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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
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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
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