GIT Pathology PDF - Dr. C. C. Chemonges

PATHOLOGY OF THE GIT DR. C. C. CHEMONGES ⦿ CONGENITAL ANOMALIES ⦿ ESOPHAGUS ⦿ STOMACH ⦿ SMALL INTESTINE ⦿ COLON ⦿ PERITONEUM ⦿ ATRESIA ⦿ FISTULA ⦿ DUPLICATIONS ⦿ DIAPHRAGMATIC HERNIA ⦿ ECTOPIA ⦿ MECKEL’S DIVERTICULA ⦿ PYLORIC STENOSIS ⦿ HIRSCHSPRUNG DISEASE ⦿ DIFFERENCE BETWEEN AGENESIS(NOT...

PATHOLOGY OF THE GIT DR. C. C. CHEMONGES ⦿ CONGENITAL ANOMALIES ⦿ ESOPHAGUS ⦿ STOMACH ⦿ SMALL INTESTINE ⦿ COLON ⦿ PERITONEUM ⦿ ATRESIA ⦿ FISTULA ⦿ DUPLICATIONS ⦿ DIAPHRAGMATIC HERNIA ⦿ ECTOPIA ⦿ MECKEL’S DIVERTICULA ⦿ PYLORIC STENOSIS ⦿ HIRSCHSPRUNG DISEASE ⦿ DIFFERENCE BETWEEN AGENESIS(NOT FORMED) AND ATRESIA (INCOMPLETE DEVELOPMENT) ⦿ ATRESIA OFTEN ASSOCIATED WITH FISTULA EX-ESOPHAGEAL ATRESIA WITH TRACHEOESOPHAGEAL FISTULA/DUODENAL ATRESIA/IMPERFORATE ANUS ⦿ STENOSIS-LUMEN REDUCED PARTIAL OR COMPLETE ⦿ OMPHALOCOELE-CLOSURE OF ABDOMINAL MUSCULATURE INCOMPLETE ⦿ GASTROSCHISIS-INVOLVES ALL LAYERS OF ABDOMINAL WALL FROM PERITONEUM TO SKIN ⦿ ECTOPIC GASTRIC MUCOSA –INLET PATCH ⦿ ECTOPIC PANCREATIC MUCOSA ⦿ GASTRIC HETEROTOPIA ` ⦿ Congenital abnormality of small intestine resulting from persistence of omphalomesenteric duct (vitelline duct) ⦿ It is true diverticulum ( containing al three layers of bowel wall ) ⦿ Vitelline duct or omphalomesenteric duct anomalies are secondary to the persistence of the embryonic vitelline duct, which normally obliterates by weeks 5–9 of intrauterine life ⦿ Meckel’s diverticulum is the most common vitelline duct anomaly During week 3 of gestation, the mid gut is open into the yolk sac, which does not grow rapidly the as of the Subsequentl as embryo. 5, y, with the yolk sac restbecomes by the narrowed connection and is then termed a yolk stalk, vitelline duct, or week omphalomesenteric duct. Normally, the vitelline duct disappears by gestational week 9, just before the mid gut returns to the abdomen ⦿ Meckel diverticulum ( rule of two) ⦿ Occur in 2% of population ⦿ 2 inch long ⦿ 2 feet from ileocecal valve ⦿ In child younger than age2 ⦿ 2 type of tissue ( ectopic stomach or pancreas ) ⦿ not attached to the abdominal wall but it is one of the most unlikely to cause symptoms. About 4% of children with a Meckel’s diverticulum develop symptoms, and more than 60% of those who develop symptoms are younger than 2 years of age.2– 5 The male-to-female complication rate ratio is about 3:1 ⦿Most complications of these abnormalities are related to ectopic tissue (gastric, pancreatic, colonic, endometriosis, or hepatobiliary). Ectopic gastric tissue usually causes bleeding from ulceration of the adjacent ileal mucosa. The ileal mucosa is not equipped to buffer the acid produced by the ectopic gastric mucosa and thus is prone to ulceration. ulceration. The site of the ulceration is most often at the junction of the normal ileal mucosa and the ectopic ⦿ Intestinal obstruction may be caused by a Meckel’s diverticulum attached to the umbilicus by a fibrous cord or by a fibrous cord between the ileum and the umbilicus and can also occur by intussusception with the diverticulum ⦿ Ulceration ⦿ Hemorrhage ⦿ Small bowel o bstruction ⦿ Diverticulitis ⦿ Perforation ⦿ The classic presentation is an older infant or young child with painless rectal bleeding (This usually consists of a large volume of bright red bleeding but can occasionally also present as dark, tarry stools) ⦿ Malena may be episodic and usually ceases without treatment; sometimes the malena is insidious and not appreciated by the family. In a young child with haemoglobin positive stools and a chronic iron deficiency anemia, the diagnosis of Meckel’s diverticulum should be considered ⦿ Intestinal obstruction, usually due to intussusception, is the most typical presentation in newborns and infants. The symptoms include crampy abdominal pain, bilious vomiting, currant-jelly stools, and abdominal distention ⦿ intestinal ischemia, such as acidosis, peritonitis, and shock, may occur first, and can be fatal in infants. ⦿ Patients with Meckel’s diverticulitis often have symptoms that resemble appendicitis. They are usually older children. Peri- umbilical pain is the first symptom. They usually do not have the same amount or intensity of vomiting and nausea ⦿ Diagnosis of a symptomatic vitelline duct malformation is dependent on the anatomic configuration and its presentation, signs, and symptoms. History and physical examination are important for the diagnosis ⦿ A complete description of the quality and frequency of the bloody stools is necessary in patients with rectal bleeding. Rectal examination and lower endoscopy is useful to identify other ⦿The test of choice for a bleeding Meckel’s diverticulum is a (Meckel’s scan), which concentrates the isotope in ectopic gastric mucosa ⦿ If obstruction from either intussusception or volvulus is suspected, plain x-rays may reveal dilated bowel loops and multiple air-fluid levels. ⦿ Symptomatic children with omphalomesenteric duct remnants should be resuscitated before intervention. Those with significant hemorrhage should be transfused ⦿ The incision chosen varies with the symptoms and the age of the patient o Children with Meckel’s diverticulitis or a bleeding Meckel’s diverticulum are operated on by using a transverse appendectomy incision with medial extension if necessary. Patients with suspected intestinal obstruction should be explored through a generous laparotomy incision. ` ⦿ Hallmark is non-bilious vomiting ⦿ Other signs include abdominal distention and bleeding from secondary inflammation ⦿ Most common cause of non-bilious vomiting is infantile hypertrophic pyloric stenosis ⦿ First described by Hirschsprung in 1888 ⦿ Ramstedt described an operative procedure to alleviate the condition in 1907 – the procedure used to this day to treat pyloric stenosis ⦿ 3/1000 live births – frequency may be increasing ⦿ Most common in whites of Northern European ancestry, less common in African Americans and rare in Asians ⦿ Four times more common in males – especially firstborn ⦿ Increased in infants with type B or O blood groups ⦿ Associated with other congenital defects incl TEF ⦿Cause is unknown, but abnormal muscle innervation, breast feeding and maternal stress in the 3rd trimester have been implicated ⦿ Elevated serum PG’s, reduced levels of pyloric nitric oxide synthase and infant hypergastrinemia have been found ⦿ Non-bilious vomiting is the initial symptom ⦿ May or may not be projectile initially ⦿ Usually progressive, occurs immediately after a feeding ⦿ Vomiting usually starts after 3 wks of age, but may develop as early as 1st week and as late as the 5th month ⦿ After vomiting, infant is hungry and wants to feed again ⦿ Progressive loss of fluid, hydrogen ion and chloride leads to a hypochloremic metabolic alkalosis. ⦿ Serum K levels are maintained ⦿ Greater awareness has led to earlier diagnosis ⦿ Jaundice occurs in 5% of infants with pyloric stenosis – associated with a decreased level of glucuronyl transferase ⦿ Diagnosis traditionally made by palpation of mass ⦿ Firm, movable, approx 2 cm in length, olive shaped and best palpated from the left ⦿ Mass located above and to the right of the umbilicus in the midepigastrum beneath the liver edge ⦿ Peristaltic wave may be present prior to emesis ⦿ Straightforward if olive is present ⦿ Difficult to distinguish from GERD esp in early stages ⦿ UGI or US can be used – but US has become the standard at most centers ⦿ Ultrasound – Sensitivity of 90% ⦿ Criteria for diagnosis – pyloric muscle thickness greater than 4 mm and an overall pyloric muscle length greater than 14mm ⦿ US pitfalls – pylorospasm may mimic those of PS, potential false-pos and false- negative readings ⦿ UGI – classic signs are elongated pyloric canal, the “double tract” sign (parallel streaks of barium in the narrowed channel, and the “shoulder sign”(bulge of pyloric muscle into the antrum). ⦿ Main pitfall of UGI is radiation exposure ⦿ Infants who are reactive to external stimulation, those fed by inexperienced caretakers, or those for whom adequate maternal-infant bonding has not been established may vomit frequently in the early weeks of life. ⦿ GERD with or without a hiatal hernia may be confused with PS esp in the early stages ⦿ Inborn errors of metabolism may produce recurrent emesis with alkalosis or acidosis and lethargy, coma or seizures. ⦿ Salt-losing CAH presents with prominent vomiting shortly after birth. Females will be virilized, but the genitals appear normal in males. Acidosis and hyperkalemia usually present. ⦿ Vomiting with diarrhea suggests gastroenteritis. ⦿ Always have to think of increased ICP, subdural hematoma ⦿ Systemic infections can also cause persistent vomiting. ⦿ Preoperative treatment is directed toward correcting the fluid/acid-base and electrolyte imbalances. ⦿ Correction of the alkalosis is essential to prevent postoperative apnea ⦿ Surgery is the treatment of choice – Ramstedt pyloromyotomy ⦿ Ramstedt pyloromyotomy – performed through a short transverse incision or laparoscopically ⦿ Underlying pyloric mass is split without cutting the mucosa and the incision is closed ⦿ Post-op vomiting occurs in ½ the patients and thought to be due to edema of the pylorus ⦿ Feedings can usually be initiated within 12-24 hours ⦿ Persistent vomiting suggests an incomplete pyloromyotomy, gastritis, GERD. ⦿ Surgical treatment is curative with a low mortality rate `  Hirschsprung’s disease is the most common cause of lower intestinal obstruction in neonates. Hirschsprung’s disease (aganglionic megacolon) is a congenital anomaly caused by migratory failure of neural crest cells leading to abnormal innervations of the bowel. The defect begins in the internal anal sphincter and extends proximally for a variable length of gut ⦿ INCIDENCE: 1\5000 live birth newborn ⦿ 70-80% is boys. (M / F. 4: 1 ) ⦿ Less common in blacks. ⦿ The fundamental pathology in HD is the absence of ganglion cells in the submucosal and intermuscular nerve plexuses and is associated with an increase in the nerve fibers in the affected segment. ⦿ That aganglionic segment usually involves the terminal intestine, i.e. the rectum or recto sigmoid. The aganglionic segment may, however, include the entire large bowel and even small bowel.. ⦿ The colon proximal to the aganglionic segment, in an effort to overcome the partial obstruction, becomes distended and its wall markedly thickened because of muscle hypertrophy ⦿ The degree of hypertrophy and dilatation depends upon the duration and degree of obstruction and thus, indirectly to the age of the patient. 1. Congenital : This type is the commonest ◾ one. Etiology of the disease is still unknown.but Genetic factors are now ◾ identified. %10 of cases have familial history, especially those with long segment disease. 2. Acquired : Degeneration of the ganglions may occur due to: -Vascular causes like after pull through procedure due to ischemia & tension. - Non vascular causes like Trypanosoma (chaga's disease). Vitamin B1 def. Chronic infection ( TB.). ◾ HD is usually a solitary anomaly in a full term, otherwise healthy infant ◾ Associated anomalies do occur in nearly 20% of cases  urogenital system (11%)  cardiovascular system (6%)  gastrointestinal system (6%),  with 8% having various other malformations ◾ Prematurity is reported in as many as 10% of those children with HD ◾ Trisomy 21 occurs in approximately 5% of 1. Failure to pass meconium in the 1st 24h of life 98% of neonates pass meconium in the first 24 hours of age.. Any newborn who fails to pass meconium in the first 24-48 hours of life should be evaluated for possible Hirschsprung's disease. 2. Neonatal Intestinal obstruction symptoms include bilious vomiting, abdominal distension and refusal to feed. 3. Recurrent Enterocolitis 4. TOXIC MEGACOLON : Fever. Abdominal distension. Bile stained vomitus. Explosive diarrhea. 5. Dehydratio perforation Spontaneous 3%,specially n.in Shock. if long segment occurs aganglionosis. 6. chronic Chronic constipation constipation in response patients to may in feeding. And may have changes have retardation. Growth Multiple fecal masses abdominal on examination. History failure to pass meconium, painless abdominal distension & constipation) Physical examinations Distended abdomen with Multiple fecal masses on abdominal examination on DRE characteristically there is  Radiolo gy1. Plain x-rays of the abdomen :Erect & supine 2. Contrast Enema. Shows narrow distal segment, funnel- shaped dilatation at level of transition zone with marked dilatation of the proximal colon. 24-hrs delayed films is important in diagnosis; it shows poor emptying with barium throughout the colon, as opposed to the child with psychogenic stool holding in whom the barium generally collects in the distal recto sigmoid. ⦿ ` Rectal biopsy : ◾ Rectal biopsy is the definitive diagnostic test and demonstrates absence of ganglion cells, nerve hypertrophy and stains indicating increased acetyl cholinesterase activity. ◾ suction mucosal biopsy (at different levels ). Can be done without anesthesia ◾ full thickness biopsy is done under general anesthesia. Electromanometry : ◾ not useful in neonate ◾ excellent screening tool in infant & children. ◾ The classic finding is the absence of the recto anal inhibitory reflex when the rectum is distended. measure pressure in the ◾ A balloon isforinflated UltraSonography: area in the associated rectum to anomalies Treatment : Decompression: introduce a rectal ⦿ tube and irrigation ⦿ Colostomy ⦿ Definitive procedures ⦿ Closing of the stoma ⦿ Chronic ◾ laxative constipation : ◾ saline enema. ◾ Work up to establish the diagnosis ◾then the definitive treatment will be planned Open surgery : There are many surgical options for Pull- through operation. All aiming at resection of aganglionic segment and anastomosing the two normal ganglionic ends. They give excellent result in 90%. a.swenso n. b.soave. c.Rehbein. d. Treatmen transanal Endorectal Pull-Trough T ⦿ It can be performed safely in infant as well ⦿ Generally one-stage surgery ⦿ No abdominal phase ⦿ The anastomosis is happening in a „safe” place at the pectinate line 1. anastomotic leak. 2. stricture. 3. retraction of the colon. 4. fecal incontinence (soiling or encopresis ). 5. persistent constipation  Feature Functional Hirschsprung’s Constipation Disease Onset 2 - 3 years At birth Delayed passage of meconium Rare Common Obstructive symptoms Rare Common Withholding behavior Common Rare Fear of defecation Common Rare Fear of incontinence Common Rare Stool size Very large Small, ribbon-like Poor growth Rare Common Enterocolitis Never Possible Rectal ampulla Enlarged Narrowed Stool in ampulla Common Rare Barium enema Lg amount of stools, Transitional zone, delayed no transitional zone emptying Anorectal manometry Normal Absent rectosphincteric refl ex Rectal biopsy Normal No ganglion cells, nerve hypertrophy and increase acetylcholinesterase activity ⦿ It is a hollow, highly distensible muscular tube that extends from the epiglottis to the gastroesophageal junction, located just above the diaphragm. ⦿ OBSTRUCTIVE AND VASCULAR DISEASES ⦿ ESOPHAGITIS ⦿ ESOPHAGEAL TUMORS ⦿ MECHANICAL-STENOSIS/ AGENESIS/ ESPHAGEAL WEB/LYE STRICTURES ⦿ FUNCTIONAL-NUT CRACKER ESOPHAGUS/DIFFUSE ESOPHAGEAL SPASM/ACHALASIA CARDIA ⦿ ESOPHAGEAL VARICES- dilated splanchno systemic junctional veins in esophagus ⦿ PATHOGENESIS One of the few sites where the splanchnic and systemic venous circulations can communicate is the esophagus. ⦿ Thus, portal hypertension induces development of collateral channels that allow portal blood to shunt into the caval system. ⦿ However, these collateral veins enlarge the subepithelial and submucosal venous plexi within the distal esophagus. ⦿ These vessels, termed varices, develop in 90% of cirrhotic patients, most commonly in association with alcoholic liver disease. ⦿ Worldwide, hepatic schistosomiasis is the ⦿ MORPHOLOGY Varices can be detected by angiography and appear as tortuous dilated veins lying primarily within the submucosa of the distal esophagus and proximal stomach. ⦿ Varices may not be obvious on gross inspection of surgical or postmortem specimens, because they collapse in the absence of blood flow. ⦿ The overlying mucosa can be intact but is ulcerated and necrotic if ⦿ Clinical Features Varices often are asymptomatic, but their rupture can lead to massive hematemesis and death. ⦿ Variceal rupture therefore constitutes a medical emergency. ⦿ Lacerations- Mallory Weiss tear/ boerhaave syndrome ⦿ Chemical and Infectious Esophagitis ⦿ Reflux esophagitis ⦿ Eosinophilic esophagitis ⦿ Barrett’s esophagus ⦿ Often associated with severe retching or vomiting, as may occur with acute alcohol intoxication. ⦿ Normally, a reflex relaxation of the gastroesophageal musculature precedes the antiperistaltic contractile wave associated with vomiting. ⦿ This relaxation is thought to fail during prolonged vomiting, with the result that refluxing gastric contents overwhelm the gastric inlet and cause the esophageal wall to stretch and tear. ⦿ Patients often present with hematemesis. ⦿ The roughly linear lacerations of Mallory-Weiss syndrome are longitudinally oriented, range in length from millimetres to several centimeters, and usually cross the gastroesophageal junction. ⦿ Boerhaave syndrome, characterized by transmural esophageal tears and mediastinitis, occurs rarely and is a catastrophic event. ⦿The stratified squamous mucosa of the esophagus may be damaged by a variety of irritants including alcohol, corrosive acids or alkalis, excessively hot fluids, and heavy smoking. ⦿ Infectious esophagitis may occur in otherwise healthy persons but is most frequent in those who are debilitated or immunosuppressed ⦿ The stratified squamous epithelium of the esophagus is resistant to abrasion from foods but is sensitive to acid. ⦿ The submucosal glands of the proximal and distal esophagus contribute to mucosal protection by secreting mucin and bicarbonate. ⦿ More important, constant LES tone prevents reflux of acidic gastric contents, which are under positive pressure. ⦿ Reflux of gastric contents into the lower esophagus is the most frequent cause of esophagitis. The associated clinical condition is termed gastroesophageal reflux disease (GERD. ⦿ MORPHOLOGY --- Simple hyperemia, may be the only alteration. In mild GERD the mucosal histology is often unremarkable. ⦿ With more significant disease, eosinophils are recruited into the squamous mucosa, followed by neutrophils, which usually are associated with more severe injury. ⦿ Basal zone hyperplasia exceeding 20% of the total epithelial thickness and elongation of lamina propria papillae, such that they extend into the upper third of the epithelium, also ⦿ The most frequently reported symptoms are heartburn, dysphagia, and, less often, noticeable regurgitation of sour-tasting gastric contents. ⦿ Rarely, chronic GERD is punctuated by attacks of severe chest pain that may be mistaken for heart disease. ⦿ Food impaction and dysphagia in adults and feeding intolerance or GERD-like symptoms in children. ⦿ The cardinal histologic feature is epithelial infiltration by large numbers of eosinophils, particularly superficially and at sites far from the gastroesophageal junction. ⦿ Treatments include dietary restrictions to prevent exposure to food allergens, such as cow milk and soy products, and topical or systemic ⦿ Barrett esophagus is a complication of chronic GERD that is characterized by intestinal metaplasia within the esophageal squamous mucosa. ⦿ Males are affected most often and typically present between 40 and 60 years of age. ⦿ The greatest concern in Barrett esophagus is that it confers an increased risk of esophageal adenocarcinoma. ⦿ Barrett esophagus is recognized endoscopically as tongues or patches of red, velvety mucosa extending upward from the gastroesophageal junction. ⦿ This metaplastic mucosa alternates with residual smooth, pale squamous (esophageal) mucosa proximally and interfaces with light-brown columnar (gastric) mucosa distally. ⦿ Goblet cells, which have distinct mucous vacuoles that stain pale blue by H&E and impart the shape of a wine goblet to the remaining cytoplasm, define intestinal metaplasia and are a feature of Barrett esophagus ⦿ Adenocarcinoma ⦿ Squamous cell carcinoma ⦿ Esophageal adenocarcinoma typically arises in a background of Barrett esophagus and long-standing GERD. ⦿ Risk of adenocarcinoma is greater in patients with documented dysplasia and is further increased by tobacco use, obesity, and previous radiation therapy. ⦿ Esophageal adenocarcinoma occurs most frequently in whites and shows a strong gender bias, being seven times more common in men ⦿ PATHOGENESIS Molecular studies suggest that the progression of Barrett esophagus to adenocarcinoma occurs over an extended period through the stepwise acquisition of genetic and epigenetic ⦿ changes. ⦿ This model is supported by the observation that epithelial clones identified in non dysplastic Barrett metaplasia persist and accumulate mutations during progression to dysplasia and invasive carcinoma. ⦿ Chromosomal abnormalities and TP53 mutation are often present at early stages of esophageal adenocarcinoma. ⦿ Additional genetic changes and inflammation also are thought to contribute ⦿ MORPHOLOGY ⦿ Esophageal adenocarcinoma usually occurs in the distal third of the esophagus and may invade the adjacent gastric cardia. ⦿ While early lesions may appear as flat or raised patches in otherwise intact mucosa, tumors may form large exophytic masses, infiltrate diffusely, or ulcerate and invade deeply. ⦿ On microscopic examination, Barrett esophagus frequently is present adjacent to the tumor. Tumors typically produce mucin and form ⦿ CLINICAL FEATURES pain or difficulty in swallowing, progressive weight loss, chest pain, or vomiting. ⦿ As a result of the advanced stage at diagnosis, the overall 5-year survival rate is less than 25%. ⦿ esophageal squamous cell carcinoma typically occurs in adults older than 45 years of age and affects males four times more frequently than females. ⦿ Risk factors include alcohol and tobacco use, poverty, caustic esophageal injury, achalasia, Plummer- Vinson syndrome, frequent consumption of very hot beverages, and previous radiation therapy to the mediastinum. ⦿ PATHOGENESIS ⦿ A majority of esophageal squamous cell carcinomas are at least partially attributable to the use of alcohol and tobacco, the effects of which synergize to increase risk. ⦿ Nutritional deficiencies, as well as polycyclic hydrocarbons, nitrosamines, and other mutagenic compounds, such as those found in fungus-contaminated foods, have been considered as possible risk factors. ⦿ HPV infection also has been implicated in esophageal squamous cell carcinoma. ⦿ The molecular pathogenesis of ⦿ In contrast to the distal location of most adenocarcinomas,half of squamous cell carcinomas occur in the middle third of the esophagus. ⦿ Squamous cell carcinoma begins as an in situ lesion in the form of squamous dysplasia. ⦿ Early lesions appear as small, gray- white plaquelike thickenings. ⦿ Over months to years they grow into tumor masses that may be polypoid and protrude into and obstruct the lumen. ⦿ Other tumors are either ulcerated or diffusely infiltrative lesions that spread within the esophageal wall, where they cause thickening, rigidity, and luminal ⦿ Clinical manifestations of squamous cell carcinoma of the esophagus begin insidiously and include dysphagia, odynophagia (pain on swallowing), and obstruction. ⦿ As with other forms of esophageal obstruction, patients may unwittingly adjust to the progressively increasing obstruction by altering their diet from solid to liquid foods. ⦿ Extreme weight loss and debilitation result from both impaired nutrition and effects of the tumor itself. Haemorrhage and sepsis may ⦿. ⦿ INFLAMMATORY DISEASE OF THE STOMACH ⦿ NEOPLASTIC DISEASE OF THE STOMACH ⦿ The stomach is divided into four major anatomic regions: the cardia, fundus, body, and antrum. ⦿ The cardia is lined mainly by mucin- secreting foveolar cells that form shallow glands. ⦿ The antral glands are similar but also contain endocrine cells, such as G cells, that release gastrin to stimulate luminal acid secretion by parietal cells within the gastric fundus and body. ⦿ The well-developed glands of the body and fundus also contain chief cells that ⦿ ACUTE GASTRITIS ⦿ ACUTE PEPTIC ULCER ⦿ CHRONIC GASTRITIS ⦿ PEPTIC ULCER DISEASE ⦿ Transient mucosal inflammatory process that may be asymptomatic or cause variable degrees of epigastric pain, nausea, and vomiting. ⦿ In more severe cases there may be mucosal erosion, ulceration, hemorrhage,hematemesis, melena, or, rarely, massive blood loss Damaging Forces: 1. Gastric acidity & 2.Peptic enzymes Defensive Forces: 1.Surface mucus secretion 2.Bicarbonate secretion into mucus 3.Mucosal blood flow 4.Apical surface membrane transport 5.Epithelial regenerative capacity ⦿ H. pylori infection ⦿ NSAID ⦿ Aspirin ⦿ Cigarettes ⦿ Alcohol ⦿ Gastric hyperacidity ⦿ Duodenal-gastric reflux ⦿ Ischemia ⦿ Shock ⦿ Delayed gastric ⦿ emptying ⦿ Host factors ⦿ The lamina propria shows only moderate edema and slight vascular congestion. ⦿ The surface epithelium is intact, although scattered neutrophils may be present. ⦿ With more severe mucosal damage, erosion, or loss of the superficial epithelium, may occur, leading to formation of mucosal neutrophilic infiltrates and purulent exudates. ⦿ Hemorrhage also may occur, manifesting as dark puncta in an otherwise hyperemic mucosa. ⦿ Stress ulcers, most commonly affecting critically ill patients with shock, sepsis, or severe trauma ⦿ Curling ulcers, occurring in the proximal duodenum and associated with severe burns or trauma ⦿ Cushing ulcers, arising in the stomach, duodenum, or esophagus of persons with intracranial disease, have a high incidence of perforation ⦿ Acute ulcers are rounded and typically are less than 1 cm in diameter. ⦿ The ulcer base frequently is stained brown to black by acid digested extravasated red cells, in some cases associated with transmural inflammation and local serositis. ⦿ Lesions may occur singly, more often multiple ulcers are present within the stomach and duodenum. ⦿ Acute stress ulcers are sharply demarcated, with essentially normal adjacent mucosa, although there may be suffusion of blood into the mucosa and submucosa and some inflammatory reaction. ⦿ Healing with complete re- epithelialization occurs days or weeks after the injurious factors are removed. ⦿ Symptoms of gastric ulcers include nausea, vomiting, and coffee-ground hematemesis. ⦿ The symptoms and signs associated with chronic gastritis typically are less severe but more persistent than those of acute gastritis ⦿ hematemesis is uncommon. ⦿ The most common cause of chronic gastritis is infection with the bacillus Helicobacter pylori. ⦿ Autoimmune gastritis, the most common cause of atrophic gastritis, represents less than 10% of cases of chronic gastritis and is the most common form of chronic gastritis in patients without H. pylori infection. ⦿ These spiral-shaped or curved bacilli are present in gastric biopsy specimens from almost all patients with duodenal ulcers and a majority of those with gastric ulcers or chronic gastritis. ⦿ The increased acid secretion that occurs in H. pylori gastritis may result in peptic ulcer disease of the stomach or duodenum; H. pylori infection also confers increased risk of gastric cancer ⦿ The incidence of H. pylori infection correlates most closely with sanitation and hygiene during an individual’s childhood ⦿ H. pylori infection most often manifests as a predominantly antral gastritis with high acid production, despite hypogastrinemia ⦿ Adhesins, which enhance bacterial adherence to surface foveolar cells ⦿ Toxins, such as that encoded by cytotoxin- associated gene A (CagA), that may be involved in ulcer ⦿ Four features are linked to H. pylori virulence: ⦿ Flagella, which allow the bacteria to be motile in viscous mucus ⦿ Urease, which generates ammonia from endogenous urea, thereby elevating local gastric pH around the organisms and protecting the bacteria from the acidic pH of the stomach. ⦿ Gastric biopsy specimens generally demonstrate H. Pylori in infected persons ⦿ The organism is concentrated within the superficial mucus overlying epithelial cells in the surface and neck regions. ⦿ Lymphoid aggregates, some with germinal centres, frequently are present and represent an induced form of mucosa- associated lymphoid tissue (MALT) that has the potential to transform into ⦿ Intestinal metaplasia, characterized by the presence of goblet cells and columnar absorptive cells, also may be present and is associated with increased risk of gastric adenocarcinoma. ⦿ H. pylori shows tropism for gastric foveolar epithelium and generally is not found in areas of intestinal metaplasia, acid- producing mucosa of the gastric body, or duodenal epithelium ⦿ An antral biopsy is preferred for evaluation of H. pylori gastritis. ⦿ Less than 10% of cases of chronic gastritis ⦿ Typically spares the antrum and induces hypergastrinemia ⦿ Antibodies to parietal cells and intrinsic factor that can be detected. ⦿ Reduced serum pepsinogen I levels ⦿ Antral endocrine cell hyperplasia ⦿ Vitamin B12 deficiency ⦿ Defective gastric acid ⦿ Autoimmune gastritis is associated with loss of parietal cells, which secrete acid and intrinsic factor. ⦿ Deficient acid production stimulates gastrin release, resulting in hypergastrinemia and hyperplasia of antral gastrin-producing G cells. ⦿ Lack of intrinsic factor disables ileal vitamin B12 absorption, leading to B12 deficiency and megaloblastic anemia (pernicious anemia); reduced serum concentration of pepsinogen I reflects chief cell loss. ⦿ Autoimmune gastritis is characterized by diffuse damage of the oxyntic (acid- producing) mucosa within the body and fundus. ⦿ Damage to the antrum and cardia typically is absent or mild. ⦿ With diffuse atrophy, the oxyntic mucosa of the body and fundus appears markedly thinned, and rugal folds are lost. ⦿ Neutrophils may be present, but the inflammatory infiltrate more commonly is composed of lymphocytes, macrophages, and plasma cells ⦿ Antibodies to parietal cells and intrinsic factor are present early in disease, but pernicious anemia develops in only a minority of patients. ⦿ The median age at diagnosis is 60 years, and there is a slight female predominance. ⦿ Autoimmune gastritis often is associated with other autoimmune diseases ⦿ Peptic ulcer disease (PUD) most often is associated with H. pylori infection or NSAID use. ⦿ In the US, the latter is becoming the most common cause of gastric ulcers as H. Pylori infection rates fall and low-dose aspirin use in the aging population increases. ⦿ PUD may occur in any portion of the gastrointestinal tract exposed to acidic gastric juices but is most common in the gastric antrum and first portion of the duodenum. ⦿ Peptic ulcers are solitary in more than 80% of patients. ⦿ Lesions less than 0.3 cm in diameter tend to be shallow, whereas those over 0.6 cm are likely to be deeper. ⦿ The classic peptic ulcer is a round to oval, sharply punched-out defect. ⦿ The base of peptic ulcers is smooth and clean as a result of peptic digestion of exudate and on histologic examination is composed of richly vascular granulation tissue. ⦿ Ongoing bleeding within the ulcer base may cause life-threatening hemorrhage. ⦿ Perforation is a complication that demands emergent surgical intervention. ⦿ Peptic ulcers are chronic, recurring lesions that occur most often in middle-aged to older adults without obvious precipitating conditions, other than chronic gastritis. ⦿ A majority of peptic ulcers come to clinical attention after patient complaints of epigastric burning or aching pain, although a significant fraction manifest with complications such as iron deficiency anemia, frank hemorrhage, or perforation. ⦿ The pain tends to occur 1 to 3 hours after meals during the day, is worse at night, and is relieved by alkali or food A. Gastric Polyps- 1. Inflammatory and Hyperplastic Polyps 2. Fundic Gland Polyps 3. Gastric Adenoma B. Gastric Adenocarcinoma. C. Lymphoma D. Carcinoid Tumor E. Gastrointestinal Stromal Tumor ⦿ Polyps, nodules or masses that project above the level of the surrounding mucosa, are identified in up to 5% of upper gastrointestinal tract endoscopies ⦿ The polyps frequently are multiple and characteristically are ovoid in shape, less than 1 cm in diameter, and covered by a smooth surface. ⦿ On microscopic examination, polyps have irregular, cystically dilated, and elongated foveolar glands. ⦿ The lamina propria typically is edematous with variable degrees of acute and chronic inflammation, and surface erosions may be present. ⦿ The frequency with which dysplasia, a precancerous in situ lesion, develops in inflammatory or hyperplastic polyps correlates with size; there is a significant increase in risk in polyps larger than 1.5 cm. ⦿ Fundic gland polyps occur sporadically and in persons with familial adenomatous polyposis (FAP) but do not have neoplastic potential. ⦿ Their incidence has increased markedly as a result of the use of proton pump inhibitors. ⦿ This likely results from increased gastrin secretion, in response to reduced acidity, and glandular hyperplasia driven by gastrin. ⦿ Fundic gland polyps may be asymptomatic or associated with nausea, vomiting, or epigastric pain. ⦿ These well-circumscribed polyps occur in the gastric body and fundus, often are ⦿ 10% of all gastric polyps ⦿ Patients usually are between 50 and 60 years of age ⦿ Males are affected three times more often than females ⦿ Adenomas almost always occur on a background of chronic gastritis with atrophy and intestinal metaplasia ⦿ The risk For development of adenocarcinoma in gastric adenomas is related to the size of the lesion and is particularly elevated with lesions greater than 2 cm in diameter. ⦿ Gastric adenomas are most commonly located in the antrum and typically are composed of intestinal-type columnar epithelium ‘ ⦿ All gastrointestinal adenomas exhibit epithelial dysplasia, which can be classified as low- or high grade ⦿ The most common malignancy of the stomach ⦿ More than 90% of all gastric cancer ⦿ Early symptoms resemble those of chronic gastritis, including dyspepsia, dysphagia, and nausea ⦿ Gastric cancer rates vary markedly with geography ⦿ Gastric cancer is more common in lower socioeconomic groups and in persons with multifocal mucosal atrophy and intestinal metaplasia ⦿ Gastric cancers are genetically heterogeneous but certain molecular alterations are common. ⦿ Mutations Germline mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, usually of the diffuse type. ⦿ patients with familial adenomatous polyposis (FAP) who have germline mutations adenomatous polyposis coli (APC) genes have an increased ⦿ Sporadic intestinal-type gastric cancer is associated with several genetic abnormalities including acquired mutations of β-catenin, a protein that binds to both E-cadherin and APC protein; microsatellite instability; and hypermethylation of genes including TGF βRII, BAX, IGFRII, and p16/INK4a. ⦿ TP53 mutations are present in a majority of sporadic gastric cancers of both histologic types. ⦿ H. pylori: Chronic gastritis, ⦿ H. pylori infection, promotes the development and progression of cancers that may be induced by diverse genetic alterations in forms of chronic inflammation. ⦿ H. pylori–induced chronic gastritis is associated with increased production of pro inflammatory proteins, such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF) ⦿ EBV: Approximately 10% of gastric adenocarcinoma are associated with Epstein- Barr virus (EBV) infection. ⦿ Morphologically, EBV-positive tumours tend to occur in the proximal stomach and most commonly have a diffuse morphology with marked lymphocytic infiltration ⦿ Gastric adenocarcinoma are classified according to their location in the stomach as well as gross and histologic morphology. ⦿ The Lauren classification that separates gastric cancers into intestinal and diffuse types correlates with distinct patterns of molecular alterations, as discussed above. ⦿ Intestinal-type cancers tend to be bulky and are composed of glandular structures similar to esophageal and colonic adenocarcinoma. ⦿ Intestinal-type adenocarcinoma typically grow along broad cohesive fronts to form either an exophytic mass or an ulcerated tumor. ⦿ The neoplastic cells often contain apical mucin vacuoles, and abundant mucin may be present in gland lamina ⦿ Diffuse gastric cancers display an infiltrative growth pattern and are composed of discohesive cells with large mucin vacuoles that expand the cytoplasm and push the nucleus to the periphery, creating a signet ring cell morphology ⦿ These cells permeate the mucosa and stomach wall individually or in small clusters. ⦿ A mass may be difficult to appreciate in diffuse gastric cancer, but these infiltrative tumours often evoke a desmoplastic reaction that stiffens the gastric wall and may cause diffuse rugal flattening and a rigid, thickened wall that imparts a “leather bottle” appearance termed linitis plastica. ⦿ Intestinal-type gastric cancer predominates in high-risk areas and develops from precursor lesions including flat dysplasia and adenomas ⦿ the incidence of diffuse gastric cancer is relatively uniform across countries, there are no identified precursor lesions, and the disease occurs at similar frequencies in males and females ⦿ The depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis remain the most powerful prognostic indicators for gastric cancer. ⦿ After surgical resection, the 5-year survival rate for early gastric cancer can exceed 90%, even if lymph node metastases are present ⦿ Extranodal lymphomas can arise in virtually any tissue, they do so most commonly in the gastrointestinal tract, particularly the stomach ⦿ In allogeneic hematopoietic stem cell and organ transplant recipients, ⦿ The bowel also is the most frequent site for Epstein-Barr virus–positive B cell lymphoproliferations. ⦿ Nearly 5% of all gastric malignancies are primary lymphomas, the most common of which are indolent extra nodal marginal zone B cell lymphomas. ⦿ In the gut, these tumors often are referred to as lymphomas of mucosa-associated lymphoid tissue (MALT), or MALTomas. ⦿ Carcinoid tumors arise from neuroendocrine organs (e.g., the endocrine pancreas) and neuroendocrine-differentiated ⦿ gastrointestinal epithelia (e.g., G-cells) ⦿ Gastric carcinoids may be associated with endocrine cell hyperplasia, chronic atrophic gastritis, and Zollinger-Ellison syndrome ⦿ These tumors were called “carcinoid” because they are slower growing than carcinomas. ⦿ WHO classification describes these as low- or intermediate grade neuroendocrine tumors. ⦿ The grade is based on mitotic activity and the fraction of cells immunohistochemcially positive for Ki67, a mitotic marker. ⦿ High-grade neuroendocrine tumors, termed neuroendocrine carcinoma, frequently display necrosis and, in the GI tract, are most common in the ⦿ Carcinoid tumors are intramural or submucosal masses that create small polypoid lesions. ⦿ The tumors are yellow or tan in appearance and elicit an intense desmoplastic reaction that may cause kinking of the bowel and obstruction. ⦿ On histologic examination, carcinoid tumors are composed of islands, trabeculae, strands, glands, or sheets of uniform cells with scant, pink granular cytoplasm and a round to oval stippled nucleus ⦿ The peak incidence of carcinoid tumors is in the sixth decade, but they may appear at any age. ⦿ Symptoms are determined by the hormones produced. ⦿ carcinoid syndrome is caused by vasoactive substances secreted by the tumor that cause cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, and right- sided cardiac valvular fibrosis. ⦿ carcinoid syndrome occurs in less than 10% of patients and is strongly associated with metastatic disease due to first pass effect of liver. ⦿ ⦿ The most important prognostic factor for gastrointestinal carcinoid tumors is location: ⦿ Foregut carcinoid tumors, those found within the stomach, duodenum proximal to the ligament of Treitz, and esophagus, rarely metastasize and generally are cured by resection. ⦿ Rare, duodenal gastrin-producing carcinoid tumors, gastrinomas, have been associated with proton pump inhibitor therapy ⦿ Midgut carcinoid tumors that arise in the jejunum and ileum often are multiple and tend to be aggressive. ⦿ In these tumors, greater depth of local invasion, increased size, and presence of necrosis and mitosis are associated with poor outcome. ⦿ Hindgut carcinoids arising in the appendix and colorectum typically are discovered incidentally. ⦿ Those in the appendix occur at any age and are almost uniformly benign. ⦿ Rectal carcinoid tumors tend to produce polypeptide hormones and may manifest with abdominal pain and weight loss; they only occasionally metastasize. ⦿. ⦿ Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the abdomen, and more than half of these tumors occur in the stomach ⦿ Overall, GISTs are slightly more common in males. The peak incidence of gastric GIST is around 60 years of age, with less than 10% occurring in persons younger than 40 years of age ⦿ 75% to 80% of all GISTs have oncogenic, gain-of-function mutations of the gene encoding the tyrosine kinase c-KIT, which is the receptor for stem cell factor. ⦿ Another 8% of GISTs have mutations that activate a related tyrosine kinase, platelet- derived growth factor receptor A (PDGFRA) ⦿ GISTs appear to arise from, or share a common stem cell with, the interstitial cells of Cajal, which express c-KIT, are located in the muscularis propria, and serve as pacemaker cells for gut peristalsis ⦿ Primary gastric GISTs usually form a solitary, well circumscribed, fleshy, submucosal mass. ⦿ Metastases may form multiple small serosal nodules or fewer large nodules in the liver; spread outside of the abdomen is uncommon. ⦿ GISTs can be composed of thin, elongated spindle cells or plumper epithelioid cells. ⦿ The most useful diagnostic marker is c-KIT, consistent with the relationship between GISTs and ⦿ Symptoms of GISTs at presentation may be related to mass effects or mucosal ulceration. ⦿ Complete surgical resection is the primary treatment for localized gastric GIST. ⦿ The prognosis correlates with tumor size, mitotic index, and location, with gastric GISTs being somewhat less aggressive than those arising in the small intestine. ⦿ Recurrence or metastasis is rare for gastric GISTs less than 5 cm across but common for mitotically active ⦿ Most of the length of the gastrointestinal tract ⦿ Affect nutrient and water transport ⦿ Site where the immune system interfaces with a diverse array of antigens present in food and gut microbes. ⦿ Most common site of gastrointestinal neoplasia ⦿ Hernias, intestinal adhesions, intussusception, and volvulus account for 80% of mechanical obstructions , while tumors and infarction account for most of the remainder ⦿ Hirschsprung Disease ⦿ Abdominal Hernia ⦿ Weakness or defect in the wall of the peritoneal cavity ⦿ Serosa-lined pouch of peritoneum called a hernia sac. ⦿ Pressure at the neck of the pouch may impair venous drainage, leading to stasis and edema. ⦿ Permanent entrapment, or incarceration, and over time, arterial and venous compromise, or strangulation, can result in infarction ⦿ Gastrointestinal tract is supplied by the celiac, superior mesenteric, and inferior mesenteric arteries. ⦿ As they approach the intestinal wall, the superior and inferior mesenteric arteries fan out to form the mesenteric arcades ⦿ Small intestine and colon to tolerate slowly progressive loss of the blood supply from one artery ⦿ Ischemic Bowel Disease ⦿ Hemorrhoids ⦿ Ischemic damage to the bowel wall ⦿ Mucosal infarction, extending no deeper than the muscularis mucosa; ⦿ Transmural infarction involving all three layers of the wall ⦿ Mucosal or mural infarctions often are secondary to acute or chronic hypoperfusion ⦿ Transmural infarction is generally caused by acute vascular obstruction. ⦿ Important causes- severe atherosclerosis (which is often prominent at the origin of mesenteric vessels), aortic aneurysm, hypercoagulable states, oral contraceptive use, and embolization of cardiac vegetations or aortic atheromas ⦿ Intestinal hypoperfusion associated with cardiac failure, shock, dehydration, or vasoconstrictive drugs. ⦿ Systemic vasculitides mesenteric venous thrombosis can also lead to ischemic disease, but is uncommon. ⦿ Other causes include invasive neoplasms, cirrhosis, portal hypertension, trauma, or abdominal masses that compress the portal drainage. ⦿ PATHOGENESIS ‘ ⦿ ischemia occur in two phases ⦿ Initial hypoxic injury occurs at the onset of vascular compromise and, although some damage occurs, intestinal epithelial cells are relatively resistant to transient hypoxia ⦿ Second phase, reperfusion injury, is initiated by restoration of the blood supply and associated with the greatest damage ⦿ The severity of vascular compromise, ⦿ Time frame during which it develops, and ⦿ Vessels affected are the major variables that determine severity of ischemic bowel disease ⦿ Intestinal segments at the end of their respective arterial supplies are particularly susceptible to ischemia ⦿ watershed zones include the splenic flexure, where the superior and inferior mesenteric arterial circulations terminate, and, to a lesser extent, the sigmoid colon and rectum where inferior mesenteric, pudendal, and iliac arterial circulations end ⦿ Intestinal capillaries run alongside the glands, from crypt to surface, before making a hairpin turn at the surface to empty into the postcapillary venules. ⦿ This anatomy protects the crypts, which contain the epithelial stem cells that are necessary to repopulate the surface ⦿ Mucosal and mural infarction may involve any level of the gut from stomach to anus ⦿ Segmental and patchy in distribution ⦿ Mucosa is hemorrhagic and often ulcerated ⦿ Bowel wall is thickened by edema ⦿ With severe disease, extensive mucosal and submucosal hemorrhage and necrosis, but serosal hemorrhage and serositis generally are absent ⦿ Blood-tinged mucus or blood accumulates within the lumen. ⦿ Coagulative necrosis of the muscularis propria occurs within 1 to 4 days and may be associated with purulent serositis and perforation ⦿ In mesenteric venous thrombosis, arterial blood continues to flow for a time, resulting in a less abrupt transition from affected to normal bowel. ⦿ Propagation of the thrombus may lead to secondary involvement of the splanchnic bed and hence acute arterial obstruction. ⦿ Microscopic examination ⦿ Atrophy or sloughing of surface epithelium ⦿ Crypts may be hyperproliferative. ⦿ Neutrophils are recruited within hours of reperfusion ⦿ Chronic ischemia is accompanied by fibrous scarring of the lamina propria ⦿ Bacterial superinfection and enterotoxin release may induce pseudomembrane ⦿ Clinical Features ⦿ Older persons with coexisting cardiac or vascular disease. ⦿ Sudden, severe abdominal pain and tenderness, sometimes accompanied by nausea, vomiting, bloody diarrhea, or grossly melanotic stool ⦿ Shock and vascular collapse within hours as a result of blood loss. ⦿ Peristaltic sounds diminish or disappear, ⦿ Muscular spasm creates boardlike rigidity of the abdominal wall ⦿ The diagnosis of intestinal infarction may be delayed or missed, with disastrous consequences. ⦿ Mucosal barrier breaks down, bacteria enter the circulation and sepsis can develop; ⦿ The overall progression of ischemic enteritis depends on the underlying cause and severity of injury ⦿ Mucosal and mural infarctions may progress to more extensive transmural infarction if the vascular supply is not restored by correction of the insult. ⦿ Chronic ischemia may masquerade as inflammatory bowel disease ⦿ CMV infection can be a complication of immunosuppressive therapy ⦿ Radiation enterocolitis occurs when the gastrointestinal tract is irradiated. ⦿ In addition to epithelial damage, radiation- induced vascular injury may be significant and produce changes that are similar to ischemic disease. ⦿ In addition to clinical history, the presence of bizarre “radiation fibroblasts” within the stroma may provide an important clue to the ⦿ Necrotizing enterocolitis is an acute disorder of the small and large intestines that can result in transmural necrosis ⦿ Most common acquired gastrointestinal emergency of neonates, particularly those who are premature or of low birth weight, and occurs most often when oral feeding is initiated ⦿ Angiodysplasia is characterized by malformed submucosal and mucosal blood vessels. It occurs most often in the cecum or right colon, and usually presents after the sixth decade of life. ⦿ 5% of the general population ⦿ Dilated anal and perianal collateral vessels that connect the portal and caval venous systems to relieve elevated venous pressure within the hemorrhoid plexus. ⦿ Factors that predispose to hemorrhoids are constipation and associated straining, which increase intra- abdominal and venous pressures, venous stasis of pregnancy, and portal hypertension. ⦿ External hemorrhoids Collateral vessels within the inferior hemorrhoidal plexus are located below the anorectal line ⦿ Internal hemorrhoids dilation of the superior hemorrhoidal plexus within the distal rectum ⦿ On histologic examination, hemorrhoids consist of thin-walled, dilated submucosal vessels that protrude beneath the anal or rectal mucosa. ⦿ Clinical Features ⦿ Hemorrhoids often manifest with pain and rectal bleeding, particularly bright red blood seen on toilet tissue. ⦿ Except in pregnant women, hemorrhoids are rarely encountered in persons younger than 30 years ⦿ Malabsorptive Diarrhea ⦿ Infectious Enterocolitis ⦿ Cystic Fibrosis ⦿ Celiac Disease ⦿ Environmental (Tropical) Enteropathy ⦿ Lactase (Disaccharidase) Deficiency ⦿ Abetalipoproteinemia ⦿ Irritable Bowel Syndrome ⦿ Microscopic Colitis ⦿ Graft-Versus-Host Disease ⦿ Defective absorption of fats, fat- and water- soluble vitamins, proteins, carbohydrates, electrolytes and minerals, and water. ⦿ Chronic malabsorption causes weight loss, anorexia, abdominal distention, borborygmi, and muscle wasting. ⦿ Hallmark of malabsorption is steatorrhea, characterized by excessive fecal fat and bulky, frothy, greasy, yellow or clay-colored stools ⦿ Diarrhea is defined as an increase in stool mass, frequency, or fluidity, typically to volumes greater than 200 mL per day ⦿ Painful, bloody, small-volume diarrhea is known as dysentery ⦿ Secretory diarrhea is characterized by isotonic stool and persists during fasting. ⦿ Osmotic diarrhea, is due to osmotic forces exerted by unabsorbed luminal solutes ⦿ Malabsorptive diarrhea caused by inadequate nutrient absorption is associated with steatorrhea and is relieved by fasting ⦿ Exudative diarrhea is due to inflammatory disease and characterized by purulent, bloody stools that continue during fasting ⦿ Disturbance in at least one of the four phases of nutrient absorption: ⦿ Intraluminal digestion, ⦿ Terminal digestion ⦿ Transepithelial transport ⦿ Lymphatic transport ⦿ Diarrhea, abdominal pain, urgency, perianal discomfort, incontinence, and hemorrhage. ⦿ Comma-shaped, gram negative bacteria that cause cholera ⦿ Endemic in the Ganges Valley of India and Bangladesh ⦿ Marked seasonal variation in most climates due to rapid growth of Vibrio bacteria at warm temperatures ⦿ Only animal reservoirs are shellfish and plankton ⦿ Few V. cholerae serotypes are pathogenic, ⦿ Noninvasive and remain within the intestinal lumen ⦿ Flagellar proteins, which are involved in motility and attachment, are necessary for efficient bacterial colonization, ⦿ and a secreted metalloproteinase that also has hemagglutinin activity is important for bacterial detachment and shedding in the stool. ⦿ the preformed enterotoxin, cholera toxin, which causes disease ⦿ There are five B subunits that direct endocytosis and a single active A subunit ⦿ A subunit is transported from the endoplasmic reticulum lumen into the cytosol, where it interacts with cytosolic ADP ribosylation factors to ribosylate and activate the G protein Gsα ⦿ This stimulates adenylate cyclase and the resulting increases in intracellular cyclic adenosine monophosphate (cAMP) open the cystic fibrosis transmembrane conductance regulator (CFTR), which releases chloride ions into the lumen. ⦿ Sodium and bicarbonate absorption are also reduced. ⦿ Accumulation of these ions creates an osmotic gradient that draws water into the lumen, leading to massive secretory diarrhea. ⦿ Remarkably, mucosal biopsy specimens show only minimal ⦿ Campylobacter jejuni is the most common bacterial enteric pathogen in developed countries and is an important cause of traveler’s diarrhea ⦿ Ingestion of improperly cooked chicken, but outbreaks also can be caused by unpasteurized milk or contaminated water. ⦿ Flagella allow Campylobacter to be motile. ⦿ This facilitates adherence and colonization, which are also necessary for mucosal invasion. ⦿ Cytotoxins that cause epithelial damage and a cholera toxin–like enterotoxin are also released by some C. Jejuni isolates. ⦿ Campylobacter infection can result in reactive arthritis, primarily in patients with HLA-B27. ⦿ Specific diagnosis is primarily by stool culture ⦿ ⦿ Watery diarrhea, either acute or with onset after an influenza-like prodrome, is the primary manifestation, and dysentery develops in 15% to 50% of patients. ⦿ gram-negative bacilli that are unencapsulated, non-motile, facultative anaerobes. ⦿ Shigella organisms are resistant to the harsh acidic environment of the stomach. ⦿ Once in the intestine, organisms are taken up by M epithelial cells, which are specialized for sampling and uptake of luminal antigens. ⦿ After intracellular proliferation, the bacteria escape into the lamina propria. ⦿ These bacteria then infect small intestinal and colonic epithelial cells through the basolateral membranes, which express bacterial receptors. ⦿ Alternatively, luminal shigellae can directly modulate epithelial tight junctions to expose basolateral bacterial receptors. Some Shigella dysenteriae serotypes also release the Shiga toxin Stx, which inhibits eukaryotic protein ⦿ Shigella infections are most prominent in the left colon, but the ileum may also be involved, perhaps reflecting the abundance of M cells in the epithelium overlying the Peyer’s ⦿ patches. ⦿ ⦿ The histologic appearance in early cases is similar to that in other acute self-limited colitides ⦿ Complications of Shigella infection are uncommon and include reactive arthritis, a triad of sterile arthritis, urethritis, and conjunctivitis that preferentially affects HLA- B27– positive men between 20 and 40 years of age. ⦿ Hemolytic uremic syndrome, which typically is associated with enterohemorrhagic Escherichia coli (EHEC), also may occur after infection with shigellae that secrete Shiga toxin. ⦿ Escherichia coli are gram-negative bacilli that colonize the healthy GI tract; most are non-pathogenic, but a subset cause human disease. ⦿ Enterohemorrhagic E. coli (EHEC) organisms are categorized as O157:H7 and non-O157:H7 serotypes. ⦿ Outbreaks of E. coli O157:H7 in developed countries have been associated with the consumption of inadequately cooked ground beef, milk, and vegetables. ⦿ Both O157:H7 and non-O157:H7 serotypes produce Shiga-like toxins and can cause dysentery. ⦿ They can also give rise to hemolytic-uremic syndrome ⦿ Enterotoxigenic E. coli (ETEC) organisms are the principal cause of traveller's diarrhea, and are spread by the faecal-oral route. ⦿ ⦿ They express a heat labile toxin (LT) that is similar to cholera toxin and a heat-stable toxin (ST) that increases intracellular cGMP with effects similar to the cAMP elevations caused by LT ⦿ Enteroinvasive E. coli (EIEC) organisms resemble Shigella bacteriologically but do not produce toxins. ⦿ They invade the gut epithelial cells and produce a bloody diarrhea. ⦿ Enteroaggregative E. coli (EAEC) organisms attach to enterocytes by adherence fimbriae. ⦿ ⦿ ⦿ Although they produce LT and Shiga-like toxins, histologic damage is minimal ⦿ members of the Enterobacteriaceae family of gram-negative bacilli ⦿ Salmonella typhi, the causative agent of typhoid feverand nontyphoid Salmonella strains that cause gastroenteritis. ⦿ Nontyphoid Salmonella infection usually is due to Salmonella enteritidis ⦿ Infection is most common in young children and elderly persons, with peak incidence in summer and fall ⦿ virulence genes encode a type III secretion system capable of transferring bacterial proteins into M cells and enterocytes---- activate host cell Rho GTP ases------ triggering actin rearrangement and bacterial uptake into phagosomes where the bacteria can grow. ⦿ A molecule that induces epithelial release of a chemo attractant eicosanoid that draws neutrophils into the lumen and potentiates mucosal damage ⦿ Like S. enteritidis, S. typhi and S. Para typhi are taken up by M cells and then engulfed by mononuclear cells in the underlying lymphoid tissue. ⦿ Thus, infection causes Peyer’s patches in the terminal ileum to enlarge into plateau-like elevations up to 8 cm in diameter. ⦿ Mucosal shedding creates oval ulcers oriented along the long axis of the ileum. ⦿ However, unlike S. enteritidis, S. typhi and S. paratyphi can disseminate via ⦿ Randomly scattered small foci of parenchymal necrosis with macrophage aggregates, termed typhoid nodules, are also present in the liver, bone marrow, and lymph nodes ⦿ Campylobacter, Shigella, Salmonella, and many other bacterial infections, including Yersinia and E. coli, all induce a similar histopathology, termed acute self-limited colitis, and these pathogens cannot be reliably distinguished by tissue biopsy. ⦿ Thus, specific diagnosis is primarily by stool culture. ⦿ The histology of acute self-limited colitis includes prominent lamina propria and intraepithelial neutrophil infiltrates cryptitis (neutrophil infiltration of the crypts) and crypt abscesses (crypts with accumulations of luminal neutrophils) also may be present. ⦿ The preservation of crypt architecture in most cases of acute self-limited colitis is helpful in ⦿ Caused by Clostridium difficile, is also known as antibiotic-associated colitis or antibiotic-associated diarrhea. ⦿ Disruption of the normal colonic microbiota by antibiotics allows C. difficile overgrowth. ⦿ Toxins released by C. difficile cause the ribosylation of small GTPases, such as Rho, and lead to disruption of the epithelial cytoskeleton, tight junction barrier loss, cytokine ⦿Norovirus Norovirus, previously known as Norwalk-like virus ⦿ Rotavirus--Children between 6 and 24months -- selectively infects and destroys mature (absorptive) enterocytes in the small intestine, and the villus surface is repopulated by immature secretory cells. This change in functional capacity results in loss of absorptive function and net secretion of water and electrolytes that is compounded by an osmotic diarrhea from incompletely absorbed nutrients.  Parasitic Disease--- ⦿ Ascaris lumbricoides,-traverses lung ⦿ Strongyloides(autoinfection) –travesrses lung ⦿ Necator americanus-- traverses lung ⦿ Ancylostoma duodenale -- traverses lung ⦿ Giardia lamblia(lactase deficiency) ⦿ Multivisceral chronic disease ⦿ Malabsorption diarrhoea,lymphadenopathy,arthrit is of undefined origin ⦿ Foamy macrophage having argyrophilic rods ⦿ Gram positive actinomycetes..Tropheryma whippelli ACCUMULATE IN LAMINA PROPRIA AND MESENTRIC LYMPHNODES CAUSING LYMPHATIC OBSTRUCTION ⦿ Chronic relapsing abdominal pain,bloating and changes in bowel habits ⦿ Syndrome with multiple illnesses ⦿ Rome criteria ⦿ Pathogenesis unknown ⦿ Psychosocial,diet,gut factors ⦿ Constipation predominant,diarrhoea predominant ⦿ Bile acid malabsorption ⦿ 20 to 40years age/female ⦿ 3days per month for over 3 ⦿ acquired pseudodiverticular outpouchings of the colonic mucosa and submucosa. ⦿ rare in persons younger than 30 years of age, but the prevalence approaches 50% in Western adult populations beyond the age of 60 ⦿ under conditions of elevated intraluminal pressure in the sigmoid colon ⦿ the unique structure of the colonic muscularis propria, where nerves, arterial vasa recta, and their connective tissue sheaths penetrate the inner circular muscle coat to create discontinuities in the muscle wall ⦿ in the colon, external longitudinal muscle layer is discontinuous, being gathered into the three bands termed taeniae coli. ⦿ small, flask-like outpouchings, usually 0.5 to 1 cm in diameter, that occur in a regular distribution in between the taeniae coli ⦿ Obstruction of diverticula leads to inflammatory changes, producing diverticulitis and peridiverticulitis. ⦿ Most persons asymptomatic ⦿ intermittent cramping, continuous lower abdominal discomfort, constipation, and diarrhea. ⦿ most often resolves spontaneously or after antibiotic treatment ⦿ chronic condition resulting from inappropriate mucosal immune activation. ⦿ two major entities, Crohn disease and ulcerative colitis CROHN’S ULCERATIVE COLITIS Ileum ± colon Colon only Skip lesions Diffuse Transmural inflammation Limited to mucosa and submucosa Toxic megacolon + Toxic megacolon - Ulcers Deep, knifelike Superficial, broad-based Stricture Yes Stricture rare ⦿ more common in females and frequently present during adolescence or in young adults. ⦿ The cause(s) of IBD remains uncertain ⦿ a combination of errant host interactions with intestinal microbiota, intestinal epithelial dysfunction, and aberrant mucosal immune responses. ⦿ Genetics ⦿ Mucosal immune responses ⦿ Epithelial defects ⦿ Microbiota ⦿ Molecular linkage analyses of affected families have identified NOD2 (nucleotide oligomerization binding domain 2) ATG16L1, and IRGM, as a susceptibility gene in Crohn disease ⦿ it is likely that some combination of derangements that activate mucosal immunity and suppress immunoregulation contribute to the development of both ulcerative colitis and Crohn disease ⦿ TH17 T cells With polymorphisms of the IL-23 receptor confer protection from Crohn disease and ulcerative colitis (IL- 23 is involved in the development and maintenance of TH17 cells). ⦿ in ulcerative colitis includes a significant TH2 component. ⦿ However, the pathogenic role of TH2 cells in IBD pathogenesis remains controversial. ⦿ defects in intestinal epithelial tight junction barrier function are present in patients with Crohn disease and a subset of their healthy first-degree relatives. ⦿ Despite a growing body of data that suggest that intestinal microbiota contribute to IBD pathogenesis, their precise role remains to be defined. ⦿ In keeping with this, some antibiotics, such as metronidazole, can be helpful in maintenance of remission in Crohn disease ⦿ terminal ileum, ileocecal valve, and cecum. ⦿ Disease is limited to the small intestine alone in about 40% of cases; the small intestine and the colon both are involved in 30% of patients; and the remainder of cases are characterized by colonic involvement only. ⦿ The presence of multiple, separate, sharply delineated areas of disease, resulting in skip lesions, is characteristic of Crohn disease ⦿ Strictures are common ⦿ The microscopic features of active Crohn disease include abundant neutrophils that infiltrate and damage crypt epithelium. ⦿ Clusters of neutrophils within a crypt are referred to as a crypt abscess and often are associated with crypt destruction. ⦿ Ulceration is common in Crohn disease, and there may be an abrupt transition between ulcerated and normal mucosa. ⦿ Repeated cycles of crypt destruction and regeneration lead to ⦿ In most patients, disease begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain. ⦿ Right lower quadrant pain, fever, and bloody diarrhea that may mimic acute appendicitis or bowel perforation. ⦿ Periods of active disease typically are interrupted by asymptomatic intervals that last for weeks to many months ⦿ Extraintestinal manifestations of Crohn disease include uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, and clubbing of the fingertips, any of which may develop before intestinal disease is recognized ⦿ involved colonic mucosa may be slightly red and granular-appearing or exhibit extensive broad- based ulcers. ⦿ The transition between diseased and uninvolved colon can be abrupt. ⦿ Ulcers are aligned along the long axis of the colon but typically do not replicate the serpentine ulcers of Crohn disease. ⦿ Isolated islands of regenerating mucosa often bulge into the lumen to create small elevations, termed pseudopolyps. ⦿ Chronic disease may lead to mucosal atrophy and a flat, smooth mucosal surface lacking normal folds. ⦿ mural thickening is absent, the serosal surface is normal, and strictures do not occur. ⦿ Inflammation and inflammatory mediators can damage the muscularis propria and disturb neuromuscular function leading tocolonic dilation and toxic megacolon, which carries a significant risk of perforation. ⦿ Histologic features of mucosal disease in ulcerative colitis are similar to those in colonic Crohn disease and include inflammatory infiltrates, crypt abscesses, crypt distortion, and epithelial metaplasia. However, skip lesions are absent and inflammation generally is limited to the mucosa and superficial submucosa ⦿ Ulcerative colitis is a relapsing disorder characterized by attacks of bloody diarrhea with expulsion of stringy, mucoid material and lower abdominal pain and cramps that are temporarily relieved by defecation. ⦿ One of the most feared long-term complications of ulcerative colitis and colonic Crohn disease is the development of neoplasia. ⦿ This process begins as dysplasia, which, just as in Barrett esophagus and chronic gastritis, is a step along the road to full-blown carcinoma. ⦿ Risk increases sharply 8 to 10 years after disease initiation. ⦿ Patients with pancolitis are at greater risk than those with only left-sided disease. ⦿ common in the colon but may occur in the esophagus, stomach, or small intestine ⦿ Without stalks are referred to as sessile. ⦿ stalks are termed pedunculated ⦿ classified as nonneoplastic or neoplastic. ⦿ inflammatory, ⦿ hamartomatous, or ⦿ hyperplastic. ⦿ clinical triad of rectal bleeding, ⦿ mucus discharge, and ⦿ an inflammatory lesion of the anterior rectal wall. ⦿ cause is impaired relaxation of the anorectal sphincter, creating a sharp angle at the anterior rectal shelf ⦿ recurrent abrasion and ulceration of the overlying rectal mucosa ⦿ sporadically and ⦿ as components of various genetically determined or acquired syndromes ⦿ disorganized, tumor-like growths composed of mature cell types normally present at the site at which the polyp develops ⦿ Juvenile Polyps ⦿ Peutz-Jeghers Syndrome ⦿ the most common type of hamartomatous polyp ⦿ sporadic or syndromic ⦿ children younger than 5 years of age. ⦿ located in the rectum, ⦿ Sporadic juvenile polyps are usually solitary but in persons with the autosomal dominant syndrome of juvenile polyposis the number varies from 3 to as many as 100 ⦿ juvenile polyposis syndrome is associated with increased risk for the development of colonic ⦿ pedunculated, smooth surfaced, reddish lesions that are less than 3 cm in diameter and display characteristic cystic spaces on cut sections. ⦿ Microscopic examination shows the spaces to be dilated glands filled with mucin and inflammatory debris ⦿ rare autosomal dominant disorder ⦿ multiple gastrointestinal hamartomatous polyps and mucocutaneous hyperpigmentation that carries an increased risk of several malignancies, including cancers of the colon, pancreas, breast,lung, ovaries, uterus, and testes, as well as other unusual neoplasms ⦿ Histologic examination demonstrates a characteristic arborizing network of connective tissue,smooth muscle, lamina propria, and glands lined by normal- appearing intestinal epithelium ⦿ epithelial proliferations that typically are discovered in the sixth and seventh decades of life. ⦿ decreased epithelial cell turnover and delayed shedding of surface epithelial cells ⦿ Left colon and typically are less than 5 mm in diameter. ⦿ singly but more frequently are multiple, ⦿ hyperplastic polyps are composed of mature goblet and absorptive cells. ⦿ Adenomas ⦿ Familial syndromes --- FAP(Familial Adenomatous Polyposis) /HNPCC ⦿ Adenocarcinoma ⦿ colonic adenomas,benign polyps that give rise to a majority of colorectal adenocarcinomas. ⦿ Colorectal adenomas are characterized by the presence of epithelial dysplasia ⦿ adenomas range from 0.3 to 10 cm in diameter and can be pedunculated or sessile, ⦿ the cytologic hallmark of epithelial dysplasia is nuclear hyperchromasia, elongation, and ⦿ the epithelium fails to mature as cells migrate out of the crypt ⦿ classified as tubular, tubulovillous, or villous on the basis of their architecture ⦿ The histologic features of sessile serrated adenomas overlap with those of hyperplastic polyps and the typical cytologic features of dysplasia are lacking ⦿ Size is the most important characteristic that correlates with risk of malignancy. , ⦿ In addition to size, high-grade dysplasia is a risk factor for cancer in an individual polyp ⦿ Familial Adenomatous Polyps-an autosomal dominant disorder marked by the appearance of numerous colorectal adenomas by the teenage years. It is caused by mutations of the adenomatous polyposis coli gene (APC).A count of at least 100 polyps is necessary for a diagnosis of classic FAP, and as many as several thousand may be present. Colorectal adenocarcinoma develops in 100% of patients with untreated FAP, often before age 30. ⦿ Specific APC mutations are also associated with the development of other manifestations of FAP and explain variants such as Gardner syndrome(with osteomas,desmoid,thyroid and dental tumors) Turcot syndrome(CNS tumors, medulloblastoma 67%,glioblastoma 33%). ⦿ Hereditary Nonpolyposis Colorectal Cancer- Lynch syndrome, originally was described as familial clustering of cancers at several sites including the colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, and skin. HNPCC is caused by inherited germline mutations in genes that encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication. At least five such mismatch repair genes have been recognized, but a majority of HNPCC ⦿ the most common malignancy of the gastrointestinal tract ⦿ Colorectal cancer incidence peaks at 60 to 70 years of age, and less than 20% of cases occur before age 50. Males are affected slightly more often than females ⦿ The combination of molecular events that lead to colonic adenocarcinoma is heterogeneous and includes genetic and epigenetic abnormalities. At least two distinct genetic pathways APC/β-catenin pathway, have been described. ⦿ APC is a key negative regulator of β- catenin, a component of the WNT signaling pathway. The APC protein normally binds to and promotes degradation of β-catenin. With loss of APC function, β-catenin accumulates and translocates to the nucleus, where it activates the transcription of genes, such as those encoding MYC and cyclin D1, which promote proliferation ⦿ Both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events, for adenomas to develop ⦿ Tumors in the proximal colon often grow as polypoid, exophytic masses that extend along one wall of the large-calibercecum and ascending colon; these tumors rarely causeobstruction. By contrast, carcinomas in the distal colontend to be annular lesions that produce “napkin ring” constrictions and luminal narrowing ⦿ composed of tall columnar cells that resemble dysplastic epithelium found in adenomas. The invasive component of these tumors elicits a strong stromal desmoplastic response, which is responsible for their characteristic firm consistency. ⦿ Some poorly differentiated tumors form few glands. ⦿ Others may produce abundant mucin that accumulates within the intestinal wall, and these carry a poor prognosis. ⦿ Tumors also may be composed of signet ring cells that are similar to those in gastric ⦿ Symptoms -fatigue and weakness due to iron deficiency anemia. Left-sided colorectal adenocarcinomas may produce occult bleeding, changes in bowel habits, or cramping left lower quadrant discomfort. ⦿ Staging -TNM ⦿ Prognosis-the two most important prognostic factors are depth of invasion and the presence or absence of lymph node metastases. REFERENCES Robbins and Cotran Pathologic Basis of Disease, 10th Edition