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Dr Dexter MD FRC Path Undercover Professor

Department of pathology SOM,SGU Grenada (W.I.)

Overview of clinical features

• Symptoms– Dysphagia– Epigastric pain– Heart burn, dyspepsia, flatulence– Loss of appetite– Nausea, Vomiting– Hematemesis

Overview of clinical features– Colicky abdominal pain – Abdominal distension– Diarrhea– Dysentery – Constipation– Alternate diarrhea and constipation– Blood in stools

• Occult- Guaiac test• Hematochezia• Melena

– Anemia

Overview of clinical features• Signs

– Epigastric tenderness– Epigastric mass– Hepatomegaly – Splenomegaly– Ascites– Visible peristalsis– Abdominal rigidity or guarding – Abdominal mass

Common investigations– Stool for occult blood– Plain X ray– Barium meal– Barium follow through– Barium enema– Upper GI endoscopy– Colonoscopy, Sigmoidoscopy– Ultrasonography – Arteriography– Fine Needle Aspiration Cytology (FNAC)– Biopsy

ORAL CAVITY

Leukoplakia• Refers to well defined ���������� �

caused by epidermal proliferations• “White plaque on the oral mucosa that can

not be removed with scraping and can not be classified clinically and microscopically as any other disease”

• Benign epithelial lesions to highly dysplastic lesions

• 3-7% undergo malignant transformation

• Precancerous until proven otherwise• Buccal mucosa, tongue, floor of mouth• Most commonly at vermillion border• Predisposing factors:

– tobacco use – ill fitting dentures, – persistent irritants– HPV infection

Erythroplakia

• Aka Erythroplasia• Less common but more ominous• Red velvety eroded area• Poorly circumscribed• Much more atypical epithelial changes (dysplasia)• Malignant transformation in more than 50%

Oral Hairy Leukoplakia(OHL)

• Seen in patients with HIV• White confluent fluffy or hairy

hyperkeratotic thickenings• Epstein Barr Virus in majority • Layers of keratotic squames on underlying

mucosal acanthosis (hyperkeratotic)• No malignant potential

ESOPHAGUS

Esophagus-Normal

• Wall has 4 layers:• Mucosa • Sub mucosa (rich network of lymphatics)• Muscularis propria• Adventitia

�In sharp contrast to rest of GIT mostly devoid of serosa

Lesions -overview

BenignBenign MalignantMalignant

Congenital malformations

Non neoplastic conditions

Neoplasms

Atresia StenosisHeterotopiaCystsDiverticula

Hiatal hernia Achalasia Mallory Weiss tear Esophagitis Barret’s esophagus Varices

Esophageal Atresia

• Disruption of elongation & seperation of esophogus and trachea during embryogenesis

• Commonly associated with tracheo-esophageal fistulas

• Maternal polyhydroamnios, single umblical artery

• Excessive drooling of saliva in new born• Choking and cyanosis with first feed

Hiatal Hernia• Herniation of stomach through enlarged

esophageal hiatus in diaphragm– Sliding type (95%)– Paraesophageal type

• Leads to incompetence of lower esophageal sphincter (LES) especially in sliding type

• Reflux of gastric contents leads to epigastric pain, heart burn (sliding type)

• Respiratory distress, volvulus, strangulation in paraesophageal type

Achalasia / cardiospasm• Incomplete relaxation of LES in response to

swallowing• Functional esophageal obstruction• Three main features

Aperistalsis Partial or incomplete relaxation of LES Increased resting tone of LES

• Primary Loss of intrinsic inhibitory innervation of LES and and smooth muscle Loss or absence of ganglion cells in myenteric plexus

• Secondary (aka pseudoachalasia) Impaired function from a variety of causes e.g. Chagas, polio, sarcoidosis

Clinical features– Gradual onset of dysphagia– Substernal discomfort – Odynophagia– Reflux of contents – vomiting – Aspiration pneumonia

• Progressive dilatation of esophagus above LES• Manometry is diagnostic • Risk of developing squamous cell

carcinoma (in about 5%)

Mallory Weiss Syndrome

• Longitudinal mucosal tears at esophageal gastric junction

• In alcoholics after bout of severe retching• In bulimics following vomiting• Inadequate relaxation of LES during

vomiting• Hematemesis • Usually heal but some times fatal

Esophagitis

• IRRITANTS - alcohol, acids, alkalis etc.• INFECTIONS - Herpes simplex and Cytomegalovirus virus, Candidiasis • UREMIA• ALLERGIC - Eosinophilic esophagitis• ANTICANCER THERAPY• HIATAL HERNIA - Sliding type

LES tone

Delayed esophageal clearance

Increased gastric volume

Reparative capacity of esophagus

CNS depressants, hypothyroidism, pregnancy, alcohol, tobacco, nasogastric intubation.

REFLUX ESOPHAGITIS

� Hyperemia� Presence of inflammatory cells

eosinophils� Elongation of lamina propria papillae � Basal zone hyperplasia

• Clinically – Heart burn – Water brash– Symptoms increase after lying down or after a

large meal– Nocturnal cough, hoarseness of voice

• Complications– Bleeding– Stricture formation– Barret’s esophagus, Adenocarcinoma– Aspiration pneumonitis

Barret’s Esophagus• “The esophageal mucosa is replaced by

metaplastic columnar epithelium because of prolonged injury i.e. chronic esophageal reflux.”

• Usually in patients with long standing reflux esophagitis

• After injury there is proliferation of stem cells which differentiate into columnar cells (more resistant to acid peptic injury)

• Salmon pink patch, tongue or large area above EG, surface becomes granular

Clinical features• Long history of reflux • Features of GERD• Asymptomatic in one third patients • 30-40 fold increased risk of

adenocarcinoma• Monitored by repeated endoscopic

biopsies to look for dysplasia

Esophageal Varices• Dilated tortuous vessels (collaterals) in the

lower end of esophagus• Associated with portal hypertension• 90% in cirrhotic patients • Dilated tortuous veins in mucosa

and submucosa• Overlying mucosa may be normal or inflamed or

ulcerated• Usually no symptoms till they rupture• Responsible for 50% deaths in patients

with advanced cirrhosis

Neoplasms

• BENIGN• Rare

• MALIGNANT (More common)

• Squamous cell carcinoma

• Adenocarcinoma (More common in US)

Squamous Cell Carcinoma

• Adults over the age of 50• More common in males• High incidence in central Asia and

Northern China• In United states incidence is 2-8

per 100,000 yearly• Blacks are at higher risk than whites

EtiologiesClinically

• Dysphagia to solid food initially• Weight loss• Chest pain, cough, hoarseness due to

direct local extension of tumor• Lymph node involvement- cervical,

mediastinal, paratracheal, tracheobronchial, gastric and celiac nodes

SCC

GROSS• 20% upper third of esophagus• 50% middle third of esophagus• 30% lower third of esophagus

PATTERNS• Exophytic• Diffusely Infiltrative• Ulcerated/ Excavated

Growth Patterns of tumors

Adenocarcinoma

• Lower third of esophagus• Barret’s esophagus is precursor lesion• Multistep process through dysplasia• Median age 50 years• Poor prognosis• Appear as flat, raised patches which

develop into large, nodular masses

• Signs and symptoms similar to squamouscell carcinoma

• Most are mucin producing adenocarcinomas

• Prognosis poor• Surveillance in Barret’s esophagus is

mandatory

STOMACH

Lesions- overview• NON

NEOPLASTIC• Pyloric stenosis• Gastritis

- Acute -Chronic

• Peptic ulcer disease

• NEOPLASTIC• BENIGN

• Gastric polyps• Adenomas• Leiomyomas

• MALIGNANT• Carcinomas• Carcinoids• Lymphomas

(MALTOMAS)

Pyloric StenosisCONGENITAL• Has genetic basis

ACQUIRED • Chronic antral

gastritis• Peptic ulcers• Malignancy

Congenital Pyloric Stenosis

• More common in first male child• Concentric hypertrophy of circular muscle • Clinically - Manifests 2-3 weeks after birth:

–– RegurgitationRegurgitation –– Projectile vomitingProjectile vomiting –– Palpable epigastric massPalpable epigastric mass –– Visible peristalsis Visible peristalsis

• Treated by surgery (myotomy)

Acute Gastritis• Is acute inflammatory process of the

mucosa usually transient in nature• Etiological factors

– NSAIDS– Excessive alcohol consumption– Heavy smoking– Ischemia and shock– Severe stress (burns, surgery)– Cancer chemotherapy– Systemic infections– Uremia

Clinical Features

• May be asymptomatic• Epigastric pain, nausea and vomiting• Hematemesis and melena• Bleeding can be fatal

• Pathogenesis is related to– Increased acid secretion with back diffusion– Decreased bicarbonate secretion– Decreased mucosal blood flow– Direct damage to epithelium

• Loss of surface epithelium = erosions• Erosions along with hemorrhage (acute

erosive gastritis)• Hyperemia, punctate areas of hemorrhage• Edema and congestion of lamina propria• Neutrophils in the surface epithelium and

lumina of the glands

Chronic Gastritis• Definition “presence of chronic mucosal

inflammatory changes leading eventually to mucosal atrophy and epithelial metaplasia”

• Etiology– Chronic infection with H. pylori– Immunologic causes (autoimmune)– Alcohol and smoking– Post surgical e.g. after antrectomy– Radiation– Granulomatous conditions

Common causes

Helicobacter pylori

• Gram negative, curvilinear, motile (flagella), non invasive and urease positive bacillus

• Associated with two types of gastritis- Antral type- Multifocal atrophic type

OTHER DISEASES CAUSED BY H.PYLORI -Peptic ulcers -Gastric carcinoma -Gastric lymphoma

H. pylori

Attracts PMNs & other inflammatory cells

EnzymesProteasesUreases Phosopholipases

Damage to mucosa

Chronic gastritis, Peptic ulcers

Uncontrolled proliferation of B cells

lymphoma

Autoimmune • Auto antibodies against parietal cells

Gland destruction

ATROPHY

Loss of Loss of Acid production intrinsic factor (Achlorhydria) VitaminB12 deficiency

(Pernicious anemia)

Mainly involves body and fundus

Hypergastrinemia

Clinical Features of chronic gastritis

• Asymptomatic • Nausea, vomiting • Epigastric discomfort• Dyspepsia • Indigestion

• Endoscopy-Boggy appearing mucosa with thick mucosal folds

• MICROSCOPY• Inflammatory infiltrate (lymphocytes,

plasma cells) in the lamina propria • PMNs in the surface epithelium and

glandular lumen (Activity)

• Lymphoid aggregates ( marker for H.pylori infection)

• Intestinal metaplasia• Glandular atrophy especially severe in

autoimmune type• Parietal cell absence in pernicious anemia• Look for DYSPLASIA especially in long

standing cases

Rapid urease test

Histopathology (special stains) Culture

polymerase chain reaction

Urea breath test

Serology (lgG, lgA)

PCR in saliva and feces

DIAGNOSIS OF H.PYLORI

ENDOSCOPY BASEDINVASIVE TESTS

NON INVASIVE TESTS

Lab investigations depend upon cause

1. Achlorhydria2. Increased gastrin levels3. Auto antibodies to parietal cell antigens4. Urease breath test5. Endoscopic biopsy

• Long term risk of gastric carcinoma esp. in autoimmune type

Autoimmune type

Acute Gastric Ulceration

• Aka stress ulcers• Small mucosal erosions to deep lesions

involving the entire mucosal thickness• Can present with massive upper GIT bleed• Usually multiple and asymptomatic• 5-10% of patients admitted in Intensive

Care Units

• Severe trauma, major surgeries• Extensive burns (Curling ulcers)• Head injuries and other intracranial lesions

(Cushing Ulcers)• Pathogenesis is related to

– Systemic acidosis and hypoxia (severe trauma and burns)

– Vagal stimulation (intra cranial lesions)

� multiple small and circular� gastric rugae are normal� base is not indurated� adjacent gastric mucosa normal

Peptic Ulcer Disease• Ulcer is defined as breach in the mucosa

of the alimentary tract that extends through the muscularis mucosae into the submucosa or deeper

• Are chronic, often solitary lesions that occur in any part of the GIT exposed to aggressive action of the gastric acid peptic juices

Sites (Descending order) • Duodenum• Stomach• Gastro esophageal junction • Margins of gastrojejunostomy• Meckel’s diverticulum• Stomach, duodenum and jejunum in

Zollinger Ellison syndrome

Clinical Features

• Burning epigastric pain 1-3 hours after meals

• Relieved by food and alkali esp. duodenal ulcers

• Worse at night• Associated weight loss• Gastric outlet obstruction

Etiopathogenesis

DAMAGING FORCES

GASTRO DUODENAL MUCOSAL DEFENSES

1) H.PYLORI- 70% of gastric and 90% of duodenal ulcers

2) NSAIDS- inhibit prostaglandin synthesis

3) ZOLLINGER ELLISON SYNDROME-multiple ulcers

4) SMOKING- impairs mucosal blood flow

5) ALCOHOL

6) PSYCHOLOGICAL STRESS

• 50% < 2cms • Round to oval, punched out with relatively

straight walls• Sharp and raised margins but not everted • Depth varies but may penetrate entire wall• Smooth and clean base • Radiating surrounding mucosal folds

• Active ulcer has four zones (From inwards )1) Necrotic fibrinoid debris2) Non specific inflammatory infiltrate

(Predominantly neutrophilic)3) Granulation tissue4) Fibrosis and collagenous scar

• Features of chronic gastritis in adjacent mucosa

• COMPLICATIONS �Bleeding �Perforation � Gastric outlet obstruction • MALIGNANT TRANSFORMATION -

Unknown in duodenal ulcer and exceedingly rare in gastric ulcers

Gastric Carcinoma

ENVIRONMENTAL

GENETIC

HOST FACTORS

Blood Gp A, Family History, HNPCC

H. pylori, Chronic atrophic Gastritis, Intestinal metaplasia Partial gastrectomy, Gastric adenoma

Diet,Smoking,Low SES

SITES�Pylorus, Antrum - 50-60%� Cardia 25%� Body and Fundus

GROWTH PATTERN� Exophytic� Flat� Exacavated

ClassificationBASED ON DEPTH

EARLY GASTRIC CARCINOMA

ADVANCED GASTRIC CARCINOMA

• Confined to mucosa and submucosa

• Regardless of involvement of regional lymph nodes

Classification

• Neoplastic glandsresemble colon

• Associated with H. pylori

• Intestinal metaplasia is precursor lesion

• Don't form glands• Infiltrate as single cells

or small clusters• Intestinal metaplasia is not

precursor lesion• Linitis plastica• Signet ring cells•Role of E cadherin

HISTOLOGICAL(LAUREN’S CLASSIFICATION)

INTESTINAL DIFFUSE

• Spread �Regional �Transcelomic �Lymphatic �Hematogenous

The ‘Virchow’s lymph node

• Mainly asymptomatic• Weight loss, anorexia, abdominal pain• Pyloric obstruction• Krukenberg tumor• Left supraclavicular lymphadenopathy

(Virchow’s lymph node)• Umbilical nodule (sister Mary Joseph nodule) • Prognosis depends upon depth of invasion and

nodal status

Clinically Gastro Intestinal Stromal Tumors (GIST)

• Mesenchymal tumors• Derived from cells of Cajal –the pace maker

cells• Many of these previously k. a. Leiomyomas• Stomach, small intestine, large intestine• Can be benign or malignant• Usually submucosal• Whorls and bundles of spindle shaped cells• C-kit (CD 117) is the tumor marker

SMALL INTESTINE

Small Intestine-Normal histology

• Lining epithelium has four types of cells�Columnar absorptive cells with microvilli�Goblet cells�Endocrine cells�Paneth cells (contain antimicrobial enzymes)

Pathological Lesions-overview

CONGENITAL ANOMALIES

MALABSORPTION SYNDROMES

INFLAMMATORY BOWEL DISEASE

NEOPLASMS

Duplication Malrotation Heterotopia Omphalocoele Duodenal atresia MECKEL’S DIVERTICULUM

Celiac sprue Tropical sprue Whipple’s disease Pancreatic insufficiency

Crohn’s disease Ulcerative colitis

Adenomas AdenocarcinomasCarcinoid tumor Lymphomas

Meckel’s Diverticulum• Incomplete of involution of vitelline duct • Rule of 2 - 2% of normal population

- with in 2 feet of ileocecal valve - average 2 cm in length

• On anti-mesenteric border• All layers of GIT (true diverticulum)• Some times lined by gastric mucosa or

pancreatic tissue

• Commonly asymptomatic• COMPLICATIONS

� Hemorrhage and Peptic ulceration� Intestinal obstruction� Diverticulitis� Perforation� Fistula

Malabsorption SyndromesSuboptimal absorption of fats, fat soluble vitamins and other vitamins,proteins, carbohydrates, electrolytes and water.

BASIC DEFECT CAN BE IN

Intra luminal digestion

Terminal digestion

Transepithelial transport

CAUSES -Celiac disease-Pancreatic insuffiency-Crohn’s disease-Cholestatic liver disease-Tropical sprue-Whipple’s disease-Giardiasis

(Giardia)

Clinical Features

• Steatorrhea, Flatus, abdominal distension• Weight loss, failure to thrive (children)• Anemia• Muscle wasting, weakness• Osteopenia,Tetany• Amenorrhea• Infertility

CELIAC DISEASE (Gluten Sensitive Enteropathy)

• Common in whites (1 in 3000)• Age of presentation 1-10 years• Pathogenesis Sensitivity to gluten

Mucosa exposed to gluten

Accumulation of T & B lymphocytes

Damage to enterocytes

MALABSORPTION

In Predisposed Persons (HLADQ2

and DQ8)

About 10% cases have dermatitis herpetiformis

• Diffuse enteritis• Changes more marked in proximal part of

intestine• Marked atrophy and loss of villi (reduced area

for absorption)• Increased intraepithelial lymphocytes• Elongated and hyperplastic crypts • Increased number of lymphocytes,

macrophages and plasma cells in lamina propria• Reversal of changes after gluten free diet

• Diagnosis -Documentation of malabsorption -Small intestine biopsy -Reversal of changes and signs and symptoms after gluten free diet-Anti tissue transglutaminase

and anti endomysial antibodies Small percentage associated with IgA deficiency

• Long term risk of intestinal lymphomas (T cell type)

Tropical Sprue (Post Infectious Sprue)

• In people living in or visiting tropics• Symptoms appear after months or even

years after visit• Pathogenesis is related to bacterial

infection superimposed on pre existing small intestine injury

• All parts of small intestine are involved equally

• Near normal to diffuse enteritis• Blunting of villi to complete flattening of villi• Difficult to differentiate from celiac disease• Responds to antibiotics

Whipple’S Disease• Systemic disease• Mainly involves intestine, joints and CNS• Caused by a gram positive sickle shaped

bacilli Trepophyrema whippelii• More common in males (10:1)• Mucosa laden with distended

macrophages in lamina propria• Contain PAS positive granules• Rod shaped bacilli can be seen on EM

• Villi are broad and expanded• Mesenteric lymphadenopathy can be seen• Similar bacilli laden macrophages in joints,

CNS• BUT No associated lymphocytic or

neutrophilic infiltration• Treated with Antibiotics

Clinically

• Arthralgias, GIT sysmptoms• Weight loss, generalized

lymphadenopathy, low grade fever• CNS symptoms (dementia, seizures)• Hyperpigmentation in sun exposed areas

Neoplasms

• 3-6 % of all GIT tumors• Benign tumors are slightly more common than malignant ones

BENIGN MALIGNANT� Adenomas� Leiomyoma� Lipoma� Hemangioma� Neuroma

� Adenocarcinoma� Carcinoid tumor� Lymphomas� Sarcomas

Carcinoid Tumor• Arise from endocrine cells• Tumors with low malignant potential• Secrete a variety of bioactive products &

hormones• Commonly secreted products are 5HT,

5-HIAA, histamine, bradykinin and kallikrein

• Metastasis to liver produces carcinoid syndrome

• Common sites-(descending order)– Small intestine (ileum)-usually multiple– Rectum – Stomach– Appendix (tip)– Colon

• Usually located in submucosa• Cut Surface- solid & yellow tan

• Fibrosis of mesentery so leads to kinking and obstruction

• Those less than 1 cms and rectal and appendiceal carcinoids – do not metastasize

• Islands, trabeculae, nests and sheets of monomorphic cells

• Have round to oval stippled nuclei (salt and pepper appearance)

• Minimal pleomorphism• EM dense core granules• IHC - chromogranin A

• Many are asymptomatic• Kinking and obstruction of bowel due to

fibroblastic reaction• Carcinoid syndrome-

– Vasomotor disturbances – wheezing, dyspnea, – Intestinal hypermotility– Systemic fibrosis, may lead to right sided valvular

lesions • Overall 5 year survival rate is 50%

GIT Lymphomas• 1-4% of all GIT malignancies• Sites

Stomach (50%)> small intestine (37%)> colon and rectum

• By definition no bone marrow, liver or spleen involvement at the time of diagnosis (However regional lymphadenopathy can be present)

• Risk factors– patients with helicobacter gastritis – people living in mediterranean,– Immunodeficient persons – celiac disease

Types of Lymphoma

• Sporadic

• Mediterranean

• Sprue associated (celiac disease)

Sporadic: (most common)• Arise from B cells of MALT tissue• MC site Stomach, SI and Colon• Appendix and esophagus RARE• Remain localized for long time• t(11:18) is characteristic

Morphology• Plaque like expansions of mucosa and

submucosa• Some times diffuse mural thickening• Diffuse sheets of small cleaved lymphoid

cells• Infiltrate and destroy epithelial glands

(Lymphoepithelial lesions)

APPENDIX

Appendix-Normal

• Average length 7 cm• Four layers as rest of GIT• Colonic type of epithelium• But mucosa and submucosa rich in

lymphoid tissue

Acute Appendicitis

• Inflammation of the appendix• Underlying obstruction of the lumen in 50-

80% cases• Pathogenesis unclear in non obstructive

cases

PathogenesisObstruction

Continued secretion of mucinous fluid

Increased intraluminal pressure

Collapse of draining veins

Ischemic injury

Bacterial proliferation

Inflammation and edema

• Edematous and congested appendix• Serosa dull and granular• Fibropurulent exudate• Severe cases gangrene• Neutrophilic exudate in mucosa, sub

mucosa and muscularis propria• Edema and congestion• Neutrophilic infiltration of the

muscularis propria is the criteria for diagnosis

Clinically

• Adolescents and young adults• Pain is the most common symptom,

initially periumblical then localizes to right quadrant

• Nausea, vomiting• Tenderness (McBurney’s point)• Mild fever, Leucocytosis (Neutrophilia )

• Complications– Perforation– Peritonitis – Periappendiceal abscess – Liver abscess – Bacteremia

Tumors of the Appendix

• Rare• Carcinoid tumors (usually incidental finding)• Adenomas• Adeno carcinomas (mucin producing)

MucoceleSwelling of the appendix because of accumulation of inspissated mucus

Obstruction Mucinous tumors

Mucinous cystadenocarcinoma

Mucinous cystadenoma

Rupture

Intraperitoneal spread

PSEUDOMYXOMA PERITONEI

• Fecolith • Stricture

Other cause-Mucinous tumorsof the ovary

LARGE INTESTINE

Large Intestine-Normal histology• Flat mucosa (no villi)• Straight tubular crypts • Epithelium composed of

– Columnar absorptive cells– Goblet cells – Endocrine cells

Pathological lesions-overview

Congenital malformations

Inflammatory lesions

Tumors & tumor like lesions

• Hirschsprung’s Disease

• Colitis• IBD

•Non neoplastic polyps•Adenomas•Adenocarcinomas•Carcinoid •Lymphomas

• Most common cause of congenital intestinal obstruction

• Incidence is 1 in 5000 to 1 in 8000• M:F is 4:1• In 10% patients of Down Syndrome• Rectum is always affected• Absence of ganglion cells in Meissner and

Auerbach’s plexus• Dilatation and hypertrophy proximal to

aganglionic segment (congenital megacolon)

Hirschsprung’s Disease

Defect in migration and survival of neuroblasts

Congenital absence of ganglion cells

Functional obstruction

DILATATION PROXIMAL TO OBSTRUCTION (megacolon)

Clinical features

• Delayed passage of meconium• Constipation • Abdominal distension• Diagnosed by rectal biopsy• Complications -Enterocolitis

-Perforation and peritonitis

Diverticular disease• Includes diverticulosis and diverticulitis• Common in western world• 50% in older than 60 years• Flask like structures ( 95% sigmoid colon)

extending from lumen through muscular layer• Pathogenesis

– Lack of dietary fiber leads to sustained bowel contractions and increased intraluminal pressure

– Herniation of colonic wall at sites of focal defects

• Not true diverticula

Clinically

• Divertculosis is usually asymptomatic but some times painless bleeding

• Diverticulitis – Lower abdominal pain– Constipation, diarrhea, flatulence– Bleeding – fever

• Diverticulitis can lead to perforation

Colitiscommon causes1) Infections bacterial

viral protozoal (Amebic colitis)

2) Necrotizing enterocolitis

3) Antibiotic associated colitis (Pseudo membranous colitis)

2) Ischemic colitis

3) Idiopathic-Inflammatory bowel disease

Clinical features of colitis

• Diarrhea– Mucoid – Bloody

• Abdominal pain (Usually below umbilicus)• Abdominal cramps• Tenesmus (painful defecation)

Amebic Colitis• Common in developing countries• Caused by Entamoeba histolytica• Cecum and ascending colon• Invades the crypts and burrows into

submucosa• Flask shaped ulcers• Little inflammatory infiltrate in the ulcer• Can produce Amebic liver abscess

Pseudo Membranous Colitis

• Associated with broad spectrum antibiotic use

• Caused by Clostridium difficile• Toxin mediated damage• Colon, particularly rectosigmoid, exhibits

raised yellow plaques• Fibrinopurulent-necrotic debris (PSEUDOMEMBRANES)

• Surface epithelium denuded• Superficially damaged crypts distended by

mucopurulent exudate which erupts to form a mushrooming cloud

• Coalescence of these clouds leads to pseudo membrane formation

•

Transmural (all layers)Mural (mucosa and submucosa) Mucosal (not deep than mucosa)

Ischemic bowel disease

1.Arterial thrombosis- systemic atherosclerosis, systemic vasculitis, hypercoagulable states, angio- graphic procedures

2.Arterial embolism- cardiac vegetations, athero-thromboembolism and angiographic procedures

3.Venous thrombosis- hypercoagulable states, Oral contraceptives, intraperitoneal, sepsis, post operative etc.

4.Non occlusive ischemia- cardiac failure, shock, dehydration5.Miscellaneous- radiation, volvulous, herniation

PREDISPOSING CONDITIONS Clinical Features

• Common in elderly • Severe abdominal pain and tenderness• Nausea, vomiting and bloody stools• Shock and vascular collapse• Mortality is very high (50-75%)• Mild features in mucosal and mural

infarction • Gangrene, perforation, peritonitis

• Hemorrhagic infarction • Intestine is edematous, congested and red

purple in color• Lumen may contain frank blood• Demarcation from normal mucosa is

sharply defined in arterial causes (Not in venous)

Chronic Ischemic colitis

• Develops insidiously• Chronic inflammation and fibrosis• Stricture formation ( Splenic flexure-the

water shed area)• Intermittent attacks of pain- Intestinal

angina• Can mimic Inflammatory bowel disease

Idiopathic Inflammatory Bowel Disease

• Includes Crohn’s disease (CD) and Ulcerative colitis (UC)

• Are chronic relapsing, inflammatory disorders of obscure origin

• CD- Granulomatous inflammation which can affect any part of GIT from mouth to anus

• UC- Non granulomatous inflammation limited to colon

Etiopathogenesis

GENETICS

? INFECTIONS ABNORMAL HOST REACTIVITY

Activation of inflammatorycells (PMNs)

cytokines & mediators

tissue injury

Net result

Crohn’s Disease• Synonyms- Terminal ileitis, regional ileitis and

granulomatous colitis• characterized by

• Sharply delimited & transmural involvement by an inflammatory process

• Presence of non caseating granulomas• Mucosal fissuring with formation of fistulas

• Common disease in U.S.(3 in 100,000)• Adolescents and young adults• More common in Jews

• Crohn’s disease involves– Small intestine alone 30%– Small intestine and colon 40%– Colon alone 30%

• Serosa dull and granular• Creeping up of mesenteric fat because of

fibrosis• Mesenteric lymphadenopathy• Mesentery thickened and fibrotic

• Long narrow thickened segments of small intestine (unlike tubercular strictures which are short in length)

• Wall is thickened (because of edema, hypertrophy, fibrosis and inflammation)

• Lumen is narrow (radiographically- String sign)

Morphology• Focal mucosal ulcers which may coalesce to

form linear ulcers• Intervening mucosa is relatively spared but

coarsely textured- Cobble stone appearance• Mucosal fissures , if penetrate deeply

Fistulas Sinus tract Perforation Localized abscess

1.Neutrophilic infiltration of the epithelium and crypt abscesses

2.Architectural distortion- Villous blunting, irregular branching crypts and crypt atrophy

3.Ulcerations (deep mucosal fissures)4.Transmural inflammation- lymphoid

aggregates scattered through out the wall (mucosa,submucosa,mucularis propria and serosa)

5.Non caseating granulomas (50% cases) In all layers even in regional lymph nodes BUT absence of granulomas does not preclude diagnosis

6.Fibrosis of mucosa ,sub mucosa and muscularis propria

Clinical features• Low grade fever, malise, weight loss• Intermittent attacks of nonbloody diarrhea, • Steady or cramping right lower quadrant pain • Palpable tender mass in right lower quadrant • Features of malabsorption• Small intestine- features of subacute intestinal

obstruction• Large intestine- features of colitis• Perianal disease- fissures, fistulas and

abscesses

Extra intestinal Manifestations

• Seen in both CD and UC (though more common with Ulcerative colitis)

• Can develop even before the onset of GI sign symptoms– Migratory polyarthritis, Sacroileitis , Ankylosing

spondylitis– Erythema nodosum– Clubbing of finger tips– Sclerosing cholangitis

• Aphthous ulcers, gall stones• 5-6 times increased risk of developing

malignancy (Less than UC)

Ulcerative Colitis• Ulcero-inflammatory disease limited to

colon and affecting mucosa and sub mucosa

• Extends in continuous fashion• More common in females• Also more common in whites• Peak between 20 and 25 years• Starts in rectum and then extends

proximally to involve whole of the colon

Clinical features• Relapsing disorder• Attacks of bloody mucoid diarrhea• Lower abdominal pain, abdominal cramps• Tenesmus• Cramping abdominal pain relieved by

defecation • Flare ups with physical and mental stress• Fever and weight loss in severe cases

• 10% cases back wash ileitis

• Serosa is usually normal

• Mucosa red granular and friable

• Broad based ulcers• Isolated islands of

regenerating mucosa bulge in between to create pseudopolyps

INTESTINAL ULCERS• Duodenal ulcers• Typhoid • Tuberculosis • Crohn’s disease• Ischemic colitis• Amebic colitis• Infective causes • Carcinomas

• Severe cases toxic damage to muscularis propria and neural plexus shut down of neuromuscular function- TOXIC MEGACOLON

• Mucosal inflammation, cryptitis, crypt abscesses, crypt distortion

• Long standing cases nuclear atypia and features of dysplasia

• When carcinoma arises, usually multicentric• Risk of carcinoma increases with pancolitis

and duration of disease ( > 10 years)

GIT Polyps

Non neoplastic Neoplastic

Inflammatory Non inflammatory Benign Malignant

A polyp is a mass that protrudes into the lumen of the gut

Hyperplastic Hamartomatous Lymphoid

Tumors of the Colon And Rectum

EPITHELIAL MESENCHYMAL LYMPHOID

Lymphomas BENIGN

BENIGN

MALIGNANT

MALIGNANT

Adenomas •Tubular •Tubulovillous•Villous

•Adeno-carcinoma

•carcinoid •GIST•Lipoma •Neuroma•Angioma

•GIST•Kaposi sarcoma

GIST-Gastrointestinal Stromal Tumors

Hyperplastic Polyp• Small nipple like protrusions• Common in elderly• Well differentiated glands and crypts lined

by non neoplastic epithelium• Because of delayed shedding there is

crowding, infoldings and serrated epithelial profile

• MOST LIKELY NO MALIGNANT POTENTIAL

Juvenile Polyp• Common in children < 5 years of age• Rectum is most common site• In adults aka retention polyp• Rarely juvenile polyposis syndrome (AD)• Usually 1-3 cms, lobulated with stalk• Lamina propria forms the bulk and

encloses abundant cystically dilated glands

• Inflammatory cells can be present• NO MALIGNANT POTENTIAL

Peutz Jeghers Polyp

• Hamartomatous polyp• P.J. syndrome is autosomal dominant• Multiple polyps in whole GIT• Melanotic pigmentation in mucocutaneous

areas, lips, perioral areas, face, genitalia and palms

• Are large pedunculated lesions

• Arborizing network of connective tissue and smooth muscle extending into the polyp and surrounds glands

• Glands are lined by an epithelium rich in goblet cells

• No malignant potential per se• BUT such patients are at risk of

developing carcinomas of pancreas, breast, lung, ovary and uterus

Normal mucosa

Hyperplastic polyp

JuvenilePolyp or retention poly

Peutz Jeghar polyp

Lymphoid polyp

Saw toothor

Summary of non neoplastic polyps

Adenomas• All arise as a result of epithelial

proliferative dysplasia• Three types-tubular, villous and

tubulovillous• Are precursor lesions of carcinoma• Risk increases with

�Polyp size (most important criteria)�Histologic architecture�Severity of dysplasia

Tubular Adenomas• Usually solitary• 90% colon• Stalked and coarsely lobulated• Adenomatous epithelium lines the glands,

seen as tall, hyperchromatic and disordered epithelium

• Invasion of the submucosal stalk constitutes invasive carcinoma

Villous Adenomas

• Larger and more ominous• Sessile, upto10 cm, velvety and

cauliflower like• Frond like villiform extensions of the

mucosa• No stalk so no buffer zone• Direct invasion of the sub mucosa

Tubulovillous Adenomas

• Contain both tubule like and villi like structures

Clinical Features• Clinically most tubular and tubulovillous

adenomas are usually asymptomatic• May present with features of anemia

because of occult blood loss• In villous adenoma loss of fluid, proteins

and electrolytes-hypoproteinemia, hypokalemia

• Rarely intussception• All adenomatous polyps are considered

potentially malignant

Familial Polyposis Syndromes• FAP-genetic defect in APC gene on

Chromosome 5• Usually tubular type• Some times in small intestine and stomach• Typically 500-2500 mucosal adenomas

(minimum number for diagnosis is 100)• Attenuated FAP• Carcinoma occurs in young individuals• Prophylactic colectomy is done• Gardner Syndrome- Tubular adenomas with

multiple osteomas and epidermal cysts• Turcot Syndrome- adenomas and CNS gliomas

Colorectal Carcinoma• Occurs in elderly individuals • Occurs in young individuals in setting of

ulcerative colitis and polyposis syndromes• Risk factors:

• Age ( 90% in older than 50 years)• dietary habits, diet low in indigestible fiber and rich in

animal fat• obesity, physical inactivity• Family history

• Antioxidants protective• 80-90% cases arise in an adenomatous polyp

(adenoma-carcinoma sequence)• 10-15% cases defect in DNA mismatch repair

genes e.g. MLH1 ( HNPCC)

Adenoma-carcinoma sequence

• Usually solitary • More than half occur proximal to splenic

flexure• Multiple sites-ulcerative colitis, polyposis

syndromes and HNPCC• Proximal colon- expohytic polypoidal

lesions and obstruction is uncommon• Distal colon- annular, encircling napkin

ring constrictions

• Neoplastic glands invading submucosa and muscularis propria

• 10-15 % can be mucin producing• Spread to regional lymph nodes is

frequent• Systemic liver, lung and bones• Prognosis -most important factor is extent

of tumor at the time of diagnosis

Clinical Features

• Asymptomatic • RIGHT SIDED- fatigue, weakness & iron

deficiency anemia (Bulky & bleed easily)• LEFT SIDED- altered bowel habits• Tumor marker - CEA• Iron deficiency anemia in elderly man is

due to GIT malignancy unless proved otherwise

Hereditary Non Polyposis Colorectal Cancer (HNPCC)

• Aka Warthin-Lynch Syndrome• Defective DNA repair genes (AD)-MLH1 gene• Fewer number of polyps as compared to FAP• More common on right side (proximal colon)• Multiple sites • Mucinous histology , increased number of

intratumoral lymphocytes• Associated with carcinomas of other sites

endometrium, ovaries, stomach, small intestine, biliary tract

Guppal GIT Path SGUSOM

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Liver-normal• Normal weight 1400-1600 gm• Anastamosing cords of hepatocytes (2 cell

thick)• Sinusoids lined by fenestrated endothelial

cells and Kupffer cells• Space of Disse -contains Ito cells

Clinical features-overview

• Symptoms:• Right upper quadrant pain• Anorexia• Yellowish discoloration of skin• Pruritus • Fever• Mental confusion• Easy bruising

• Signs:– Icterus – Hepatomegaly – Splenomegaly – Palmar erythema– Spider angiomas – Gynecomastia– Testicular atrophy– Purpura– Skin pigmentation– Tenderness in right hyopchondrium

Chronic liver disease

Laboratory investigations• Serum bilirubin – Direct and Indirect• Transaminases – Alanine amino transferase

(ALT) and Aspartate amino transferase (AST) ALT is more specific for liver injury than AST. ALT (Cytosolic enzyme) and AST (Primarily Mitochondrial)

• In Alcoholic Liver Disease AST/ALT >2• Viral hepatitis AST/ALT <1

• Alkaline phosphatase- Levels are increased in obstructive liver disease

• �-glutamyl transferase (GGT) – Alcoholic liver disease

• Serum albumin- Decreased levels in chronic liver diseases

• Prothrombin time- Prolonged in acute and chronic liver diseases

• Serum ammonia levels-raised in hepatic failure • Immunological markers -Anti smooth muscle

antibodies, anti mitochondrial antibodies• Viral markers and antibodies to various viral

proteins

• Ultrasonography • Endoscopic Retrograde Cholangio

Pancreatography (ERCP)• FNAC• Percutaneous needle biopsy

Jaundice• Yellowish discoloration of skin• Yellowish discoloration of sclera-Icterus• Because of accumulation of bilirubin• When bilirubin levels > 2.0 mg/dl it is

clinically evident• Both conjugated & unconjugated bilirubin

can accumulate• CHOLESTASIS -in addition to bilirubin

retention of bile salts and cholesterol

163

Bilirubin & Bile FormationAged RBCs Hepatic hemoproteins Minor

Premature destruction of RBC componentprecursors in bone marrow

Heme BiliverdinHeme oxygenase(MPS)

Reductase(MPS)

Released in circulationBound to albumin

Bilirubin

Carrier mediated uptakeAt sinusoidal membrane

Conjugation in ER

Bilrubin glucouronides(water soluble) in bile

Bacterial deconjugasesIn intestine Urobilinogens

Feces

Reabsorbed Small amount in urine

1

234

56

1- 4 unconjugated hyperbilirubinemia5,6 conjugated hyperbilirubinemia

JaundiceConjugated bilirubin

• Water soluble• Excreted in urine• Loosely bound to

albumin• Aka direct bilirubin

Unconjugated bilirubin• Water insoluble • Lipid and alcohol

soluble• Can not be excreted in

urine• Tightly bound to

albumin• Aka indirect bilirubin

Present Absent

Absent Present in excess

Present Absent

Urine Bilirubin

Urine urobilinogen

Urine bile salts

Obstructive jaundice

Hemolytic jaundice

Predominantly Unconjugated Hyperbilirubinemia

� PREHEPATIC:Excess Production Of Bilirubin –Hemolytic anemias, resorption of blood from internal hemorrhages, ineffective erythropoiesis

� HEPATIC:a) Reduced Hepatic Uptake- Drugs interfering

with carrier system & few cases of Gilbert syndrome

b) Impaired Bilirubin Conjugation- Diffuse hepatocellular damage e.g. viral hepatitis, cirrhosis etc., Physiologic jaundice of new born, breast milk jaundice, Crigler-Najjarsyndrome I & II

Predominantly Conjugated Hyperbilirubinemia

c) Decreased Hepatic Secretion Of Bilirubin Glucuronides- deficiency in membrane transporters (Dubin Johnson and Rotor syndromes), hepatocellular damage (Viral hepatitis), Drugs,

� POSTHEPATIC:Extrahepatic Biliary ObstructionGall stones, Ca head of pancreas, Ca of extrahepatic bile ducts, Biliary atresia

Cholestatic liver disease

• Caused by hepatocellular dysfunction/intra or extra hepatic biliary obstruction

• Pruritus• Skin xanthomas• Features of fat malabsorption• Elevated alkaline phosphatase• Extra hepatic biliary obstruction is

amenable to surgery

Cirrhosis• Defined by three characteristicsa) Bridging fibrous septaeb) Parenchymal nodules created by

regenerationc) Architectural disruption• Changes should be diffuse not focal• Micronodular < 3mm nodules• Macronodular > 3 mm nodules

170

Pathogenesis

HepatocellularInjury

Regeneration

Progressive fibrosis

CIRRHOSIS

Causes of Cirrhosis

• Alcoholic liver Disease (Most common)• Viral hepatitis• Biliary tract diseases• Hereditary hemochromatosis• Wilson’s disease• Alpha 1 anti trypsin deficiency• Cryptogenic cirrhosis

Rare

PathogenesisChronic inflammation (TNF-�,TGF-ß & IL-10)

Cytokine production by endogenous Cells (Kupffer cells, hepatocytes)

Disruption of ECM Direct stimulation of Ito cells by toxins

Stimulate Ito cells

DEPOSITION OF COLLAGEN I & III IN SPACE OF DISSE & HEPATIC LOBULES

Loss of fenestrations In endothelial cells

Impaired hepatocellular Secretion of proteins (Albumin, Clotting factors)

New vascular channels In fibrous septae

Shunting of blood

Obstruction of Biliary channels

Jaundice

Clinically

• May be clinically silent• Non specific signs and symptoms• Signs and Symptoms are usually because

of�Portal hypertension�Ascites �Splenomegaly�Features of Liver failure

Portal Hypertension

• Simply means increased resistance to portal blood flow

• Can also occur in many disorders other than cirrhosis

• Normal= 5-10 mm Hg

Consequences of Portal Hypertension

Ascites Portosystemic shunts Sites-�Cardioesophageal junction �Rectum �Retroperitoneum �Abdominal wall

Congestive Splenomegaly

Hepatic Encephalo-pathy

Clinically asEsophageal varices Hemorrhoids Caput medusae

Viral Hepatitis• Most common infective disease of the liver• Many systemic viral infections also involve liver

e.g. Infectious mononucleosis, CMV, yellow fever etc.

• However the term viral hepatitis is used for group of diseases caused by a group of hepatotropic viruses

• They are hepatitis viruses A to E• Virological aspects will be taught in microbiology

course

Hepatitis A• Caused by single stranded RNA virus• Incubation period is 2-6 weeks• Does not cause chronic hepatitis• No carrier state• Common in children• Spread is by feco-oral route• Diagnosis- IgM appear at the onset of sign

and symptoms• After few months IgG

Hepatitis B (Serum Hepatitis)• Caused by enveloped DNA virus• Long incubation period 4-26 weeks• Present in all pathological and

physiological fluids • Transmission occurs by

� Transfusion of blood and blood products� Sexual intercourse� I/V drug abuse� Homosexuals� Needle stick injuries

Structure of HBV

• Nucleocapsid core-Has core antigen (HBcAg) and HBeAg

• Envelope glycoprotein is HBeAg

• DNA polymerase• HBX role in

hepatocellular carcinoma

Serologic Diagnosis

• Pre symptomatic stage HBsAg, HBcAg and DNA polymerase

• With onset of Symptoms-Anti HBc IgM• Later on- Anti HBe and Anti HBs• Window period- Anti HBc IgM• Replication markers- HBeAg, DNA

polymerase and HBsAg

Hepatitis C• Most important cause of transfusion

associated hepatitis and chronic liver disease

• Incubation period is 1-3 weeks• Much more propensity for chronicity• Single stranded RNA virus• Inherently unstable virus so no vaccine yet• PERSISTENT INFECTION and CHRONICITY ARE

HALL MARK

Hepatitis D

• Is replication defective RNA virus• Infective only when encapsulated by

HBsAg• Either co-infection or established HBV

infection before (super infection)• Super infection is more dangerous

Hepatitis E

• Enterically transmitted, as endemics• Unenveloped single stranded RNA virus• NO CHRONICITY• Usually a self limited illness• But high mortality in pregnant females• Severe cholestasis which persists for

longer period

Clinico pathologic Syndromes (viral hepatitis)

• Asymptomatic infection• Carrier state• Acute hepatitis• Chronic hepatitis• Fulminant hepatitis

Asymptomatic Infection•Identified incidentally

•Elevated transaminases

Carrier State

• Healthy carriers• Chronic carriers

– Harbour virus – Can transmit Infection – Usually have no signs & symptoms• Normal liver biopsy• Ground glass hepatocytes• Features of chronic hepatitis in hepatitis C

Acute Viral Hepatitis

• Incubation period• Pre-icteric or symptomatic phase• Icteric phase• Convalescence• Signs and symptoms usually abate with onset of

jaundice • Predominantly conjugated type• Enlarged reddened liver some times greenish

because of cholestasis

Morphology of Acute Viral HepatitisARCHITECTURE

HEPATOCYTES SINUSOIDS PORTAL TRACTS

• Ballooning degeneration

• Necrosis (Lytic/ bridging / confluent / massive)

• Regeneration (disarray)

• Reactive changes

• Kupffer cell hyperplasia• Contain cell debris

• Inflammation Mononuclear

•May spill into adjacent hepatocytes (k.a.Interface hepatitis)

Lobular disarray

190

Acute Viral Hepatitis

Chronic Hepatitis• Symptomatic, biochemical or clinical evidence of

continuing or relapsing hepatic disease of > 6 months duration in addition to histological documentation of inflammation and necrosis

• Mainly by HBV and HCV• Clinically non specific Signs and symptoms• On examination- Mild hepatomeagly, spider

angiomas, palmar erythema and mild splenomeagly

• Prothrombin time prolonged

Other causes of chronic hepatitis

• Alcoholism• Wilson’s disease• Alpha 1 anti trypsin deficiency• Drugs • Autoimmune

Chronic Viral Hepatitis

• Shares some features with acute viral hepatitis

• Hepatocyte injury, necrosis, regeneration• Portal tracts show mononuclear

inflammation• Fibrosis- can be portal, periportal or

bridging fibrous septae

• In HCV - a few special features– Bile ductular proliferation in portal tracts– Presence of lymphoid aggregates – Fatty change of the hepatocytes

Fulminant Hepatitis• Denotes clinical hepatic insufficiency that

progresses rapidly to hepatic encephalopathy with in 2-3 weeks

• Viral hepatitis is the most important cause (60-70% cases)

• Remaining cases - drug and chemical toxicity

• Rare causes include ischemic necrosis, acute fatty liver of pregnancy, Wilson’s disease

Fulminant Hepatitis• Morphology is same regardless of

causative agent• Because of massive loss of liver

parenchyma liver is shrunken• Acute yellow atrophy• Massive destruction of hepatocytes

involving adjacent lobules• Collapsed reticulin framework• Little inflammation in first week

Autoimmune hepatitis• Common in females• Morphological features of chronic hepatitis• Young female with jaundice, spider nevi, acne , hirsutism• Amenorrhea can occur• Extrahepatic autoimmune disease can be seen e.g.

Sjogren syndrome, arthritis, ulcerative colitis• INVESTIGATIONS:• Hyperbilirubinemia, elevations in aminotransferases• hypergammaglobulinemia• Anti nuclear and anti smooth muscle antibodies• Anti LKM (Liver kidney microsomal type) antibodies• Respond to immunosuppressive therapy

Alpha-1 Antitrypsin Deficiency

• Autosomal recessive disorder• Markedly low levels of alpha antitrypsin (is

protease inhibitor) • Is a glycoprotein encoded by PiMM gene on

chromosome 14• Synthesized by liver• Most allelic variants have slightly reduced levels• PiZZ is homozygote form (markedly levels)

Alpha-1 Antitrypsin Deficiency

• Associated hepatic syndromes are variable– Neonatal hepatitis with or without cholestasis– Smoldering chronic inflammation– Cirrhosis at early age

• characterized by round to oval globular cytoplasmic inclusions

• These are acidophilic and indistinct on H & E• strongly PAS positive• Risk of hepatocellular carcinoma • Liver transplantation is the only treatment

Alcoholic Liver Disease

• 3 patterns of liver disease– Hepatic steatosis– Alcoholic hepatitis– Cirrhosis

201

ALCOHOL

• Shunting of normal substrates towardslipid synthesis,

• Defective assembly of lip-oproteins

• Catabolism of fat

Induction of P-450

Toxic metabolites

Free radicalsIn MES

Acetaldehyde Lipid peroxidation

Hepatocyte-acetaldehyde adducts

Immunologically alteredhepatocytes

Susceptible to Immunological attackBy alcohol

oxidation React with membranes & proteins

Hepatic injury

Steatosis NecrosisInflammationFibrosis

ALD

Morphology Of Alcoholic Steatosis

• Occurs even with moderate intake• Liver is grossly enlarged, is soft and

greasy• Microvesicular and Macrovesicular• Fat granulomas or lipogranulomas

Alcoholic Hepatitis1) Hepatocyte swelling (water and lipids)

and necrosis2) Mallory bodies-Tangled skeins of

intermediate filaments• Are seen as eosinophilic cytoplasmic

inclusionsOther causes of Mallory’s hyaline-

• Primary biliary cirrhosis• Wilson’s disease• Chronic cholestasis• NASH (Non Alcoholic

Steato Hepatitis)

• Neutrophilic reaction- neutrophils permeate lobules and accumulate around degenerating hepatocytes (especially those having Mallory’s hyaline)

• Admixed macrophages and lymphocytes are also present

• Fibrosis- Perivenular initially • Later on perisinusoidal aka Chicken wire

fibrosis– Steatosis– Steatonecrosis– Mallory’s hyaline

Highly suggestive of Alcoholic hepatitis

Alcoholic Cirrhosis

• Initially enlarged yellow fatty liver later over the span of years brown, non fatty and shrunken

• Is micronodular• Macronodules may be formed at a later

stage

• Jaundice, ascites• Wasted extremities, palmar erythemas• Esophageal varices• Splenomeagly• Spider angioma, palmar erythema,

testicular atrophy• Elevated levels of alkaline phosphatase,

gamma glutamyl transferase• Elevated serum transaminases AST/ALT

ratio >2

• Prolonged prothrombin time• Hypoproteinemias reversal of albumin

globulin ratio• Long term outlook varies• Important causes of death include

�Hepatic coma�Upper GIT bleed� Intercurrent infections�Hepatorenal syndrome�Rarely hepatocellular carcinoma

Non alcoholic fatty liver disease (NAFLD or NASH)

• Changes like ALD in non drinkers• Steatosis with or without hepatitis• Risk factors

– Obesity– Insulin resistance– Hyperlipidemias

• Usually asymptomatic• Mild elevation of serum transferases• May lead to cirrhosis

Hemochromatosis• Excessive accumulation of iron• Characterized by

�Micronodular cirrhosis �Diabetes mellitus�Skin pigmentation

• Can be genetic (primary) or acquired (secondary)

• Primary- AR (HFE gene on chromosome 6)-increased Fe absorption- Common in males

Causes of Secondary Hemochromatosis

• Parentral iron overload -Repeated blood transfusions -Iron dextran injections

• Ineffective erythropoiesis -beta thalassemias -other chronic hemolytic anemias

• Increased oral intake- Bantu’s disease

• Chronic liver disease

Pathogenesis

EXCESSIVE IRON ACCUMULATION

Iron catalyzes free Radical formation

Lipid peroxidation

Stimulation of collagen synthesis

Direct damage to DNA

HEAPTIC INJURYAND FIBROSIS

• Deposition of iron in �Liver �Pancreas �Myocardium �Pituitary �Adrenals �Thyroid and Parathyroid �Joints and skin

• In liver:• Initially golden yellow pigment in cytoplasm of

periportal hepatocytes• Later on whole of the lobule, bile duct

epithelium and even in Kupffer cells• NO INFLAMMATION• Ultimately cirrhosis• Hepatic iron concentration increased

(normal < 1000�gm/gm dry weight of liver)• Iron is stained with Prussian blue• Hepatomegaly, abdominal pain

• PANCREAS– Intensely pigmented– Diffuse interstitial fibrosis– Hemosiderin in both acinar and Islet cells– Diabetes mellitus

• HEART– Hemosiderin in myocardial fibres– Delicate interstitial fibrosis

• SKIN– Slate gray coloration– Iron in dermal melanophages– Increased melanin production

Clinical Features

• Genetic variety rarely manifests before 40• More common in males• Hepatomeagly• Abdominal pain• Skin pigmentation (Sun exposed areas)• Diabetes mellitus• Cardiac dysfunction

Clinical Features

• Death because of cirrhosis or cardiac disease

• 200 fold increased risk of hepatocellular carcinoma

• Screening is done by serum iron and ferritin levels

• Genetic studies (In patients with family history)

Wilson’s Disease

• Autosomal recessive disorder• Gene on chromosome 13• Characterized by accumulation of toxic

levels of Cu in Liver, Brain and Eyes

WILSON’S DISEASEDietary copper

After absorption goes to liver

In hepatocytes Cu+�2 globulin

Plasma

Senescent ceruloplasmin

Defect in ATP7B gene (chromosome 13)

Cu transporting ATPase On canalicular memebrane

Ceruloplasmin

Excreted in bile

Cu

Excessive cu in hepatocytes

TOXIC INJURY TO LIVER

Spills in blood and damages Brain, eyes and other organs

Morphology

• In liver variable morphology � Fatty change � Acute hepatitis � Chronic hepatitis � Ultimately cirrhosis� Rarely massive necrosis

• BRAIN –– Deposited in basal ganglia, – may even produce cavitation

• EYES –– Deposits of copper in Descemet’s membrane

of corneal limbus k.a. Kayser Fleischer ring– In some sun flower cataracts

Clinically• Presentation is rare before 6 years of age• Features of acute or chronic liver disease• Neuropsychiatriac manifestations, chorea• In some patients -hemolytic anemia• Investigations

� Decreased serum ceruloplasmin levels� Increased hepatic Cu (>250�gm/gm dry

weight of liver is diagnostic)� Increased urinary copper excretion

222

Secondary Biliary Cirrhosis

•Caused by extra hepatic obstruction

Cholestasis

Secondary inflammation

Fibrosis

Secondary bacterial infection

Ascending cholangitis

• Yellow green pigmented liver• Cut surface- Hard and granular with

coarse fibrous septae• Embedded bile ducts in septae (May

contain inspissated bile)• Extensive proliferation of small bile ducts

and edema• Marked feathery degeneration of

hepatocytes and bile lakes

Primary Biliary Cirrhosis

• Chronic, progressive and fatal liver disease

• Possibly autoimmune• Non suppurative, granulomatous

destruction of medium sized bile ducts• Disease of middle aged women(6:1)

225

PathogenesisAutoimmune etiology

Aberrantly expressed mitochondrial Ag on surfaceof biliary epithelium

Auto reactive T cells

ANTI MITOCHONDRIALANTIBODIES

DESTRUCTION OF BILE DUCTS

Other associated autoimmuneDisorders may be present

• bile ducts destroyed by granulomas (Florid duct lesion)

• Bile duct proliferation in portal tracts upstream the obstruction

• Dense infiltrate of lymphocytes, plasma cells, macrophages and occasional eosinophils

• Ultimately cirrhosis (indistinguishable from secondary biliary cirrhosis)

Clinically• Pruritus • Jaundice develops late• Hepatomeagly• Raised alkaline phosphatase levels• Raise cholesterol levels, xanthomas• Anti mitochondrial antibodies in 90%• Death usually occurs because of liver

failure

228

Primary sclerosing cholangitis• Inflammation, fibrosis and dilatation of intra

and extra hepatic ducts• M>F• Two third have chronic ulcerative colitis• ? Gut derived toxins• ? Immunological mediated• Onion skin fibrosis of the bile ducts• Lymphocytic infiltrate of the portal tracts• Strictures, ERCP- beading of the biliary tree,• Cholestasis• P-ANCA in about 80% cases

Neoplasms of The Liver• Malignant

• Hepatoblastoma• Hepatocellular

carcinoma• Cholangiocarcinoma• Metastasis

• Benign� Hepatic adenomas

• Long term oral contraceptive use

• Can be picked incidently

• May produce hemorrhage

Hepatocellular Carcinoma

• Aka Hepatoma• Global distribution is strongly related to

prevalence of HBV• Highest frequencies in Taiwan,

Mozambique and China• Male preponderance• Usually in adult life

Etiopathogenesis

• HBV• Chronic liver disease (HCV & Alcoholism)• Aflatotoxins• But many factors interact age, sex,

chemicals, nutrition, alcohol, viruses etc.• Exact pathogenesis varies between HBV

prevalent population Vs low incidence population

Morphology

• Unifocal• Multifocal• Diffuse infiltrative• Are usually paler than surrounding hepatic

parenchyma• Strong propensity for invading vascular

channels (portal vein, IVC)

• Well differentiated to poorly differentiated type

• Trabecular,sinusoidal or pseudoacinar pattern

• Bile production by tumor cells• Cirrhosis in adjacent liver parenchyma

Fibrolamellar Variant

• M=F• No association with HBV or cirrhosis• Usually single hard tumor with fibrous

bands traversing through it• Well differentiated polygonal cells in cords

or nests, separated by fibrous septae

Clinical Features of HCC• Not characteristic• Usually masked by underlying liver disease• Ill defined upper abdominal pain, fatigue,

cachexia• Raised alpha fetoprotein levels in 60-75%

(markedly increased)• Diagnosis- FNAC, biopsy• Fibrolamellar variant has better

prognosis

FALSE POSITIVE AFP•Yolk sac

tumors,• Pregnancy,•Fetal distress, • Cirrhosis, •Massive liver necrosis

Cholangiocarcinoma

• Is carcinoma of bile duct origin• No well known risk factors• Only known influences are

– primary sclerosing cholangitis, – Parasites- Clonorchis sinesis – exposure to Thorotrast

• Cut surface - Firm and Gritty

• M/E- well differentiated tumors• Well defined glandular and tubular

structures• Abundant stroma (Desmoplasia)• Hematogenous and lymphatic metastasis

usually present (More common than HCC)• Death usually occurs with in six months

PANCREAS

Pancreas-Normal

• About 15 cm in length• Weight 60-140 gm• Histologically two separate components• Exocrine & Endocrine pancreas• Exocrine - 80-85%, composed of acini• Endocrine - Islets of Langerhans

Pathological lesions

Inflammatory lesions

Neoplasms

•Acute pancreatitis•Chronic pancreatitis

•Pancreatic Ca•Endocrine tumors

-Insulinomas-Gastrinomas

Acute Pancreatitis• Characterized by acute onset of

abdominal pain resulting from enzymatic necrosis and inflammation of the pancreas

• 80% cases are associated with GALL STONES and ALCOHOLISM

• Other important CAUSES include� Infections –Mumps, Coxsackie and

Mycoplasma

� Acute ischemia – Shock, trauma, vascular thrombosis, embolism, vasculitis etc.

� Hyperlipoproteinemias (uncommon)

� Drugs –Diuretics, Azothioprine,

�Estrogens, sulfonamides etc

Pathogenesis• Basic mechanism is release of

inappropriately activated pancreatic enzymes

• Cause auto digestion of the pancreas• Hence subsequent inflammation• Three proposed mechanisms for release

of these enzymes• All above listed causes lead to one of

these three mechanisms244

PANCREATIC DUCT OBSTRUCTION

• Gall stones• Ductal concretions

PRIMARY ACINAR CELL INJURY

• Drugs• Trauma• Ischemia• viruses

DEFECTIVE INTRA-CELLULARTRANSPORT OF PROENZYMES

• Alcohol• Metabolic injury

Interstitial edema

Impaired blood flow

ischemia

Delivery of proenzymesto lysosomes

ACINAR CELL INJURY

1 2 3

Morphology• Interstitial edema • Focal areas of fat necrosis in pancreas and

peripancreatic tissue• Also in fatty tissue of the abdominal cavity• Appear radiopaque on radiographs• Severe cases –necrosis of pancreatic tissue

(acini, ducts and islets)• If sufficient damage to vessels then hemorrhage

in parenchyma (Hemorrhagic pancreatitis)

• Blue black areas of hemorrhage admixed with chalky areas of fat necrosis

• vacuolated adipocytes are converted to shadowy outlines of cell membranes

• Calcium salts are seen as basophilic masses on microscopy

247

Clinical Features• Pain can vary from mild

to very severe• Usually severe epigastric

pain with nausea and vomiting

• Constant, intense and is referred to upper back

• Release of enzymes, toxins and cytokines in circulation leads to activation of systemic inflammatory response

• OTHER CAUSES OF EPIGASTRIC PAIN (GIT)

• Esophagitis (reflux)• Gastritis • Peptic ulcers• Cholecystitis

• Leucocytosis• DIC• Hemolysis• Peripheral vascular collapse• Shock with ATN, ARDS• Hypocalcemia, tetany• Raised amylase levels in first 24 hours• Followed by lipase with in 72-96 hours• Complications-

• ARDS• ATN• Pancreatic abscess

Pancreatic pseudocyst-• Localized collections of pancreatic

secretions • There occurs drainage of secretions

from ducts into interstitium• no true epithelial lining• Can get infected

Chronic Pancreatitis

• Repeated bouts of mild to moderate pancreatic inflammation with loss of pancreatic parenchyma and its replacement by fibrous tissue

• Common in middle aged alcoholics• Pancreatic divisum in about 12%• Other cause very rare• 40% no obvious cause

Pathogenesis

• Associated :• Ductal obstruction by concretions• Oxidative stress• Decreased secretion of lithostatin (a protein

that inhibits preipitation of calcium carbonate)

• Once interstial fibrosis, further affects ductal secretions

• Densely fibrotic, small sized organ• Hard, ducts may be dilated & may contain

concretions• Irregularly distributed areas of fibrosis• Sparing of Islets (diabetes is not a

common feature)• Chronic mononuclear infiltrate around

lobules and ducts• Some time squamous metaplasia of duct

epithelium

Clinical Features• Repeated attacks of moderately severe pain• Or persistent abdominal and back pain• Later on pancreatic insufficiency and diabetes

may develop• Features of malabsorption, corrected by

pancreatic enzyme supplements• Diagnosed by high degree of suspicion• X ray and CT- calcifications• Pseudocysts in 10% • Moderately increased risk of carcinoma

(Alcohol)

Carcinoma of The Pancreas• Fifth most common cause of death in U.S.• Only convincing association is with

smoking• Other proposed risk factors like alcohol,

diet rich in fats are not consistent• Familial relapsing pancreatitis (very rare

itself) is strongly associated with Carcinoma pancreas

• Head 60-70%• Body 5-10%• Tail 10-15%• Diffuse involvement in 20%• All are adenocarcinomas arising from duct

epithelium• Carcinoma of the head of pancreas

causes obstruction to bile flow

• Ca of Head – early symptoms, jaundice• Ca of body and tail- detected late• Invade adjacent retroperitoneal structures• Usually moderately to poorly differentiated

adenocarcinomas• Well differentiated tumors are very rare• Dense stromal fibrosis (desmoplasia)• Propensity for perineural invasion

Clinical Features• Remain silent till late• Pain is usually first symptom (because of

invasion posterior abdominal wall and nerves• Obstructive jaundice• Trousseau’s sign (migratory thrombophlebitis) in

10%(because of release of platelet activating factors and procoagulants from tumor and its necrotic products)

• No single specific marker• Raised levels of CA 19-9• Very bad prognosis

Islet Cell Tumors

• Neuroendocrine origin• Resemble carcinoids tumors• Functional (elaborate pancreatic enzymes)

or non functional• Insulinomas• Gastrinomas (Zollinger Ellison Syndrome)

Insulinomas• Usually benign, solitary• Arise from ß cells1) Signs and symptoms because of hypoglycemia2) Hypoglycemia accentuated by fasting and

relieved with intake of glucose3) Low blood glucose levels• Aka Whipple’s triad• Insulin levels are increased• Histologically appear as giant islets

Gastrinomas ( Zollinger- Ellison Syndrome)

• Can also arise in duodenum and peripancreatic tissues

• Hypergastrenemia• Multiple ulcers- esophagus, stomach,

duodenum and jejunum• Refractory to conventional treatment

GALL BLADDER

Lesions-Overview

• Cholelithiasis• Acute cholecystitis• Chronic cholecystitis• Carcinoma

Cholelithiasis (Gall Stones)

• 10% population of northern hemisphere of western countries

• More common in Latin American countries• Two main types- Cholesterol and Pigment

stones• Cholesterol stones are more common (80%)

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Risk FactorsCHOLESTEROL STONES

PIGMENT STONES

� Common in western

� Advancing age

� Female sex hormones

�Rapid weight reduction

� Gall bladder stasis

� Hyperlipidemia syndromes

� Common in Asians

� Chronic hemolytic syndromes

� Biliary infections

� Ileal disease e.g. Crohn’sdisease, ilealresection and cystic fibrosis of pancreas

Pathogenesis

Cholesterol stones Pigment stones

Biliary lipid

Supersaturation

Gall bladder hypomotility & cholesterol nucleation

Cholesterol monohytrate crystals

Accretion

Cholesterol stones

Promoters are mucus hypersecretion, hypomoility & ca salts

Hemolysis Infection of the biliary tract

Release of microbial � glucuronidases

Hydrolysis of bilirubin glucuronides

Unconjugate d bilirubin Calcium salts

PIGMENT STONES

+

Morphology• CHOLESTEROL STONES• Pure cholesterol stones are pale yellow• With increasing proportion of calcium carbonate,

phosphates and bilirubin exhibit discoloration• Multiple and faceted• Granular and hard external surface• Glistening radiating crystalline palisade• Mostly radiolucent• Cholesterolosis-excess cholesterol esters

accumulate in lamina propria and look like yellow flecks

• PIGMENT STONES• Black usually in sterile bile• Brown in infected biliary tract• Mainly composed of ca salts of bilirubin • Black stones are multiple and crumble on

touch• Brown stones are few in number & are

soapy in consistency (retain fatty acids because of bacterial phospholipases)

• Are radio opaque (Ca content)

Clinically• 70-80% asymptomatic• May present with pain constant or colicky • Complications include�Empyema�Perforation �Fistulas �Cholangitis�Pancreatitis�Gall stone ileus� Increased risk of carcinoma

Cholecystitis

ACUTE CHRONIC ACUTE ON CHRONIC

Calculous Acalculous Calculous Acalculous(Common)

(Rare, occurs in severly ill

patients)

Acute Cholecystitis (Pathogenesis)

Chemical irritation and inflammation in setting of obstruction to flow

Mucosal phospholipase convert lecithin to lysolecithin

Damage to glycoprotein layer of mucosa

Further release of prostaglandins from mucosa

All these events lead to mucosal & mural inflammation

Gall bladder dysmotility and increased intraluminal pressure

Later on bacterial contamination

• Enlarged tense gall bladder• Reddish, blotchy or greenish black

external surface• Lumen contains stones

some times pus (Empyema gall bladder)• Wall is edematous & thickened• Severe cases gangrene

Clinically

• Pain right hypochondrium or epigastrium • May appear like surgical emergency• Associated fever, nausea and vomiting• Rarely jaundice if obstruction of CBD• Most patients recover

Chronic Cholecystitis

• Can be sequel of repeated bouts of acute cholecystitis

• BUT more commonly no antecedent attacks of acute cholecystitis

• Role of gall stones is not clear• Microorganisms can be cultured from bile

in one third patients

Morphology• Serosa usually smooth and glistening but

some times granular because of fibrosis • Wall is thickened• Lumen usually contain stones or clear

secretions (Hydrops gall bladder) – Mucosa is normal– Sub epithelial and sub serosal fibrosis– Mononuclear infiltrate

• Rarely extensive dystrophic calcification k. a. PORCELAIN GALL BLADDER (increased association with cancer)

Carcinoma Gall Bladder

• Occurs in seventh decade of life• Slightly more common in females• Stones in 60-90% patients• Other risk factors include pyogenic and

parasitic infections of the biliary tract• Carcinogenic derivatives of bile may play a

role

• Infiltrating or exophytic type• Some times poorly defined seen as diffuse

thickening and induration of gall bladder• Fundus is the most common site• Some have papillary architecture • Most invade liver by the time they are

discovered