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Robbins. Ch. 15 Oral cavity and gastrointestinal tract.

1.Oral cavity.
1.1 Ulcerative and inflammatory lesions. Aphthous ulcers (canker Sores): extremely common, small, painful, shallow ulcers. They are more common in the first two decades of life and are often triggered by stress, fever, ingestion of certain foods, and activation of inflammatory bowel disease. Are self-limited and usually resolve within a few weeks. Herpesvirus infection: transmitted from person to person, most often by kissing. In most adults primary infection is asymptomatic, virus persists in a dormant state within ganglia. With reactivation vesicles containing clear fluid appear. They soon rupture, leaving shallow, painful ulcers that heal within a few weeks. As a result of changes in sexual practices, genital herpes produced by HSV type 2 is increasingly seen in the oral cavity. Oral candidiasis. Candia albicans is a normal inhabitant of the oral cavity found in 30 to 40% of the population. Pseudomembranous candisiasis is the most common fungal infection of the oral cavity. In the particularly vulnerable host, candiadiasis may spread into the oesophagus. Local candidal lesions may appear in vagina in healthy young women. AIDS and Kaposi Sarcoma. They may take the form of candidiasis, herpetic vesicles, or some other microbial infection. Hairy leukoplakia is an uncommon lesion seen vitually only in persons infected with HIV. Caused by EBV infection of the epithelial cells. 1.2. Leukoplakia and erythroplakia. Refers to a wihitish, well-definded mucosal patch or plaque caused by epidermal thickening or hyperkeratosis. Can not be scraped off and cannot be characterized as any other disease. More frequent among older men. Appear as localized, smooth or roughened, leathery , white , discrete areas of mucosal thickening. Strong association with the use of tabacco. Important finding because 3% to 25% undergo transformation to squamous cell carcinoma. Three somewhat related lesions must be differentiated; - Hairy leukoplakia; - Verrucous leukoplakia, shows a corrugated surface caused by excessive hyperkeratosis, diffuse warty type of oral lesion; - Erythroplakia refers to red, velvety, often granular, circumscribed areas that may or may not be elevated, having poorly defined, irregular boundaries. 1.3. Cancers of the oral cavity. About half result in death within 5 years and indeed may have already metastasized by the time primary lesion is discovered. Tend to occur late in life. Lesions may cause local pain or difficulty in chewing. A significant number are not discovered until beyond cure. The overall 5-year survival rates after surgery and adjuvant radiation and chemotherapy are about 40%. 1.4. Salivary and gland diseases. Sialadenitis. Inflammation of the major salivary glands. Most common lesion is mucocele, resulting form blockage or rupture of salivary gland duct, with consequent leakage of saliva into the

surrounding tissues. Most often found in the lower lip. - Mumps (bof?), may produce enlargement of all the major salivary glands but predominantly the parotids. Most important cause is paramyxovirus, an RNA virus related to the influenza and parainfluenza viruses. - Bacterial sialadenitis often occurs secondary to ductal obstruction, may also arise after retrograde entry of oral cavity bacteria. S. aureus and S. viridans. - Chronic sialadenitis arises from decreased production of saliva with subsequent inflammation cause autoimmune sialademitis -> Sjogren syndrome. Salivary gland tumors. About 80% of tumors occur within parotid glands. Males and females are affected about equally, in the sixth of seventh decade of life. Whatever the type, they present clinically as a mass causing swelling at the angle of the jaw. Most malignant tumor of the salivary gland is mucoepidermoid carcinoma, occurs mainly in parotids. - Pleomorphic adenoma: accounts for more than 90% of benign tumors of salivary glands. Slow-growing well-demarcated, apparently encapsulated lesion rarely in the superficial parotid. Nonetheless often present for years before being brought to medical attention. - Warthin tumor: infrequent benign tumor occurs virtually only in the region of the parotid gland. Generally a small, well encapsulated , round to ovoid mass that on transection often reveals mucin-containtin cleftlike or cystic spaces. 2 characteristic features 1. A two-tiered epithelial layer lining the branching, cystic, or cleftlike spaces; 2. Well-developed lymphoid tissue sometimes forming germinal centres.

2.Esophagus.
Produces dysphagia (difficulty swallowing), heartburn (retrosternal burning pain), hematemesis and melena 2.1. Anatomic and motor disorders. Achalasia. Means failure to relax. Denotes incomplete relaxation of the lower esophageal sfincter in response to swallowing. Produces functional obstruction. Three major abnormalities in achalsia: 1. Aperistalsis. 2. Partial or incomplete relaxation of the lower esophageal sphincter. 3. Increased resting tone of the lower esophageal sphincter. Chagas disease causes destruction of the myenteric plexus of the esophagus, duodenum, colon ureter. In primary achalasia there is progressive dilatation of the esophagus above the level of the lower espoghageal sphincter. Stasis of food may produce mucosal inflammation and ulceration proximal to the lower esophageal sphincter. Characterized clinically by progressive dysphagia and inability to completely convey food to the stomach. Hiatal hernia. Separation of the diaphragmatic crura and widening of the space between muscular crura and the esophageal wall permits a dilated segment of the stomach to protrude above the diaphragm. Sliding hernia constitutes 95% of cases. Suffer from heartburn or regurgitation of gastric juices into the mouth. These symptoms are likely result from incompetence of the lower esophageal sphincter than from the hiatal hernia per se. Lacerations (mallory-weiss syndrome). Longitudinal tears in the esophagus at the esophagogastric junction. Encountered in chronic alcoholics after a bout of severe retching or vomiting. Pathogenesis is inadequate relaxation of the musculature of the lower esophageal

sphincter during vomiting. Tears may involve only the mucosa or may penetrate the wall. Infection of the defect may lead to an inflammatory ulcer or the mediastinitis. Account for 5-10% of upper gastrointestinal bleeding episodes. 2.2. Varices. When portal venous blood flow into the liver is impeded by cirrhosis or other causes, the resultant portal hypertension induces the formation of collateral bypass channels wherever the portal and systemic systems communicate. Blood flow is thereby diverted through the stomach veins into the plexus of oesophageal subepithelial and submucosal veins, thence into the azygos veins and the superior vena cava. Increased pressure in the oesophageal plexus produces dilated tortuous vessels called varices. Variceal rupture produces massive haemorrhage into the lumen. Varices produce no symptoms until they rupture. 2.3. Esophagitis. The inflammation may have many origins: prolonged gastric intubation, uremia, ingestion of corrosive or irritant substances. Gastroesophageal reflux disease. Many presumed contributory factors: - Decreased efficacy of oesophageal antireflux mechanisms. - Inadequate or slowed esophageal clearance of refluxed material; - Presence of a sliding hiatial hernia; - Increased gastric volume; - Impaired reparative capacity of the esophageal mucosa Dominant manifestation is heartburn, sometimes accompanied by regurgitation of sour brash. Potential consequences of severe reflux are bleeding, development of stricture, and Barrett oesophagus, with its predisposition to malignancy. 2.4. Barrett esophagus. Replacement of the normal distal stratified squamous mucosa by metaplastic columnar epithelium containing goblet cells. Complication of long-standing gastroesophageal reflux. More commone in whites. Prolonged and recurrent gastroesophageal reflux is thought to produce inflammation and eventually ulceration of the squamous epithelial lining. Healing occurs by ingrowth of progenitor cells and re-epithelialization. In the microenvironment of an abnormally low pH in the distal espohagus caused by acid reflux, the cells differentiate into columnar epithelium. Have a 30 to 100 fold greater risk of adenocarcinoma. 2.5. Oesophageal carcinoma. Two type: squamous cell carcinomas and adenocarcinomas. Squamous cell carcinomas constitute 90% of oesophageal cancers. Adenocarcinomas associated with Barrett esophagus. Squoamous cell carcinomas are more common in blacks worldwide. Squamous cell carcinomas. Retartded passage of food through the esophagus, prolonging mucosal exposure to potential carcinogens such as those contained in tobacco and alcoholic beverages. Mutations p53 are detected in as many as 50% of these tumors and are generally correlated with the use of tobacco and alcohol. Adenocarcinoma. Barrett is the only recognized precursor of esophageal adenocarcinoma. Degree of dysplasia is the strongest predictor of the progression of cancer. In barrett tissue there is increased cell proliferation, and chromosomal abnormalities become apparent in highgrade dysplasia. It is insidious in onset and produces dysphagia and obstruction gradually and late. Weight loss, anorexia, fatigue, and weakness appear, followed by pain, usually related to swallowing. Diagnosis is made by endoscopic biopsy.

3. Stomach.
3.1. Gastritis.

Inflammation of gastric mucosa. Chronic gastritis. Defined as presence of chronic inflammatory changes in the mucosa leading eventually to mucosal atrophy and epithelial metaplasia. H. pylori shows in American adults older than the age of 50 prevalence rates approaching to 50%. Most individuals with the infection also have the associated gastritis but are asymptomatic. It is a non-invasive, non-spore forming, S-shaped gram-negative rod. Gastritis develops as result of the combined influence of bacterial enzymes and toxins and release of noxious chemicals by recruited neutrophils. After initial exposure gastritis may develop in 2 patterns: 1.) an antral-type with high acid production and high risk for developing duodenal ulcer. 2.) pangastritis with multifocal mucosal atrophy, with low acid secretion and increased risk for adenocaricnoma. Autoimmunegastritis represent no more than 10% of cases of chronic gastritis, production of antibodies to the gastric gland parietal cells, in particular to the H,K-ATPase. Leads to gland destruction and mucosal atrophy. Usually causes few symptoms or no symptoms: upper abdominal discomfort and nausea and vomiting can occur. Most important is the relationship of chronic gastritis to the development of peptic ulcer and gastric carcinoma. Long-term risk of gastric carcinoma for persons with H.pylori is increased about fivefold. Acute gastritis. Acute mucosal inflammatory process, usually of a transient nature. May be accompanied by hemorrhage into the mucosa and, in more severe circumstances, by sloughing of the superficial mucosal epithelium. Pathogenesis is poorly understood. Frequently associated with: - NSAIDS; - Excessive alcohol consumption; - Heavy smoking; - Treatment with cancer chemotherapeutic drugs; - Severe stress; - Reflux of bilious material after distal gastrectomy. It may be asymptomatic, may cause variable epigastric pain with nausea and vomiting, or may present as overt hematemesis, melena. Overall it is one of the major causes of hematemesis, particularly in alcohlics. 3.2. Gastic ulceration. Are defined histologically as a breach in the mucosa that extends through the muscularis mucosae into the submucosa or deeper. Contrasted to erosion, in which there is breach in the epithelium of the mucosa only Peptic ulcers. Remitting, relapsing lesions that are most often diagnosed in middle-aged to older adults. Even with healing, the propensity to develop peptic ulcers remains. Duodenal ulcers are more frequent in persons with alcoholic cirrhosis , chronic obstructive pulmonary disease, chronic renal failure, and hyperparathyroidism. Two conditions are key for development 1.) H. pylori infection. 2.) mucosal exposure to gastric acid and pepsin. The infection is present in 70-90% of persons with duodenal ulcers and in about 70% of those with gastric ulcers. - H.pylori does not invade the tissues, it induces an intense inflammatory and immune response. Increased production of IL-1,6,8 and TNF. IL-8 is produced by mucosal epithelial cells and recruits and activates neutrophils. - Epithelial injury is mostly caused by a vasuolating toxin called VacA. H. pylori secretes a urease that breaks down urea to from toxic compounds. Bacterial proteases and phospholipases break down the glycoprotein-lipid complexes in the gastric mucus, thus weakening the first line of mucosal defense. - H. pylori enhances gastric acid secretion and impairs duodenal bicarbonate production. Favors gastric metaplasia in the first part of duodenum. Only 10-20% of individuals worldwide who are infected with H.pylori actually develop peptic ulcers. There are bacterial factors, strains producing VacA and CagA cause more intense

tissue inflmmation. NSAIDs are the major cause of peptic ulcer disease in persons who do not have H.pylori infection. The effects range from acute erosive gastritis and acute gastric ulceration to peptic ulceration. Risk factors are increasing age, higher dose, and prolonged usage. Suppression of prostaglandin synthesis, increased secretion of hydrochloric acid and reduces bicarbonate and mucin production. Loss of mucin degrades the mucosal barrier that normally prevents acid from reaching the epithelium. Cigarette smoking impairs mucosal blood flowing and healing. Alcohol has not been proved to directly cause peptic ulceration. Corticosteroids in high dose and with repeated use promote ulcer formation. They cause epigastric pain, burning, or boring, a significant minorty first come to light with complications such as hemorrhage or perforation. The paint ends to be worse at night. Bleeding is the chief complication ,occuring in as many as 1/3 of patients. Acute gastric ulceration. May appear after severe physiologic stress, are called stress ulcers. Generally, there are many lesions located mainly in the stomach. - Severe trauma - Chronic exposure to gastric irritant drugs; - extensive burns; - Traumatic or surgical injury to the CNS; Pathogenesis is uncertain. Although prophylactic antacid regimens and blood transfusions may blunt the impact of stress ulceration, the single most important determinant of clinical outcome is the ability to correct the underlying condition. 3.3. Gastric tumors. Gastric polyps. Polyp is applied to any nodule or mass that projects above the level of the surround mucosa. In the gastrointestinal tract it is generally restricted to mass lesions arising in the mucosa. Gastric polyps are uncommon. 1.) hyperplastic polyps (80%), 2.) fundic gland plyps (10%), 3.) adenomatous polyps (5%). All three types arise in the setting of chronic gastritis. There is a definite risk of an adenomatous polyp harbouring adenocarcinoma. Gastric carcinoma. Second leading cause of cancer-related deaths in the world. In most countries there has been a steady decline in the overall incidence and the mortality of gastric cancer. 5-year survival rate less than 20%. - Intestinal type : arise from gastric mucous cells that have undergone intestinal metaplasia in the setting of chronic gastritis. Better differentiated, more common type in high-risk population. 2:1 male predominancs - Diffuse variant: arise de novo from native gastric mucous cells. Tends to be poorly differentiated. Occurs at an earlier age with female predominance. Both are generally asymptomatic and can be discovered only by repeated endoscopie examination in persons at high risk. Only hope for cure is early detection and surgical removal.

4. Small and large intestines.


4.1. Developmental anomalies. - Atresia: complete failure of development of the intestinal lumen, stenosis; narrowing of the intestinal lumen with incomplete obstruction; - Duplication: takes the form of well-formed saccular to tubular cystic structures; - Meckel diverticulum: most common and innocuous of the anomalies. Results from failure of involution of the omphalomesenteric duct, leaving a persistent blind-ended tubular protrusion as long as 5-6cm. Generally are asymptomatic, except when they permit bacterial overgrowth that depletes vit b12; - Omphalocele: congenital defect of the periumbilical abdominal musculature that creates a membranous sac, into which the intestines herniate; - Malrotation: can prevent the intestines from assuming their normal intra-abdominal positions;

- Hirschprung disease. Hirschprung disease: Congential megacolon. Results when, during development, the migration of neural crest-derived cells along the alimentary tract arrests at some point before reaching the anus. An aganglionic segment is formed. Causes functional obstruction and progressive distention of the colon. Are absent from the muscle wall and submucosa. Is heterogeneous. 50% of familial cases result from mutations in RET genes and RET ligands. A delay occurs in the initial passage of meconium, which is followed by vomiting in 48-72 hours. The principal threat to life is superimposed enterocolitis with fluid and electrolyte disturbances. 4.2. Vascular disorders. Ischemic bowel disease. Insidious loss of one vessel may be without effect, thanks to the rich anastomoses between the vascular beds. Severity of injury ranges from transmural infarction, involving all visceral layers, to mural infarction of the mucosa and submocosa, sparing the muscular wall, to mucosal infarction, if the lesions extends no deeper than the muscularis mucosae. Transmural infarction is caused by acute occlusion of a major mesenteric artery. Predisposing conditions: - Arterial thrombosis: severe atherosclerosis, systemic vasculitis; - Arterial embolism: cardiac vegetations, angiographic procedures; - Venous thrombosis: hypercoagulable states induced by oral contraceptives or antithrombin III deficiency. - Nonocclusive ischemia: cardiac failure

It most common occurs in the later years of life. Sudden onset of abdominal pain. Onset of pain tends to be more sudden with mesenteric embolism than with arterial or venous thrombosis. Because this condition may progress to shock and vascular collapse within hours. Mortality rate approaches 90% largely because the window of time between onset of symptoms and perforation caused by gangrene is so small. Angiodysplasia. Dilations of submucosal and mucosal blood vessels are seen most often in the cecum or right colon. They are prone to rupture and bleed into the lumen. The hemorrhage may be chronic and cause severe anemia. Hemorrhoids. Variceal dilations of the anal and perianal submucosal venous plexuses. Common predisposing conditions are straining stool and venous statis of pregnancy in young women. 4.3. Colonic diverticulosis. Diverticulum is a blind pouch that communicates with the lumen of the gut. Prototype is Meckel diverticulum. Diverticulosis: the colon is unique in that the outer longitudinal muscle coat is not complete but is gathered into three equidistant bands. Focal defects in the muscle wall are created where nerves and arterial vasa recta penetrate the inner circular muscle coat alongside the taeniae. Connective tissue sheaths accompanying these penetrating vessels provide potential sites for herniations. Two influences are thought to be important: 1.) Exaggerated peristaltic contractions, 2.) focal defects.

They are mostly asymptomatic and discovered only at autopsy. In only 1/5 of the cases does intermittent cramping exist. 4.4. Bowel obstruction. Small bowel is most commonly affected. Four entities- hernias, intestinal adhesions, intussusception, and volvulus- account for at least 80% of the cases.

4.5. Enterocolitis (diarrheal diseases). Many are caused by microbiologic agents; others arise in the setting of malabsorptive disorders and idiopathic inflammatory bowel diseases. An increase in stool mass, stool frequency, or stool fluidity is perceived as diarrhea by most persons. Often accompanied by pain, urgency, perianal discomfort, and incontinence. Major types of disease are: - Secretory diarrhea; - Osmotic diarrhea; - Exudative diarrhea; - Malabsorption diarrhea. Infectious enterocolitis. Most common offenders are rotavirus, caliciviruses and enterotoxigenic E. Coli. Viral gastroenteritis: viral infections of epithelium destroys these cells. Repopulation of the small intestinal villi with immature enterocytes leads to net secretion of water and electrolytes by an osmotic diarrhea. Rotavirus, Calicivirus. Bacterial enteroclitis: There are several mechanisms; Ingestion of preformed toxin, infection of toxigenic organism, infection by enteroinvasive organisms. Bacterial replication in the gut depends on three key bacterial properties: 1.) ability to adhere to mucosal epithelial cells, 2.) ability to elaborate enterotoxins, 3.) Capacity to invade. Protozoal infection: Entamoeba histolytica is a dysentery causing protozoal parasite spread by fecal-oral contamination. Amebae invade the crypts of colonic glands and burrow down into the submucosa. Giardia lamblia is an intestinal protozoan spread by water contaminated with feces. It attaches to small intestinal mucosa but do not appear to invade. Malabsorption syndromes. Characterized by defective absorption of fats, fat-soluble and other vitamins , proteins , carbohydrates, electrolytes and minerals, and water. Most common presentation is chornic diarrhea; - Intraluminal digestion, in which proteins, carbohydrates and fats are broken down. Process begins in mouth with saliva, receives a boost from gastric peptic digestion, and continues in the small intestine; - Mucosal absorption: water, electrolytes, and nutrients are absorbed and transported into the cell; - Nutrient delivery: delivery from intestinal cells into lymphatics. Host of disorders interrupt these three digestive functions, either directly or indirectly. Defects of intraluminal digestion: osmotic diarrhea fromundigestes nutrients, and

steatorrhea. Latter can arise either form inadequate action of pancreatic lipases or form inadequate solubilization of fat by hepatic bile. Most common cause are pancreatic insufficiency. Defects of mucosal malabsorption: Lactose intolerance. Caused by deficiency of dissacharidase (lactase). Intestinal mucosa is morpholically normal. Deficiency of apolipoprotein B makes the mucosal epithelial cell unable to export lipid. Protein is required for assembly of dietary lipids into chylomicrons. Deficiency causes diarrhea and steatorrhea in infancy and significant failure to thrive. Celiac disease, gluten-sensitive enteropathy, where there is immunological sensitivity to gluten, the component of wheat and related grains. Gliadin peptides are efficiently presented by antigen-presenting cells in the lamina propria of the small intestine to CD4+ T-cells, driving an immune response to gluten. Age of presentation with symptomatic diarrhea and malnutrition varies from infancy to mildadulthood; removal of gluten from the diet is met with dramatic improvement. Tropical sprue, occurs almost exclusively in persons living in or visiting the tropics. Appearance of malabsoprtion within days or a few weeks of an acute diarrheal enteric infection strongly implicates and infectious process. Whipple disease, a rare systemic infection that may involve any organ of the body but principally affects the intestine, CNS, and joints. Passage of abnormally bulky, forthy, greasy, yellow or gray stools is prominent feature of malabsorption, accompanied by weight loss and anorexia. 4.6. Inflammatory bowel disease. Result from an abnormal local immune response against the normal flora of the gut, probably against some self antigens. May affect any portion of the gastrointestinal tract from esophagus to anus but most often involves the ileum; Ulcerative colitis is a nongranulomatous disease limited to the colon. Dynamic balance between 1.) factors that activate the host immune system and 2.) host defenses that down-regulate inflammation and maintain the integrity of the mucosa. Ulcerative colitis has been associated with HLA-DRb1, whereas DR7 and DQ4 alleles are associated with 30% of crohn disease. Immunologic factors; - Primary damaging agents appear to be CD4+ cells. - In crohn disease tissue inflammation may be result of secretion of the cytokine IL-17 by a recently discovered subset CD4+ T cells. Inflammatory cytokine TNF may play an important pathogenic role in Crohn. Microbial factors: sites affected by IBD are awash in bacteria. It is quite likely that microbes provide the antigenic trigger to a fundamentally dysregulated immune system. Inflammation causes 1.) impaired integrity of the mucosal epithelial barrier, and 2) loss of surface epithelial cell absorptive function. Ultimately causes outright mucosal destruction. These events give rise to the intermittent bloody diarrhea. Therapeutic interventions act entirely through non-specific down regulation of the immune systome. Crohn disease. May affect any level of alimentary tract, from mouth to anus , but most commonly located at the terminal ileum. As a systemic inflammatory disease with predominant gastrointestinal involvement. Characterized by: - Sharply limited transmural involvement of the bowel by an inflammatory process with mucosal damage; - Presence of noncaseating granulomas; - Fistula formation. Presentation is highly variable and unpredictable. Recurrent episodes of diarrhea, crampy, abdominal pain, and fever lasting day to weeks. Some melena is present in about 50% of cases with colon involvement. Consequences of Crohn disease include 1.) Fistula, 2.) abdominal abcesses or peritonitis; 3.) intestinal stricture. Ulcerative colitis. Limited to mucosa and submucosa. Begins in the rectum and extends proximally in a continuous fashion. Important differences:

- Well-formed granulomas are absent; - There are no skip lesions; - Mucosal ulcers rarely extend below the submucosa; - Mural thickening does not occur, serosal surface is usually completely normal; - Appears to be high risk of carcinoma development. Chronic relapsing disorder marked by attacks of bloody mucoid diarrhea that may persist for days, weeks or months and then subside. Presentation is usually insidious, with cramps, tenesmus, an dcolicky lowe abdominal pain that is relived by defecation. Grossly bloody stools.

4.7. Tumors of small and large intestines. Adenocarcinomas constitute the vast majority of colorectal cancers and represent 70% of all malignancies arising in the gastrointestinal tract. - Polyp is a mass that protrudes into the lumen of the gut; Traction may create a stalked, or

pendunculated polyp. Polyp may be sessile. - Polyps may be formed as the result of abnormal mucosal maturation , inflammation , or architecture. Are non-neoplastic and do not have malignant potential. - Polyps that arise as the result of epithelial proliferation and dysplasia are termed adenomatous polyps. - Hyperplastic polyps are most common polyps of colon and rectum. When single , they do not have malignant potential. Non-neoplastic Polyps. Represent about 90% of all epithelial polyps in the large intestine and are found in more than half of all persons > 60. Histologically , they contain abundant crypts lined by welldifferentiated goblet or absorptive epithelial cells, separated by scant lamina propria. Adenomas. Neoplastic polyps that range from small often penduculated, tumors to large lesions that are usually sessile. Well-defined familial predisposition to sporadic adenomas. All adenomatous lesions arise as the result of epithelial proliferation and dysplasia, which may range from mild to severe as to represent transformation to carcinoma. Segregated into four subtypes: 1. Tubular adenomas- mostly tubular glands, most common. 2. Villous adenomas villous projections. 3. Tubulovillous adenomas- a mixture of above. 4. Sessile serrated adenomas- serrated epithelium lining the crypts. Malignant risk with an adenomatous polyp is as follows: - Cancer is rare in adenomas < 1cm; - Likelihood of cancer is high in sessile villous adenomas > 4cm; - Severe dysplasia is often found in villous areas. - Maximum diameter is the chief determinant of the risk of an adenomas harbouring carcinoma; architecture does not provide substantive independent information. Clinical features: Usually asymptomatic, until such time that occult bleeding leads to clinically significant anemia. Familial Polyposis Syndromes (FAP). Are uncommon autosomal dominant disorders. FAP typically develop 500-2500 colonic adenomas that carpet the mucosal surface; a minimum of 100 is required for de diagnosis. The risk of colonic cancer is virtually 100% by midlife, unless a prophylactic colectomy is performed. Genetic defect underlying FAP has been localized to the APC gene on chromosome 5q21. - Peutz-jeghers syndrome: polyps are uncommon hamartomatous polyps that occur as part of the rare autosomal dominant Syndrome, characterized in addition by melanotic mucosal and cutaneous pigmentation. - Cowden syndrome: characterized by hamartomatous polyps and by an increased risk of neoplasms of the thyroid, breast, uterus and skin. Colorectal Carcinoma. 98% are adenocarcinomas. Peak incidence 60 to 70 years of age. Males are affected about 20% more often than females. The diatary factors receiving most attention are: 1. Low content of unabsorbable vegetable fibre; 2. A corresponding high content of refined carbohydrates; 3. A high fat content; 4. Decreased intak of protective micronutrients such as vitamins A, C and E.

Colorectal carcinogenesis: Two pathogenetically pathways 1.) APC/Beta-catenin pathway. 2.) mismatch repair pathway. First pathway is characterized by chromosomal instability associated with stepwise accumulation of mutations in a number of oncogenes and tumor suppressor genes.

Morphologic and molecular change sin the adenom-carcinoma sequence it is postulated that loss of one normal copy of the tumor suppressor gene APC occurs early. Individuals may be born with one mutant allele, making them extremely prone to develop colon cancer, or inactivation of APC may occur later in life. This is the first hit. The loss of the intact copys of APC follows (second hit). Other mutations include those on K-ras , located at 18q21 involving SMAD2 and SMAD4, and in the inactivation of the tumor suppressor gene p53, leading ot the emergence of carcinoma, in which additional mutations occur. Second pathway: there is accumulation of mutations, but the involved genes are different. May be no detectable antecedent lesions, or the tumors may develop from sessile serrated adenomas.

Defects in mismatch repair genes result in microsatellite instability and permit the accumulation of mutations in numerous genes. If these mutations affect genes involved in cell survival and proliferation , cancer may develop Clinical features: Remain asymptomatic for years; symptoms develop insidiously and frequently have been present for months, sometimes years, before diagnosis. - Cecal and right colonic : fatigue, weakness, and iron deficiency anemia. - Lef-sided lesions: may produce occult bleeding, changes in bowel habit or crampy left lower quadrant discomfort. All colorectal tumors spread by direct extension into adjacent structures and by metastasis through the lymphatic and blood vessels. Favored sites for metastasis are lymph nodes, liver, lungs and bones. Neoplasms of the small intestine. Tumors account for only 3-6% of all gastroinestinal tumors. - Adenocarcinoma of the small intestine: Most small bowel carcinomas arise in the duodenum. Cramping pain, nausea, vomiting, and weight loss are the common presenting signs and symptoms. But appear late in the course of these cancers. Other gastrointestinal cancers. - Gastrointestinal lymphoma: systemic dissemination of Non-hodgkin lymphomas. Primary gastrointestinal lymphomas reveal no evidence of liver, spleen, or bone marrow involvement at the time of diagnosis; can be B- or T-cell origin. Most common = MALT lymphoma. Result of H. pylori associated with chronic gastritis. Intense activation of T and B cells in the mucosa. This leads to polyclonal B-cell hyperplasia and eventually to the emergence of a monoclonal B-cell neoplasm. MALT lymphoma cells are CD5 and CD10 negative, and a t(11;18) translocation is common. - Carcinoids: generating bioactive compounds, particularly peptide and nonpeptide hormones. Tumors arising from endocrine cells; may develop in the pancreas or peripancreatic tissue, lungs, billary tree, and even liver. Clinical features: Frequently asymptomatic , including virtually all that aris in the appendix. Secretory products of some carcinoids can produce a variety of syndromes or endocrionpathies.

Appendix.
5.1. Acute appendicitis. Is associated with obstruction in 50-80% of cases, usually in the form of a fecalith and, less commonly , a gallstone, tumor, or ball of worms. With continued secretion of mucinous fluid, the build up of intraluminal pressure is sufficient to cause collapse of the draining veins. Obstruction and ischemic injury than favor bacterial exudation. Nevertheless, a significant minority of inflamed appendices have no demonstrable luminal obstruction. Classic case is marked by: 1.) mild periumbilical discomfort, followed by, 2.) anorexia, nausea, and vomiting, 3.) right lower quadrant tenderness, which transformed into 4. Deep constant ache or pain in the right lower quadrant. Fever and leukocytosis appear early in the course. 5.2. Tumors of the appendix. Carcinoids are the most common. Only worthy lesions worth mentioning are mucocele of the appendix and mucinous neoplasms. Mucocele refers to dilation of the lumen of the appendix by mucinous secretion. Caused by neoplastic obstruction.

Ch.16 The liver, Gallbladder, and biliary tract.

1. The liver.

Liver has task of maintaining the bodys metabolic homeostasis. The liver has enormous functional reserve. Surgical removal of 60% of the liver of a normal person produces minimal and transient hepatic impairment, and regeneration restores most of the liver mass within 4-6 weeks. The functional reserve can mask to some extent the clinical impact of early liver damage.

1.1. Patterns of hepatic injury. - Degeneration and intracellular accumulation. More serious damage to hepatocytes may cause marked cell enlargement. Substances may accumulate in viable hepatocytes, e.g. fat droplets known as steatosis. Multiple tiny droplets that do not displace the nucleus -> microvasculair steatosis (appear at alcoholic liver disease, acute fatty liver of pregnancy). A single droplet that displaces the nucleus, macrovasculair steatosis (obese or diabetic individuals). - Necrosis and apoptosis. In coagulative necrosis, poorly stained mummified hepatocytes remain. In apoptosis hepatocytes become shrunken, pyknotic , and intensely eosinophilic. With ischemia, hepatic necrosis is distributed around the central vein , centrilobular necrosis. Between the periportal parenchyma and inflamed portal tracts , interface hepatitis. - Regeneration. Cell death or tissue resection triggers hepatocyte replication, recognized by the presence of mitoses or by the detection of cell cycle markers. The cells of the canals of Hering constitute a reserve compartment of progenitor cells, knowns as Oval cells. - Fibrosis. Formed in response to inflammation or direct toxic insult to the liver. Lasting consequences on hepatic blood flow and perfusion of hepatocytes. May develop within or around portal tracts or around the central vein, deposited directly within the sinusoids. - Cirrhosis. Liver develops nodules regenerating hepatocytes by bands of scars tissue. Normal liver architecture is destroyed. - Ductular reaction. Number of intrahepatic bile ducts and canals of hering may increase -> known as ductular reaction. Usually associated with fibrosis and inflammation. 1.2. Clinical syndromes. Hepatic failure. Develops as the end point of progressive damage to the liver. Less commonly result of sudden and massive destruction of hepatic tissue. 80-90% of hepatic function must be lost. 1. Acute liver failure with massive hepatic necrosis. Caused by drugs or fulminant viral hepatitis. Progress from onset of symptoms to hepatic encephalopathy within 2-3 weeks. Histologically massive hepatic necrosis. Uncommon but life-threatening condition. 2. Chronic liver disease. 3. Hepatic dysfunction without overt necrosis. May be viable but unable to perform normal metabolic function , as in acute fatty liver of pregnancy, tetracycline toxicity. Clinical features: Jaundice, impaired hepatic synthesis and secretion of albumin leads to hypoalbuminea. Hyperammonemia due to defective hepatic urea cycle function. Impaired oestrogen metabolism and consequent hyperestrogenemia are causes of palmar erythema and spider angiomas on the skin. In the male, hyperestrogenmia leads to hypogonadism and gynecomastia. It is life threatening for several reasons. Accumulation of toxic metabolites, high susceptibility to failure of multiple organ systems, massive hemorrhage. Hepatic Encephalopathy. Patients show a spectrum of disturbances in brain function, ranging from subtle behavioural abnormalities in brain function, to marked confusion and stupor, to deep coma and death. May progress over hours or days. Asterixis/flapping tremor: pattern of nonrhytmic, rapid extension-flexion movements of the head and extremities. Two physiologic conditions: 1.) severe loss of hepatocellular function and 2.) shunting of blood from portal to systemic

circulation around the chronically diseased liver. Net result is exposure of the brain to an altered metabolic mileu. Hepatorenal syndrome. Appears in individuals with severe liver disease, consists of de development of renal failure without primary abnormalities of the kidneys themselvers. Kidney function promptly improves if hepatic failure is reversed. Exact cause is unknown. Heralded by a drop in urine output, associated with rising blood urea nitrogen and creatinine values. Ability to concentrate urine is retained, producing a hyperosmolar urine devoid of proteins and abnormal sediment. Cirrhosis. Three main characteristics: - Bridging fibrous septa: delicate bands or broad scars around multiple adjacent lobules. - Parenchymal nodules. - Disruption of the architecture of the entire liver. Most common cause are chronic alcoholism and chronic hep B/C. Major mechanisms are hepatocellular death, regeneration, progressive fibrosis, and vascular changes. Development requires that cell death occur over long periods of time and be accompanied by fibrosis. Fibrosis is a wound-healing reaction that progresses to scar

formation when the injury involves not only the parenchyma but also the supporting connective tissue. Liver has no true basement membrane; delicate framework containing type IV collagen and other proteins that lie in space of Disse. In cirrhosis, type I and III collagen are deposited in the space of Disse. Major source of excess collagen cirrhosis are the persisinusoidal stellate cells, which lie in the space of Disse. Normally function as storage for vitamine A and fate, during the development of fibrosis they become activated, and transform into myofibroblast-like cells. Express smooth muscla alfa-actin. Activated stellate cells produce growth factors, cytokines, and chemokines that cause their further proliferation and collagen synthesis. Non specific manifestations: anorexia, weight loss, weakness.

Portal The dominant accounting for from increased the sinusoids perivenular arterial and contribute by normally lowclinical portosystemic splenomegaly, Ascites: detectable involves hepatic lymph,

hypertension. intrahepatic cause is cirrhosis, most cases of portal hypertension. Result resistance to portal flow at the level of and compression of central veins by fibrosis. Anastomoses between the portal systems in the fibrous bands also imposing arterial pressure on the pressure portal venous system. 4 major consequences: 1.) acites, 2.) formation of venous shunts, 3.) congestive 4.) hepatic encephalopathy. collection of excess fluid clinically when at least 500mL. Pathogenesis sinusoidal hypertension, leakage of renal retention of sodium and water.

Portosystemic shunt: principal sites are veins around and within the rectum, the cardioesophageal junction, the retroperitoneum and the falciforme ligament of the liver. Important are the esophagogastric varices that appear in about 65%.

Jaundice and cholestasis. Results from retention of bile. Hepatic bile formation serves two major functions: 1.) bile constitutes the primary pathway for the elimination of bilirubin, excess cholesterol and xeniobiotics that are insufficiently water soluble to be excreted into urine. 2.) Promote emulsification of dietary fat in the lumen of the gut. Cholestasis is defined as systemic retention of not only bilirubin but also other solutes. Heme oxygenase oxidazes heme to biliverdin, which is then reduced to bilirubin by biliverdin reductaes. Bilirubin thus formed outside the liver in cells of the mononuclear phagocyte system is released and bound to serum albumin. Hepatocellular processing: 1.) carrier-mediated uptake, 2.) cystosolic protein binding and delivery to the endoplasmic reticulum, 3.) conjugation with one or two molecules of glucuronic acid by bilirubin uridine diphosphateglucuronosyltransferase and, 4.) excretion of the water-soluble into bile. Jaundice occurs when the equilibrium between bilirubin production and clearance is disturbed by one or more of the following mechanisms: - Excessive production of bilirubin; - Reduced hepatic uptake; - Impaired conjugation; - Decreased hepatocellular excretion; - Impaired bile flow.

Because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient mild unconjugated hyperbilirubinemia, termed neonatal jaundice.

1.3. Infectious and inflammatory disorders. Those in which the hepatic lesion may be prominent include miliary tbc, malaria, the salmonelloses, candidiasis, and ambebiasis. Systemic viral infections: 1.) EBV may cause mild hepatitis during acute phase, 2.) CMV or HSV infections, 3.) yellow fever. 1.3.1. Viral hepatitis. HepA (HAV). Benign, self-limited disease, with an incubation period of 15-50 days. Does not cause chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis. Case fatalities are very low , about 0,1%, and are more likely to occur when patients have preexisting liver disease. It is spread by ingestion of contaminated water and foofd and is shed in the stool for 2-3 weeks before and 1 week after onset of jaundice. HAV viremia is transient, blood-borne transmission of HAV occurs only rarely. It reaches the liver from the intestinal tract after ingestion, replicates in hepatocytes, and is shed in the bile and feces. Virus itself does not seem to be toxic to hepatocytes, liver injury seems to result from T cell-mediated damage. IgM antibodies against HAV appear in blood at the onset of symptoms. Best diagnostic marker for the disease; igG antibody persists beyond convalescence. HepB (HBV). Can produce: - Acute hepatitis with recovery and clearance of the virus; - Nonprogressive chornic hepatitis; - progressive chronic disease ending in cirrhosis; - Fulminant hepatitis with massive liver necrosis; - Asymptomatic carrier state. HBV remains in blod during the last stages of prolonged incubation period (4-26 weeks) and during active episodes of acute and chronic hepatitis. Contact with body secretions such as saliva, sweat, tears, breast milk etc are ways of transmission, vertical transmission, sexual transmission. HVB replication does not involve the integration of the virus, but integrated HVB is frequently found in cells. After exposure there is a long , 120 days, incubation period. - HBsAg appears before the onset of symptoms; - Anti-HBs does not rise until the acute disease is over, usually not detectable for a while after disappearance of HBsAG, may persist for life; - HBeAG, HBV-DNA and DNA polymerase appear in serum soon after HBsAG; - IgM and anti-HBc becom detectable before onset of symptoms. Over a period of months it is replaced by IgG anti-HBc. The host immune response to the virus is the main determinant of the outcome of the infection. Strong response by virus-specific CD4+ and CD8+ interferon gamma-producing cells are associated with the resolution of acute infection. Hepatocyte damage is believer to result from damage to the virus-infected cells by CD8+ cytotoxic T cells. HepB can be prevented by immunization.

(li= resolution active infection, re= progression to chronic infection). HepC (HCV). Major cause of liver disease. The major route of transmission is through blood inoculation, with IV drug use, accounting for over 40% of cases in USA. HCV infection has a much higher rate than HBV of progression to chronic disease and eventual cirrhosis. Incubation period ranges from 2-26 weeks. The clinical course of acute hepatitis is asymptomatic in 75% of individuals. In persistent infection, circulating HCV-RNA is detectable, and aminotransferase show episodic elevations, or continuous elevation with fluctuating levels. Persistent infection occurs in 80-85% of individuals. Cirrhosis develops in 20%.

(li= resolution active infection, re= progression to chronic infection). HepD (HDV). Unique RNA virus that is replication defective, causing infection only when it is capsulated by HBsAg. Arises in two settings: 1.) acute coinfection after exposure to serum containing both HDV and HBV , 2.) superinfection of a chronic carrier of HBV with a new inoculum of HDV. HepE (HEV). Enterically transmitted. Endemic in india. In most cases, the disease is self-limited. It is not associated with chronic liver disease or persistent viremia. High mortality rate among pregnant women (20%). Incubation period after exposure is 6 weeks. Clinical features and outcomes of viral hepatitis. - Asymptomatic infection: identified only on the basis of minimally elevated serum aminotransferases or by the presence of antiviral antibodies; - Acute viral hepatitis: are easily detected for HBV infections but only rarely diagnosed for HVC. Acute hepatitis, whatever the agent, can be divided into: 1.) an incubation period, peak infectivity occurs during the last asymptomatic days of the incubation period and the early days of acute symptoms 2.) a symptomatic preicteric phase, marked by general fatigability, nausea, and loss of appitite. Physical examination reveals mildly enlarged liver- 3.) a symptomatic icteric phase, jaundice is caused predominantly by conjugated hyperbilirubemia and hence is accompanied by dark-colored urine related to the presence

of conjugated bilirubin. Unconjugated hyperbilirubinemia can also occur -> stools may become light colored due to cholestasis. 4.) convalescence. - Chronic hepatitis: Symptomatic , biochemical, or serologic evidence of continuing or relapsing hepatic disease for more than 6 months, with histologically documented inflammation and necrosis. Etiology rather than the histologic pattern is the most important determinant of the probability of developing progressive chronic hepatitis. - Carrier state: An individual without manifest symptoms who harbours and therefore can transmit an organism. There are those who 1.) harbour one of the viruses but are suffering little or no adverse effects, 2.) those who have no progressive liver damage but are essentially free of symptoms or disability. Individuals with impaired immunity are particularly likely to become carriers. - Fulminant hepatitis: very small proportion may develop acute liver failure, resulting from massive hepatic necrosis. 1.3.2. Autoimmune hepatitis. A syndrome of chronic hepatitis in persons with heterogeneous set of immunologic abnormalities. Histologic features are indistinguishable from chronic viral hepatitis. - Female predominance (70%); - Abscence of serologic markers of a viral infection; - Elevated serum IgG; - High titers of autoantibodies in 80%; - Presence of othe rforms of autoimmune diseases. 1.3.3. Pyogenic liver abcess. The organisms reach the liver through one of the following pathways: 1.) ascending infection in the biliary tract, 2.) vascular seeding, 3.) direct invasion of the liver from a nearby source, 4.) a penetrating injury. Liver abscesses are associated with fever and, in many instances with right upper pain and tender hepatomegaly. 1.4. Alcoholic- and drug induced liver disease. Alcoholic liver disease. There are three distinctive forms of alcoholic liver disease: 1.) Hepatic steatosis (fatty liver); 2.) Alcoholic hepatitis; 3.) Cirrhosis. 90-100% of heavy drinkers develop fatty liver, and of those, 10-35% develop alcoholic hepatitis. However, only 8-20% of chronic alcoholics develop cirrhosis. Short term ingestion of as much as 80gm of ethanol per day generally produces mild, reversible hepatic changes, such as fatty liver. Women seem to be more susceptible to hepatic injury. Induction of cytochrome P-450 by alcohol leads to augmented transformation of other drugs to toxic metabolites. Hepatocellular steatosis results from 1) shunting of normal substrates away from catabolism and toward lipid biosynthesis. 2.) impaired assembly and secretion of lipoproteins;3.) increased peripheral catabolism of fat. - Acetaldehyde (major intermediate metabolite of alcohol) induces lipid peroxidation and acetaldehyde-protein adduct formation, which may disrupt cytoskeletal and membrane function. - Alcohol directly affects microtubule organization, mitochondrial function, and membrane fluidity. - Reactive oxygen species are generated during oxidation of ethanol. generation of acetyldehyde and free radicals is maximal in the centrilobular region of the parenchyma, this region is most susceptible to toxic injury. Pericellular fibrosis and sinusoidal fibrosis develop in this area of the lobule. Hepatic steatosis may give rise to hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase. It is estimated that it takes 15-20 years of excessive drinking are necessary to develop alcoholic hepatitis. Nonspecific symptoms are malaise, anorexia, weight loss, upper abdominal discomfort , tender hepatomegaly, and fever and the lab

findings of hyperbilirubinemia, elevated alkaline phosphatase. Cirrhosis may be clinically silent, discovered at autopsy or when stress such as infection tips the balance toward hepatic insufficiency. In the end-stage alcoholic causes of death are: 1.) hepatic failure, 2.) massive gastrointestinal hemorrhage, 3.) an intercurrent infection, 4.) hepatorenal syndrome, 5.) hepaotcellular carcinoma 3-6%. Drug-induced liver disease. Drug reactions may be classified as predictable (intrinsic) reactions or unpredictable (idiosyncratic) ones. Predictable may occur in anyone who accumulates a sufficient dose. Unpredictable reactions depend on idiosyncrasies of the host, the hosts propensity to mount an immune response to the antigenic stimulus. Drug induces chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis or autoimmune hepatitis. 1.5. Metabolic and inherited liver disease. 1.5.1. Nonalcoholic fatty liver disease. A common condition. Fatty liver and liver disease develop in individuals who do not drink alcohol. The latter is similar to alcoholic hepatitis involves hepatocyte destruction, parenchymal inflammation with neutrophils and mononuclear cells, and progressive pericellular fibrosis. - Type 2 diabetes; - Obesity; - Dyslipidemia; Insulin resistance results in the accumulation of triglycerides in hepatocytes by at least three mechanisms: 1.) impaired oxidation of fatty acids, 2.) increased synthesis and uptake of fatty acids, and 3.) decrease hepatic secretion of very-low density lipoprotein cholesterol. Fat-lade hepatocytes are highly sensitive to lipid peroxidation products, which can damage mitochondrial and cause apoptosis. NAFLD may be asymptomatic, but some may have fatigue, malaise, right upper quadrant discomfort, or more severe symptoms of chronic liver disease. 1.5.2. Inhertited metabolic diseases. Hemochromatosis. Excessive accumulation of body iron, most of which is deposited in the parenchymal organs such as the liver en pancreas. Four genetic variants. Most common form is recessive disease. Cause by mutations in the HFE gene. There is also secondary iron overload, by multiple transfusions, ineffective erythropoiesis , and increased iron uptake. Iron accumulates over the lifetime of an individual from excessive intestinal absorption. Total iron accumulation may exceed 50gm, over 1/3 accumulates in the liver. The gene , HFE, is located on the short arm of chromosome 6 close to HLA gene. The role of HFE in regulating iron uptake is complex and not fully understood. Regulate the levels of hepcidin. Hepcidin normally down-regulates the efflux of iron from the intestines and macrophages into the plasma and inhibits iron absorption. Hepcidin levels are reduced when there is increased iron absorption. Two common mutations in the HFE gene, C282Y and H63D. Hemochromatosis manifests typically after 20gm of storage iron has accumulated. Excessive iron seems to be directly toxic to tissues by the following mechanisms: 1.) lipid peroxidation by iron-catalyzed free-radical reactions, 2.) stimulation of collagen formation , and 3.) direct interactions of iron with DNA. It has and male predominate (5:1). Symptoms usually first appear in the fifth to sixth decades of life. Hepatomegaly , abdonimal pain, skin pigmentation, destruction of pancreatic islets, cardiac dysfunction, and atypical arthritis. Treatment of iron overload does not remove the risk for development of hepatocellular carcinoma, because of the oxidative damage of DNA produced by iron. Wilson disease. Characterized by the accumulation of toxic levels of copper in many tissues and organs, principally in the liver, brain and eye. Mutation in ATP7B. The initial steps of copper

absorption and transport to the liver are normal. However, absorbed copper fails to enter the circulation in the form of ceruloplasmin, and biliary excretion of copper is markedly diminished. It causes toxic liver injury by 1.) promoting the formation of free radicals, 2.) binding to sulfhydryl groups of cellular proteins, and 3.) displacing other metals in hepatic metalloenzymes. Age at onset is extremely variable. Most common presentation is acute or chronic liver disease. Neuropsychiatric manifestations, frank psychosis, or a parkinson disease like ysndrome. Kayser-fleischer rings! Alfa1-Antitrypsin deficiency. Abnormally low serum levels of this protease inhibitor. The major function of AAT is the inhibition of proteases, particularly neutrophil elastase released at sites of inflammation. Deficiency leads to pulmonary emphysema. The PiZ polypeptide contains a single amino acid substitution that results in misfolding of the nascent polypeptide in the hepatocyte endoplasmic reticulum. Because the mutant protein cannot be secreted by the hepatocyte, it accumulates in the endoplasmic reticulum and undergoes excessive lysosomal degradation. The disease may remain silent until cirrhosis appears in middle to later life. Neonatal cholestasis. Clinical presentation of infants with any form of neonatal cholestasis is fairly typical, with jaundice , dark urine, light or acholic stools, and hepatomegaly. Reye syndrome. Rare disease characterized by fatty change in the liver and encephalopathy. Primarily affects children younger than 4 years of age. Pernicious vomiting, accompanied by irritability or lethargy and hepatomegaly. Although most patients recover, about 25% progress to coma. Death occurs from neurologic deterioration or liver failure. The pathogenesis involves a generalized loss of mitochondrial function. Has been associated with aspirin administration during viral illnesses. 1.6. Diseases of the intrahepatic biliary tract. Primary biliary cirrhosis. Destruction of intrahepatic bile ducts, portal inflammation and scarring, and the eventual development of cirrhosis and liver failure over years to decades. Primary feature is a nonsuppurative destruction of small en medium-sized intrahepatic bile ducts. There are high titers of antimitochondrial antibodies. The onset is insidious, usually presenting as pruritus; jaundice develops late. Over a period of two or more decades , the individuals develop hepatic decompensation , including portal hypertension with variceal bleeding, and hepatic encephalopathy. Serum alkaline phosphatase and cholesterol levels are almost always elevated. Primary sclerosing cholangitis. Chronic cholestatic disorders, characterized by progressive fibrosis and destruction of extrahepatic and large intrahepatic bile ducts. The ducts show a characteristic beading of the contrast medium in the affected segments of the biliary tree. Commonly seen in association with inflammatory bowel disease, particularly ulcerative colitis. The cause is unknown. Symptoms at presentation include progressive fatigue, pruritus, and jaundice. Persistent elevation of serum alkaline phosphatase. Severely afflicted persons show symptoms associated with chronic liver disease. Cholangiocarcinoma may develop in 1015% with a medium time of 5 years from diagnosis. 1.7 Circulatory disorders. 1.7.1. Impaired blood flow into the liver. Hepatic artery inflow. Liver infarcts are rare, double blood supply to the liver. Interruption of the main hepatic artery does not always produce ischemic necrosis. The one exception is hepatic artery thrombosis in the transplanted liver.

Portal vein obstruction and thrombosis. Blockage may be insidious and well tolerated or may be catastrophic and potentially lethal. Typically produces abdominal pain, ascites and other manifestations of portal hypertension. May arise from following: - Peritoneal sepsis; - Pancreatitis, that initiates splenic vein thrombosis; - Thrombogenic diseases; - Vascular invasion by cancer. Intrahepatic thrombosis of portal vein radicle, when acute , does not cause ischemic infarction but instead results in sharply demarcated area of red-blue discoloration (so called infarct of Zahn). 1.7.2. Impaired blood flow through the liver Most common is cirrhosis. In sickle cell disease. Passive congestion and centrilobular necrosis. Right-sided cardiac decompensation leads to passive congestion of the liver, can cause centrilobular necrosis, and perivenular fibrosis in the areas of necrosis. Peliosis hepatis. Sinusoidal dilation occurs in any condition in which efflux of hepatic blood is impeded. Rare condition in which the dilation is primary. Although clinical signs are generally absent even in advanced peliosis, potentially fatal intraabdominal hemorrhage or hepatic failure may occur. 1.7.3. Hepatic vein outflow obstruction. Budd-chiari syndrome. Results from thrombosis of two or more major hepatic veins and is characterized by hepatomegaly, weight gain, ascites, and abdominal pain. Mortality when left untreated is high. Sinusoidal obstruction syndrome. Damaged endothelial cells slough off and create emboli that block blood flow. Endothelial damage is accompanied by passage of red blood cell into the space of Disse, proliferation of stellate cells, and fibrosis of terminal branches of hepatic vein. Now occurs primarily in the first 20-30 days after bone marrow transplantation. 1.8. Tumors and hepatic nodules. Most common hepatic neoplasms are metastatic carcinomas , with colon, lung, and breast heading the list as sites of primary tumor. Hepatocellular nodules. - Focal nodular hyperplasia, localized, well demarcated but poorly encapsulated lesion, consisting of hyperplastic hepatocyte nodules with central fibrous scar. - Macroregenerative nodules, appear in cirrhotic livers. Are larger than surrounding cirrhotic nodules but do not display atypical features. - Dysplastic nodules, are lesions larger than 1mm in diameter and appear in cirrhotic livers. Benign tumors. Most common are cavernous hemangiomas. Well-circumscribed lesions consisting of endothelial cell-lined vascular channels and intervening stroma. They appear as discrete red-blue, soft nodules , usually less than 2cm in diameter. Hepatic adenoma: May be pale, yellow-tan or bile-stained, well demarcated nodules found anywhere in the hepatic substance but often beneath the capsule. May reach 30cm in

diameter. Portal tracts are absent: instead, prominent arterial vessels and draining veins are distributed through the substance of the tumor. Significant for three reasons: 1.) when they present as an intrahepatic mass, may be mistaken for hepatocellular carcinoma, 2.) subcapsular adenomas are at risk for rupture, 3.) although adenomas are not considered precursors of hepatocellular carcinoma, mutations carry a risk of developing into cancers. Hepatocellular carcinomas (HCC). Constitutes approximately 5,4% of all cancers. There are three major associations: infection with HBV or HCV, chronic alcoholism, and aflatoxin exposure. Many variables , including age, chemicals, gender, viruses, hormones, alcohol etc interact with the development. The development or cirrhosis seems to be an important, but not requisite, contributor. It develops from small-cell high grade dysplastic nodules in cirrhotic livers. These nodules may be monoclonal and may contain chromosomal aberrations similar to those seen in HCCs. The tumors may arise from both mature hepatocytes and progenitor cells. An important criterion is nodule vascularization, visualized by imaging. The following entities seem to be important: - Cell death, hepatocyte replication, and inflammation -> contributors to DNA damage. - Poor regulation of hepatocyte replication by point mutations, such as Beta-catenin. - Defects in DNA repair. Neither HBV nor HCV contains oncogenes. Tumorigenic capacity of theses viruses probably relates primarily to their capacity to cause continuing cell death , chronic inflammation, and regeneration. The overall prognosis of HCC is grim. Median servival is 7 months, with death from 1.) profound cachexia, 2.) gastrointestinal or esophageal variceal bleeding, 3.) liver failure with hepatic coma.

2. Disorders of the gallbladder and the extrahepatic biliary tract.


2.1. Gallbladder diseases. Cholelithiasis (gallstones). Afflict 10-20% of adult population. Bile is the only significant pathway for elimination of excess cholesterol from the body. Cholesterol is water insoluble. When cholesterol concentrations exceeds the solubilizing capacity of bile, cholesterol can no longer remain dispersed and nucleates into solid cholesterol monohydrate crystals. Can occur when: - Supersaturation of the bile; - Hypomobility of the gallbladder (stasis); - Mucus hypersecretion to trap crystals. Risk factors are: Age and gender, ethenic and geographic, heredity, environment, acquired disorders. 80% remain asymptomatic throughout life. Symptoms are striking: pain tends to be excruciating, either constantly or colicky. Inflammation of the gallbladder, in association with stones, also generates pain. Cholecystitis. Inflammation of the gallbladder may be acute, chronic, or acute superimposed on chronic, and almost always occurs in association with gallstones. Acute calculous cholecystitis. Acute inflammation that contains stones and is precipitated by obstruction of the gallbladder neck or cystic duct. Symptoms may appear with remarkable suddenness. Is initially the result of chemical irritation and inflammation of the gallbladder wall in the setting of obstruction to bile outflow. Acute non-calculous cholecystitis. Most of these cases occur in seriously ill patients: 1.) postoperative state after major, nonbiliary surgery, 2.) severe trauma, 3.) severe burns ,4.) sepsis. Chronic cholecystitis.

Almost always associated with gallstones. Gallstones do not seem to have a direct role in the initiation of inflammation or the development of pain. Steady upper abdominal pain often radiating to the right shoulder. Fever, nausea, leukocytosis, and prostration are classic; presence of conjugated hyperbilirubinemia suggests obstruction of the common bile duct. Chronic choly.. does not have a striking manifestation of the acute forms and is usually characterized by recurrent attacks of either steady or colicky epigastric or right upper quadrant pain. 2.2. Disorders of extrahepatic bile ducts. Choledocholithiasis and cholangitis. Considered together because they frequently go hand in hand. Choledocholithiasis is the presence of stones within the biliary tree. Symptoms may develop because of 1.) biliary obstruction, 2.) pancreatitis, 3.) cholangitis, 4.) hepatic abcess, 5.) chronic liver disease with secondary biliary cirrhosis, or 6.) acute calculous cholecystitis. Cholangitis, term used for acute inflammation of the wall of the bile ducts, almost always caused by bacterial infection of the normally sterile lumen. Uncommon causes include tumors, indwelling stents or catheters. Bacteria most likely enter the biliary tract trough the sphincter of Oddi. Usual pathogens are E.coli, Klebsiella, Clostridium, Bacteroides, or Enterobacter. Usuallly produces fever, chills , abdominal pain and jaundice. Secondary biliary cirrhosis. Prolonged obstruction of the extrahepatic biliary tree results in profound damage to the liver itself. Most common cause of obstruction is extrahepatic cholelithiasis. Biliary atresia. Accounting for 1/3 of infants with neonatal cholestasis. Defined as a complete obstruction of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts. Features include 1.) inflammation and fibrosing stricture of the heaptic or common bile ducts; 2.) inflammation of major intrahepatic bile ducts, with progressive destruction, 3.) periportal fibrosis and cirrhosis within 3-6 months of birth. Clinical course, present with neonatal cholestasis. Have normal birth weights and postnatal weight. Stools change. Without surgical intervention, death usually occurs within 2 years of birth. 2.3. Tumors. Carcinoma of the gallbladder. Develops from the epithelial lining of the organ. Only rarely it is discovered at resectable stage, and the mean 5-year survival is 5%. Preoperative diagnosis is the exception, occuring in fewer than 20% of patients. Presenting symptoms are insidious and typically indistinguishable from those associated with cholelithiasis. Cholangiocarcinomas. Are adenocarcinomas with biliary differentiation arising from cholangiocytes in ducts within and outside of the liver. Occur mostly in individuals of 50-70 years of age. Because both intra- and extrahepatic cholangiocarcinomas are generally asymptomatic until they reach and advanced stage, the prognosis is poor. Risk factors include primary sclerosing cholangitis and fibrocystic diseases of the biliary tree. Common to the risk factors is that they all cause chronic cholestasis and inflammation.

Ch. 17. The pancreas.


Adult pancreas is a transversely oriented retroperitoneal organ extending from the c loop of the duodenum to the hilum of the spleen. A complex lobulated organ with distinct endocrine and exocrine elements. The endocrine portion constitutes only 1-2%. The islet of langerhans; secrete insulin, glucagon, and somatostatin. The exocrine pancreas is composed of acinar cells that produce the digestive enzymes, and the ductules and ducts that convey them to the duodenum. The acinar cells produce mostly proenzyme forms of

digestive enzymes and store them in membrane bound zymogen granules. When acinar cells are stimulated to secrete, the granules fuse with the apical plasma membrane and release their contents into the central acinar lumen. It is then transported to the duodenum. Amylase and lipase are exceptions and are secreted in an active form. The strategy behind this is to prevent self-digestion. Auto digestions of the pancreas has a number of fail-safe mechanisms: - Majority of pancreatic enzymes are synthesized as proenzymes; - Proenzymes are sequestered in membranebound zymogen granules; - Activation requires conversion of trypsinogen to trypsin by duodenal enteropetidase; - Trypsin inhibitors are also secreted by acinar and ductal cells; - Trypsin contains a critical self-recognition cleavage site that allows trypsin to inactivate itself in situations wherein there is a high local concentration of activated enzyme; - Most of the secreted enzymes are relatively inactive in the bicarbonate-rich pancreatic fluid. 1.1. Congenital anomalies. - Agenesis: very rarely, pancreas may be totally absent, a condition usually associated with additional severe malformations that are incompatible with life; - Pancreas divisum, an incidence of 3-10%. Occurs when the fetal duct systems of the pancreatic primordia fail to fuse. The main pancreatic duct (wirsung) is very short and drains only a small portion of the head of the gland, while the bulk of the pancreas drains through the minor sphincter. The relative stenosis caused by the bulk predisposes to chronic pancreatitis; - Annular pancreas, relatively common. Outcome is a ring of pancreatic tissue that completely encircles the duodenum. - Ectopic pancreas, occurs in about 2% of the population; favoured sites are stomach and duodenum; - Congenital cysts, result from anomalous ductal development. In polycystic disease, kidney, liver, and pancreas can all contain cysts. They are lined by duct-type cuboidal epithelium or can lack a cell lining altogether. 1.2. Pancreatitis. Acute pancreatitis. Group of reversible lesions characterized by inflammation. Relatively common. Approximately 80% of cases are attributable o either biliary tract disease or alcoholism. Other causes are: Non-gallstone obstruction, Medications including thiazide diuretics/estrogens/sulfonamides, infections with mumps, metabolic disorders, trauma/both blunt force and iatrogenic. 10-20% of patients have no identifiable cause. Histologic changes seen in acute pancreatitis strongly suggest auto digestion. Trypsin is central in this process. If trypsin is inappropriately generated from its proenzyme trypsinogen, it can activate other proenzymes. Three possible pathways can incite the initial enzyme activation that may lead to acute pancreatitis: - Pancreatic duct obstruction; increases intraductal pressure, and allows accumulation of an enzyme-rich intestinal fluid. Since lipase is secreted in an active form, this can cause local fat necrosis; - Primary acinar cell injury, comes into play in acute pancreatitis caused by ischemia, viruses, drugs and direct trauma; - Defective intracellular transport of proenzymes within acinar cells.

The manner in which alcohol causes pancreatitis is unknown. Clinical features. Abdominal pain. It is primary diagnosed by the presence of elevated plasma levels of amylase and lipase. Full-blown acute pancreatitis is a medical emergency of the first magnitude. Characteristically the pain is constant and intense and is often referred to the upper back. Manifestations are attributable to systemic release of digestive enzymes and explosive activation of the inflammatory response. Patients show increased vascular permeability, leucocytosis, disseminated intravascular coagulation. Lab findings include markedly elevated serum amylase during the first 24hours, followed by rising serum lipase levels. The enlarged inflamed pancreas can be visualised by CT or MRI. The crux of management is supportive therapy. Pancreatic pseudocysts. Liquefied areas of necrotic pancreatic tissue become walled of by fibrous tissue to form a cystic space, lacking an epithelial lining. Cause massive enlargement. Chronic pancreatitis. Longstanding inflammation and fibrosis of the pancreas with destruction of the exocrine pancreas. Chief distinction between acute and chronic is the irreversible impairment in pancreatic function in the latter. Most common cause is long term alcohol abuse. Less common causes are; long-standing pancreatic duct obstruction, tropical pancreatitis, hereditary pancreatitis due to PRSS1 mutations. Pathogenesis is not well defined, several hypotheses are: - Ductal obstruction by concretions, increase the protein concentration of pancreatic secretions and these proteins can form ductal plugs; - Oxidative stress, free radicals in acinar cells, leading to membrane lipid oxidation; - Toxic-metabolic; - Necrosis-fibrosis. It can present itself in several different ways. The diagnosis of chronic pancreatitis requires a high degree of suspicion. Gall-stone induced obstruction may present as jaundice or elevations in serum levels of alkaline phosphatase. It is usually not acutely life-threatening, the long-term outlook for individuals with chronic pancreatitis is poor, with 50% mortality rate over 20-25 years. Severe pancreatic exocrine insufficiency and chronic malabsorption may develop. 1.3. Pancreatic neoplasms.

Serous cystadenomas. Account for about of all pancreatic cystic neoplasms; they are composed of glycogen rich cuboidal cells surrounding small cysts containing clear, straw-colored fluid. They are almost uniformly benign. Mucinous cystic neoplasms. Almost always arises in women, in the body or tail of the pancreas, and present as painless, slow-growing masses. Tumors can be benign, borderline malignant, or malignant. Intraductal papillary mucinous neoplasms. Produce cysts containing mucin, and can be benign, borderline malignant or malignant. IPMNs arise more frequently in men than in women and more frequently involve the head of the pancreas. Pancreatic carcinoma. Has one of the highest mortality rates. The 5-year survival rate is less than 5%. Pathogenesis: Progressive accumulation of genetic changes in pancreatic epithelium. Antecedent lesions are called pancreatic intraepithelial neoplasias (PanINs). The epithelial cells in PanINs show dramatic telomere shortening, potentially predisposing these lesions to accumulating additional chromosomal abnormalities on their way to becoming invasive carcinoma. - K-ras gene is the most frequently altered oncogene in pancreatic cancer; mutations impair the intrinsic GTPase activity; - the p16 is most frequently inactivated tumor suppressor gene in pancreatic cancer. - SMAD4-tumor suppressor gene is inactivated in 55% of pancreatic cancers; codes for a protein that plays an important role in signal transduction downstream of the transforming growth factor-beta-receptor. - Inactivation of the p53 tumor suppressor gene occurs in 50-70% of pancreatic cancers. P53 acts both as cell cycle checkpoint and as an inducer of apoptosis.

Clinical features: typically remain silent until their extension impinges on some other structure. Pain is usually the first symptom. Obstructive jaundice can be associated with carcinoma in the head of the pancreas. Weight loss, anorexia and generalized malaise are signs of advanced disease.

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