritants – psychologic stress,

caffeine, alcohol, tobacco use2. Autoimmune – most common cause of

atrophic gastritis; < 10% of cases3. Less common causes – radiation,

chronic bile reflux, mechanical injury, systemic disease (Crohn’s, amyloidosis, graft-versus-host disease)

Chronic Gastritis: Helicobacter pyloriChronic Gastritis: Helicobacter pylori

• H. pylori present in gastric biopsy specimens of almost all patients with duodenal ulcers, gastric ulcers or chronic gastritis

• Present in 90% of patients with chronic gastritis affecting the antrum

• Most common cause of duodenal ulcer

• 2nd most common cause of gastric ulcer

• Increased risk of gastric CA and gastric lymphoma


• Most common cause of chronic gastritis

Most often presents as predominantly antral gastritis with high acid production

Some progress to involve the gastric body and fundus associated with multifocal mucosal atrophy, reduced acid secretion, intestinal metaplasia, and increased risk of gastric adenoCA


• Four important virulence factors:

1. Flagella rapid motility easily penetrate mucus layer

2. Urease generates ammonia increase local gastric pH

3. Adhesins enhance bacterial adherence to surface foveolar cells

4. Toxins (cytotoxin-associated gene A or CagA) poorly-defined mechanisms



• Morphology:

Organism typically found in the antrum

Antral mucosa usually erythematous with coarse or nodular appearance

Neutrophilic infiltrates within lamina propria accumulate in lumen of gastric pits create pit abscesses

Intra-epithelial neutrophils & subepithelial plasma cells characteristic

(+) lymphoid aggregates with germinal centers induced MALT may transform to lymphoma


H. pylori bacteria (red arrow) imbedded in stomach lining. Courtesy of wikimedia

commons.

Active chronic H. pylori gastritis. The gastric mucosa contains large numbers of lymphocytes and plasma cells while polymorphs infiltrate the foveolar epithelium. The surface epithelium shows marked degenerative changes. Hematoxylin and eosin; magnification, ×100.

Chronic H. pylori gastritis. This low-power view shows marked glandular atrophy, lymphoid follicles, and centrally a focus of intestinal metaplasia. H&E

×25.

Chronic Gastritis: Autoimmune GastritisChronic Gastritis: Autoimmune Gastritis

• < 10% of cases of chronic gastritis

• Typically spares the antrum & includes hypergastrinemia

• Characterized by:1. Antibodies to parietal cells & intrinsic

factor – detected in serum and gastric secretions

2. Reduced serum pepsinogen I concentration

3. Antral endocrine cell hyperplasia4. Vitamin B12 deficiency5. Defective gastric acid secretion

Autoimmune gastritisAutoimmune gastritis

• Pathogenesis:

Loss of parietal cells absent gastric acid production stimulation of gastrin release hypergastrinemia and hyperplasia of antral gastrin-producing G cells

Lack of intrinsic factor disables ileal vitamin B12 absorption B12 deficiency slow-onset megaloblastic anemia (pernicious anemia)

Autoimmune gastritisAutoimmune gastritis

Chronic Gastritis Complications: PUDChronic Gastritis Complications: PUD

• Most often associated with H. pylori-induced hyperchlorhydric chronic gastritis

• May occur in any portion of the GIT exposed to acidic gastric juices most common in the gastric antrum & first portion of duodenum

• Risk of development higher in males; females affected during or after menopause

• Gastric ulcers generally develop on a background of chronic gastritis



Gastric Ulcers

• Primary underlying causes: H. pylori infection (>70%) and NSAID use

• Other contributory factors:1. Zollinger-Ellison syndrome

Multiple peptic ulcerations in the stomach, duodenum, and even jejunum due to uncontrolled gastrin release by a tumor

2. Cigarette smoking Impair mucosal blood flow & healing

3. High-dose corticosteroids Suppress PG synthesis & impair

healing


Duodenal Ulcers

• More frequent in individuals with:1. Alcoholic cirrhosis2. COPD3. Chronic renal failure (+)

hypercalcemia stimulate gastrin release

4. Hyperparathyroidism – similar mechanism as CRF

• NEVER malignant!


• Morphology:

4x more common in proximal duodenum Duodenal ulcers usually within a few

centimeters of pyloric valve & involve anterior duodenal wall

Gastric ulcers predominantly located along the lesser curvature near the interface of the body and antrum

Solitary in > 80%

Lesions < 0.3 cm in diameter usually shallow; those > 0.6 cm usually deeper ulcers


• Morphology:

Classic ulcer: four layers in sequence noted in histologic sections

1. Necrotic debris2. Inflammation with predominance

of neutrophils3. Granulation tissue (repair tissue)4. Fibrosis


The inner lining of the stomach consists of a very thick mucosal layer consisting of tall rows of glandular cells running parallel to each other. The thick mucosa has a deep narrow gap extending to the bottom of the mucosa. This gap is the ulcer.

Normal stomach mucosa (40X2.8) Stomach mucosa with ulcer (40X2.0)


Feature Gastric Ulcers Duodenal Ulcers

% of ulcer cases 25% 75%

Epidemiology Male:female ratio 1:1Smoking does not cause PUD but delays healing

Male:female ratio 2:1Risk increased with MEN I, cirrhosis, COPD, renal failure, hyperparathyroidism

H. pylori ~ 80% of cases 90 – 95% of cases

Pathogenesis Defective mucosal barrier due to H. pyloriMucosal ischemia (reduced PGE), bile reflux, delayed gastric emptyingBAO & MAO normal to decreased

Defective mucosal barrier due to H. pyloriIncreased acid prod’n (inc. parietal cell mass)

BAO & MAO both increased


Feature Gastric Ulcers Duodenal Ulcers

Location Single ulcer in lesser curvature of antrum (same location for cancer)

Single ulcer on anterior portion of 1st part of duodenum ffed by single ulcer on posterior portion (danger for perforation into pancreas)

Complications Bleeding (most commonly in left gastric artery)Perforation

Bleeding (most commonly in gastro - duodenal artery)Perforation (air under the diaphragm, pain radiates to left shoulder)Gastric outlet obstruction, pancreatitis

Clinical findings

Burning epigastric pain soon after eating

Burning epigastric pain 1 – 3 hours after eating

Chronic Gastritis Complications: Mucosal Chronic Gastritis Complications: Mucosal Atrophy and Intestinal MetaplasiaAtrophy and Intestinal Metaplasia

• Long-standing chronic gastritis loss of parietal cell mass intestinal metaplasia

• Presence of goblet cells

• Increased risk of gastric adenocarcinoma greatest in autoimmune gastritis

Due to overgrowth of bacteria produce carcinogenic nitrosamines

Chronic Gastritis Complications: DysplasiaChronic Gastritis Complications: Dysplasia

Chronic gastritis

Epithelium exposed to

Free radical damage

Proliferative stimuli

Genetic alterations

DYSPLASIA

CARCINOMA

Chronic Gastritis Complications: DysplasiaChronic Gastritis Complications: Dysplasia

• Morphologic hallmarks:

Variations in epithelial size, shape and orientation

Coarse chromatin texture Hyperchromasia Nuclear enlargement

Chronic Gastritis Complications: Gastritis Chronic Gastritis Complications: Gastritis CysticaCystica

• Exuberant reactive epithelial proliferation

• Associated with entrapment of epithelial-lined cysts

• May be found in:1. Submucosa gastritis cystica

polyposa2. Deeper layers of gastric wall

gastritis cystica profunda

• May mimic invasive adenocarcinoma

Hypertrophic GastropathiesHypertrophic Gastropathies

• Uncommon

• Giant cerebriform enlargement of the rugal folds due to epithelial hyperplasia without inflammation

• Associated with excessive growth factor release

Hypertrophic Gastropathies: Menetrier’s Hypertrophic Gastropathies: Menetrier’s DiseaseDisease

• Rare; due to excessive secretion of TGF-α

• Diffuse hyperplasia of foveolar epithelium of the body and fundus

• Protein-losing enteropathy hypo-proteinemia

• Increased risk of gastric adenoCA in adults

• Characteristic feature: hyperplasia of foveolar mucous cells

Hypertrophic Gastropathies: Menetrier’s Hypertrophic Gastropathies: Menetrier’s DiseaseDisease

Microscopic appearance of Menétrier's disease.

There is marked hyperplasia of the crypts accompanied by mild atrophy of the underlying secretory mucosa.

Hypertrophic Gastropathies: Hypertrophic Gastropathies: Zollinger-Ellison SyndromeZollinger-Ellison Syndrome

• Cause: gastrin-secreting tumors (gastrinomas) most commonly found in SI and pancreas 60% - 90% of gastrinomas malignant 25% of patients with MEN I

• Clinical: duodenal ulcers or chronic diarrhea

• Morphology: 5x increase in number of parietal cells

doubling of oxyntic mucosal thickness

Hyperplasia of mucous neck cells Mucin hyperproduction Proliferation of endocrine cells within

oxyntic mucosa

Hypertrophic Gastropathies: Hypertrophic Gastropathies: Zollinger-Ellison SyndromeZollinger-Ellison Syndrome

Gastric Polyps: Inflammatory & Hyperplastic Gastric Polyps: Inflammatory & Hyperplastic PolypsPolyps

• ~75% of all gastric polyps are inflammatory or hyperplasic polyps

• Most common in 50 – 60 yrs old individuals

• Develop in association with chronic gastritis

• Risk of dysplasia correlates with size

Gastric Polyps: Inflammatory & Hyperplastic Gastric Polyps: Inflammatory & Hyperplastic PolypsPolyps

Gross appearance of gastric polyps of hyperplastic type. Many of the lesions show central umbilication.

Low-power microscopic view of gastric polyps of hyperplastic type. The cystic dilatation of the glands is more evident on the left side.

Gastric Polyps: Fundic Gland PolypsGastric Polyps: Fundic Gland Polyps

• Occur sporadically in patients with familial adenomatous polyposis (FAP)

• Increased incidence in patients undergoing proton pump inhibitor therapy Reduced gastric acidity increased

gastrin secretion glandular hyperplasia

• 5x more common in women; ave. age 50 y/o

• Well-circumscribed lesions with a smooth surface

Gastric Polyps: Fundic Gland PolypsGastric Polyps: Fundic Gland Polyps

Endoscopic image of fundic gland polyposis taken on retroflexion of gastroscope. This patient was chronically taking proton pump inhibitors.

H&E stain of fundic gland polyp showing shortening of the gastric pits with cystic dilatation.

Gastric Tumors: Gastric AdenomaGastric Tumors: Gastric Adenoma

• 10% of all gastric polyps progressive increase in incidence with age

• 50 – 60 yrs old; males > females (3:1)

• Increased incidence in patients with FAP

• Almost always occur on a background of chronic gastritis with atrophy & intestinal metaplasia

• Risk of adenocarcinoma related to size of lesion (> 2 cm in diameter)


• Usually solitary; antrum

• Majority with intestinal type of epithelium

• All GI adenomas have epithelial dysplasia that can be classified as low grade or high grade.


Gross appearance of gastric adenomatous polyps. The larger lesion is a tangle of fingerlike projections.

Adenomatous polyp. (From Oota K, Sobin LH: Histological typing of gastric and oesophageal tumours, Geneva, World Health Organization, 1977)

Gastric Tumors: Gastric AdenocarcinomaGastric Tumors: Gastric Adenocarcinoma

• Most common malignancy of the stomach

• Risk factors:1. Intestinal metaplasia due to H.

pylori - most important2. Nitrosamines, smoked foods (Japan),

diets lacking fruits/vegetables3. Type A chronic atrophic gastritis4. Menetrier’s disease


• Pathogenesis:

1. Diffuse gastric cancer Germline mutations in CDH1

(encodes E-cadherin) BRCA2 mutations p53 mutations

2. Intestinal type gastric cancer Individuals with FAP Mutations in β catenin Microsatellite instability Mutations in p53, TGFβRII, BAX,

IGFRII & p16/INK4α


Morphology:

• Classified according to location in the stomach, gross & histologic morphology

• Most involve gastric antrum; lesser curvature > greater curvature

• If with intestinal morphology bulky and composed of glandular structures; exophytic or ulcerated

• If with diffuse morphology infiltrative pattern; composed of signet ring cells that do not form glands


Morphology:

• Diffuse type not associated with H. pylori

May infiltrate stomach wall desmoplastic reaction that stiffens the gastric wall called linitis plastica (leather bottle appearance)

Produce Krukernberg tumors of the ovaries


Gross appearance of gastric adenocarcinoma of polypoid type.

Gross appearance of gastric adenocarcinoma of

ulcerative type showing marked resemblance to

chronic peptic ulcer.


Typical gross appearance of diffuse carcinoma of linitis

plastica type. Practically the entire wall of the stomach is involved by tumor. Note the prominence of rugal folds.


Gastric adenocarcinoma of intestinal type.

Diffuse type of gastric adenocarcinoma. An Indian file pattern of infiltration of the muscularis externa can

be appreciated.


Clinical:

• Weight loss (most common), epigastric pain with vomiting

• Metastasis to left supraclavicular node (Virchow’s node)

• Paraneoplastic skin lesions1. Acanthosis nigricans2. Multiple outcroppings of seborrheic

keratoses• Metastasis to umbilicus (Sister Mary

Joseph sign)• Common metastatic sites: liver, lung,

ovaries


Gastric Tumors: LymphomaGastric Tumors: Lymphoma

• Most common extra-nodal site is GIT, particularly the stomach

• Nearly 5% of all gastric malignancies

• Often referred to as lymphomas of mucosa-associated lymphoid tissue (MALTomas)

• Usually arises at sites of chronic inflammation

• Most common cause: chronic H. pylori infection


• Dense lymphocytic infiltrate in the lamina propria Infiltrate the gastric glands focally

create lymphoepithelial lesions diagnostic

• Express the B cell markers CD19 and CD20

• Most common presenting symptoms are dyspepsia and epigastric pain


EXTRANODAL MARGINAL ZONE B-CELL (MALT)LYMPHOMA — This tumor, previously called MALT-typelymphoma or MALT lymphoma is now called extranodalmarginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in the WHO classification system.


MALT-type malignant lymphoma of stomach involving mucosa and submucosa.

Gastric Tumors: Carcinoid TumorGastric Tumors: Carcinoid Tumor

• Arise from diffuse components of endocrine system – majority found in the GIT; > 40% in the small intestines

• Associated with: endocrine cell hyperplasia, chronic atrophic gastritis, & Zollinger-Ellison syndrome

• Best considered as well-differentiated neuro-endocrine carcinomas


• Gross: Intramural or submucosal masses Yellow or tan in color Very firm due to intense desmoplastic

reaction cause bowel kinking and obstruction

• Microscopic: islands, trabeculae, strands, glands, or sheets of uniform cells with scant, pink, granular cytoplasm and round to oval stippled nucleus

• Positive for endocrine granule markers (synaptophysin and chromogranin A)


• Clinical:

Tumors that produce gastrin cause Zollinger-Ellison syndrome

Ileal tumors cause carcinoid syndrome Cutaneous flushing, sweating,

bronchospasm, colicky abdominal pain, diarrhea, and right-sided cardiac valvular fibrosis

Strongly associated with metastatic disease


• Most important prognostic factor is location1. Foregut tumors

Found within the stomach, duodenum proximal to ligament of Treitz, and esophagus

Rarely metastasize & cured by resection

2. Midgut tumors Jejunum and ileum Multiple and aggressive

3. Hindgut tumors Appendix (at the tip) and colorectum Discovered incidentally Rarely > 2 cm in diameter except if

proximal colon


Small carcinoid tumor of the stomach composed of enterochromaffin-like cells.


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