GI

PATHOLOGY ORAL CAVITY DISEASE Gingivitis

EXAM I CAUSES CLINICAL FEATURES Gingiva squamous mucosa around the teeth; Chronic gingivitis inflamm of gingiva characterized by erythema, edema, bleeding; May occur at any age but most prevalent and severe in adolescence PATHOGENESIS MORPH/HISTO Due to poor oral hygiene resulting in build up of plaque and calculus around and on the tooth surface and beneath the gumline; Dental plaque: biofilm composed of bacteria, salivary protein, and desquamated epithelial cells Calculus (tartar) is mineralized plaque LAB DX/PROG TX reducing accum of plaque and calculus thru brushing, flossing, reg dental visits

Periodontitis

Inflamm of supporting teeth structures including periodontal ligaments, alveolar bone and cementum; due to a shift in the usual bacterial flora of the mouth combined w/ poor oral hygiene; may be assoc w/ a variety of systemic illnesses such as AIDS, Diabetes, leukemia, Crohns disease, sarcoidosis, polymorphonuclear defects Most common fibrous proliferative lesions of the oral cavity

may cause infective endocarditis, lung and brain abscesses and poor preg outcomes

Inflamm/reactive lesions

Fibroma (61%) irritation fibroma seen at bite fibroma line on buccal mucosa or gingivodental margin Peripheral ossifying young and teenage females fibroma (22% with 15 to 20% recurrence rate after excision Pyogenic granuloma Highly vascular prolif seen in kids, young adults and may regress, undergo fibrous (12%) resembling granulation tissue commonly preg (preg tumor) maturation or develop into a (may have alarming rapid peripheral ossifying fibroma growth) Peripheral giant-cell granuloma (5%) Aphthous ulcers Common superficial ulcerations (single or multiple) of oral mucosa which are painful and recurrent; these are normal mouth ulcers Mostly seen in first 2 decades of life; Cause unknown Resolve in 7 to 10 days Recurrent may be assoc w/ celiac disease and IBS

Glossitis

beefy red tongue caused by atrophic papillae and thinning of the mucosa exposing the underlying vasculature seen in many def states; def of vit B12, riboflavin (B2), niacin, pyridoxine (B6), sprue, iron deficiency

may have glossitis characterized by ulcerations due to jagged carious teeth, ill fitting dentures or rarely syphilis, inhalation burns or ingestion of corrosive substances

Plummer -Vinson combo of iron-deficiency syndrome (or anemia + glossitis + Paterson-Kelly esophageal dysphagia usually syndrome) due to a web DISEASE Geographic tongue CAUSES CLINICAL FEATURES PATHOGENESIS MORPH/HISTO The tongue develops multiple Over a period of days or weeks, Uncertain cause, some foods may areas of desquamation (loss) the smooth areas and the exacerbate problem; resolves of the filiform papillae in whitish margins seem to w/in mths several irregularly shaped but migrate across the surface of well-defined areas. the tongue by healing on one The smooth areas resemble a border and extending on map, thus the name another (migratory) geographic tongue. F:M = 3:1 LAB DX/PROG TX no proven tx, resolves spont.

Fissured tongue

normal variant; its cause is Melkersson-Rosenthal unknown; Prevalence of 2-5% syndrome is a rare condition of population; dorsal surface consisting of a triad of of the tongue appears to persistent or recurring lip or have deep fissures or grooves facial swelling, intermittent that become irritated if food seventh (facial) nerve paralysis debris collects in them (Bell palsy), and a fissured tongue -the etiology of this syndrome is also unknown Herpes simplex virus Initial infection is usually Fever, anorexia, irritability, asympt occurring during lymphadenopathy with vesicles preschool years but may have and ulcerations thruout the acute herpetic mouth, especially of the gingivostomatitis in 10 to gingiva; recurrent: Localized 20%; Recurrent infections group of small vesicles (1-3 due to reactivation of latent mm) on lips, nasal orifices, HSV-1 residing in ganglia buccal mucosa, gingiva and hard palate; may predispose to reactivation including trauma, allergies, URI, immunosupp

benign

brush the tongue gently with a soft toothbrush to keep the fissures clean of debris and irritants

Tzanck test - examine vesicle fluid for giant cells from cell fusion and intranuclear viral inclusions

diff from other infections make sure kids stay w/ oral findings: Measles hydrated or rubeola (a paramyxovirus) Koplik spots on buccal mucosa; Scarlet fever (caused by toxin producing Group A streptococcus) - strawberry tongue; Enteroviruses - hand-foot- and-mouth disease (mainly coxsackie virus A 16 in US)

Oral candidiasis

may be a normal component common in babies of the oral flora in ~50% of ppl; MC form is pseudomembr. form or thrush->superficial, gray- white membrane which can be scraped off revealing an erythematous base; May occur in those with immunosupp due to diabetes, transplant recipients, AIDS, neutropenia; may also occur if normal oral flora eradicated by antibiotics Caused by EBV Characterized by white, 80% of patients have HIV and the Micro: hyperparakeratosis and confluent, hairy patches on rest have some other type of acanthosis w/ balloon cells in the the lateral aspects of the immunosupp upper spinous layer --> pic tongue due to hyperkeratosis which cannot be scraped off like thrush Gross: Solitary or multiple white patches with a variety of appearances form smooth, thin and well demarcated to irregular, thick and diffuse; MC locations are buccal mucosa, floor of mouth, ventral surface of tongue, palate and gingiva; Micro: Varies from hyperkeratosis and acanthosis to marked dysplasia and carcinoma in situ PATHOGENESIS

can scrap this off

Hairy leukoplakia

CANNOT be scraped off like thrush

Leukoplakia

more common from 40 to 70 defined as a white patch in the years of age and in those that oral cavity which cannot be use tobacco scraped off and cannot be diagnosed as another disease either clinically or pathologically

"

must be considered premalignant until proved otherwise by biopsy

DISEASE Erythroplakia

CAUSES CLINICAL FEATURES less common but much more likely to have malignant transformation than leukoplakia; red plaque

MORPH/HISTO LAB Gross: Red, velvety possibly eroded area which may be level with the surrounding mucosa or slightly depressed; Micro: 90% show dysplasia, carcinoma in situ or carcinoma w/ intense subepi inflamm w/ vasc dilation (causing red appearance)

DX/PROG "

TX

Squamous cell carcinoma (SCC) of the oral cavity

95% of head and neck; middle aged men who smoke tobacco and alcohol; 50% of oropharyngeal CA has oncogenic HPV, especially in the tonsils, base of tongue and oropharynx; may complain of ear pain, w/ a mass on the tonsil referring pain

hyperkeratinization and pearly appearance w/ no organization whatsoever; inflamm, vasc congestion

Gross: MC locations ventral surface of tongue, floor of mouth, lower lip, soft palate and gingiva Appearance raised, firm pearly plaques or irregular roughened or verrucous areas on a background of leukoplakia or erythoplakia; May b'c ulcerated protruding masses as they enlarge; Micro: Begin as dysplastic lesions which may or may not progress to full thickness dysplasia or CIS before invading; SCC may vary from well diff keratinizing to anaplastic CA (however, degree of diff is NOT correlated with behavior)

Early stage oral cancer has 80% survival at 5 years which drops to 19% for late stage cancer; rate of second primary tumors is 3-7% per year; overall survival of head and neck is 50%

ESOPHAGUS esophageal obstruction

1. Functional obstruction due 2. Stenosis may be congenital 3. Mucosal webs ledge-like 4. Schatzki ring Rings are to esophageal dysmotility but often due to scarring from protrusions of mucosa (less than circumferential and thicker than chronic GE reflux, irradiation or 5mm protrusion and ~2-4 mm webs caustic injury thick) into the lumen; MC in women over 40; associated w/ chronic GE reflux, chronic graft- versus-host disease or blistering skin disease; Plummer-Vinson syndrome Web with Fe deficiency, glossitis, increased tone of the lower esophageal sphincter (LES), incomplete LES relaxation and aperistalsis of the esophagus Primary: Idiopathic failure of distal esophageal inhibitory neurons, thus it relaxes; Secondary: Chagas disease from Trypanosoma cruzi infection causes destruction of myenteric plexus with loss of peristalsis and esophageal dilation; Achalasia-like disease w/ diabetic neuropathy, infiltrative diseases such as amyloidosis or sarcoidosis, polio, etc

Achalasia

Esophageal Diverticuli Pseudodiverticuli only mucosa protrudes though the wall, not the muscularis Pulsion diverticuli Occurs from increased stress Zenker diverticulum to the esophageal wall from (pharyngoesophageal diffuse esophageal spasm diverticulum) located causing increased pressure at immediately above the upper a weak spot in the wall esophageal sphincter, very rare, occurs in men and the elderly; Sx: halitosis, regurgitation, dysphagia (fills up with food causing mass effect); complications are aspiration and pneumonia

Epiphrenic diverticulum: immed above lower esophageal sphincter due to esopageal propusion agasitn a closed lower esophageal sphincter

Traction diverticuli due to pulling forces on the outside of esoph. from an adjinflam DISEASE CAUSES process Mallory-Weiss tears Longitudinal tears of the distal esophagus just above the GE junction (may involve the stomach as well) associated with severe retching or vomiting classically assoc w/ acute ethanol intoxication; Likely occurs due to sudden rise in intraluminal esophageal pressure due to failure of cricopharyngeus muscle to relax from neuromuscular dysfunction in prolonged vomiting Esophageal injury due to alcohol, acids or alkalis, very hot fluids, heavy smoking, pill- induced; Iatrogenic - irradiation, chemotherapy, graft versus host disease; Infections: immunosupp w/ MC-> Herpes, CMV or fungal

CLINICAL FEATURES

PATHOGENESIS look at linear streak -->

MORPH/HISTO

LAB

DX/PROG TX generally self limited, not requiring Rx; Rarely, a distal esophageal rupture may occur (Boerhaave syndrome) a life threatening emergency

Esophagitis

Esophagus may be involved with desquamative skin disease such as bullous pemphigoid or epidermolysis bullosa Rarely, Crohns disease

Reflux esophagitis most freq GI dx and cause of (Gastroesophageal esophagitis; MC in adults reflux disease (GERD)) over 40 but also occurs in infants and children; conditions which exacerbate GERD include alcohol and tobacco use, obesity, CNS depressants, pregnancy, hiatal hernia, delayed gastric emptying and increased gastric volume; Severity of sx not necessarily related to degree of histologic changes to esophagus

Marked elongation of papillae; Basal zone hyperplasia; Eosinophils in mucosa and neutrophils with more severe esophagitis

gross: may only see redness (complications may be ulcerations, Barretts or stricture formation) Micro:Normal mucosal histology with mild disease; eosinophils are present in the squamous mucosa and neutrophils with more severe injury; Basal zone hyperplasia > than 20% of total epithelial thickness; Elongation of lamina propria papillae, extending into upper 1/3 of the epithelium

complications include ulcerations, hematemesis, melena, stricture development and Barrett esophagus

Eosinophilic esophagitis

Increasing incidence seen in atopic individuals not assoc w/ acid reflux with no improvement using proton pump inhibitors

adults - food impaction and dysphagia; Children - feeding intolerance or GERD-like symptoms left: reg esophagitis; right: eosinophilic esophagitis -->

large numbers of eosinophils in the squamous epithelium, particularly superficially

avoid food allergens, corticosteroids

Barrett esophagus

intestinal metaplasia of the esophageal mucosa is lined by esophageal squamous non-keratinzed stratified mucosa and confers an squamous epithelium --> increased risk for esophageal adenocarcinoma (However, most people with Barrett do not develop carcinoma)

Complication of chronic GERD; Barrett occurs in 10% of people with symptomatic GERD, most common in white males, 40 to 60 years of age

Gross: Red, velvety tongues or gastric mucosa is lined by patches of mucosa extending columnar glandular epithelium -> upward from the GE junction into the esophagus w/intervening pale tan squamous mucosa; Long segment (3 cm or more of esophagus involved) versus short segment (less than 3 cm is involved); Micro: Intestinal metaplasia as defined by the presence of goblet cells (mucous vacuoles imparting the shape of a goblet to the cell); Foveolar mucous cells are NOT goblet cells MORPH/HISTO LAB Morph: On venogram, varices appear as tortuous dilated veins lying in the submucosa of the distal esophagus and proximal stomach and directly beneath the esophageal epi; At autopsy, varices may not be obvious since they collapse with no blood flow; ucosal ulceration may occur w/hemorrhage into the wall of the esophagus; W/ past rupture, venous Gross:Location is distal 1/3 of esophagus and may involve the gastric cardia; Varies from flat or raised patches to large masses;may have ulcerations and diffuse infiltration and invasion w/o large masses; Micro: Glands, mucin formation or may be small poorly diff cells; may have diffuse infilt. of signet ring cells; Barrett esophagus may be adjacent to the tumor

can only be diagnosed by see big goblet cells, endoscopic evidence of which do not normally abn esophageal mucosa belong in esophagus AND histo evidence of intestinal metaplasia; followed by regular endoscopies and biopsies to look for the dev of DYSPLASIA (characterized by cytologic and architect. abn)

DISEASE Esophageal varices

CAUSES Dilated congested venous plexus of the distal esophagus (and proximal stomach); due to portal HTN (mostly due to hepatic cirrhosis)

CLINICAL FEATURES PATHOGENESIS Unruptured varices are usually asympt.; rupture may lead to massive hemorrhage

DX/PROG 1/2 pts die from 1st bleeding episode despite therapy; In survivors, re- hemorrhage may occur in over 50% within a year

TX sclerotherapy by endoscopic injection of thrombotic agents, balloon tamponade, rubber band ligation

esophageal tumors Adenocarcinoma Caucasian; M7x>W; freq w/ Barrett esophagus due to longstanding GERD; Other risk factors: tobacco, obesity and prior radiation therapy

May discover on endoscopy for Progression of Barrett esophagus monitoring of Barrett is due to a stepwise accum of esophagus or in the initial genetic and epigenetic defects evaluation of GERD; MC: pain over time or diff swallowing, wt loss, hematemesis, CP, vomiting

POOR prognosis! when sx occur, the tumor is at an advanced stage at dx w/ overall 5 year survival less than 25%; 5 year survival is 80% w/ cancer limited to mucosa or submucosa

Squamous cell adults >45, M>F; AA>C; carcinoma Risk factors: In US, alcohol and tobacco are major risk factors and felt to have a synergistic effect; nutritional deficiencies, nitrosamines and other mutagenic compounds, fungus contaminated food, HPV is some high risk areas, poverty, caustic esophageal injury, achalasia, tylosis (genetic disorder with hyperkeratosis of palms and soles and oral leukoplakia), Plummer-Vinson syndrome, frequent consumption of very hot drinks SMALL INTESTINE Intestinal obstruction Adhesions bowel gets attached to another part of itself, but doesn't cut off blood supply Volvulus Twisting of a segment of Usual locations: Adults- cecum, Often associated with congenital bowel on its mesenteric base sigmoid colon, or SI; Children - intestinal malrotation of gut in of attachment; Leads to SI kids obstruction, infarction, gangrenous bowel Intussusception Telescoping of a proximal segment of bowel into the distal segment; usually idiopathic; MC occurs at terminal ileum -> ileocolic intussusception DISEASE CAUSES Hirschsprung Disease AKA congenital toxic megacolon; by congenital absence of PNS ganglion cells in the rectum and sigmoid colon resulting in obstruction 80% male; usually sporadic :1 per 5,000 live births Leads to obstruction, ischemia, intestinal mucosal bleeding term currant jelly stool; MC in infants and children

Gross: middle 1/3 of esophagus; Early lesions are gray-white plaque like thickenings which grow into tumor masses that protrude into and obstruct the esophageal lumen; May be ulcerative and diffusely infiltrative causing diffuse thickening of wall and narrowing of lumen; May invade mediastinal structures; Micro:Most are moderately diff SCC w/ less common histologic variants such as verrucous SCC, spindle cell and basaloid

TX: surgical exploration to untwist and resect gangrenous bowel

Contrast enema is diagnostic in approx 95% of intussusception cases and it is therapeutic and curative in most cases w/ less than 24-hour duration LAB DX/PROG TX TX: Surgical resection

CLINICAL FEATURES PATHOGENESIS MORPH/HISTO failure to pass meconium, the part w/ ganglion cells is the obstructive constipation; may good part; lack of inhibitory have occasional passage of activity but increased extrinsic stool or diarrhea if only a short innerv. Is causing uncoordinated segment of rectum is affected; peristalsis and increased tone Prox innerv colon may b'c massively distended (15 cm in diameter) w/ mm wall hypertrophy and rupture/perforation, may have superimposed enterocolitis and electrolyte abnormalities

Ischemic bowel disease

Causes of acute arterial obstruction include severe atherosclerosis, aortic aneurysm, hypercoagulable states, oral contraceptives, embolization of cardiac vegetations or aortic atheromas; Hypoperfusion assoc w/ cardiac failure, shock, dehydration or vascoconstrictive drugs; Systemic vasculitides; Mesenteric venous thrombosis

Acute transmural infarction Initial hypoxic injury Epithelial morph: Mucosal and mural sudden onset severe abdl pain, cell lining the intestines are infarction (mural involves mucosa w/ N&V, bloody D or melanotic relatively resistant to hypoxia and submucosa) usually the result stools; may progress to shock Reperfusion injury greatest of chronic or acute hypoperfusion: and death due to blood loss damage occurs during this phase Continuous lesions or segmental and/or sepsis; Mucosal and with infiltration of neutrophils and patchy, Dark red or purple mural infarctions and release of inflammatory mucosa with possible hemorrhage May have non-specific abd mediators and free radical and ulceration and thickened complaints, intermittent production edematous bowel wall but absent bloody stool,etc; May dev Major variable in ischemic bowel serosal involvement; collateral circulation in chronic disease: the severity of vascular Transmural infarction usually due ischemia or progress to more compromise; the vessels affected; to acute arteria obstruction extensive infarction if the time frame substantial portion of bowel underlying cause of ischemia involved with sharp demarcation not corrected between normal and infarcted bowel which is dusky red to purple and edematous with serositis; Perforation may occur

histo: Atrophic epi w/ fibrotic lamina propria (chronic) or sloughing of epi w/possibly hyperproliferative crypts trying to replace the epi; w/ acute ischemia, neutrophils infiltrate w/in hrs of reperfusion; Bacterial superinfection may occur in acute ischemic damage

red dusky bowel

Dysentery

Painful, bloody small-volume diarrhea Diarrhea Increase in stool mass, frequency or stool fluidity, > 200 g/day; Severe cases may exceed 14 L per dluid Secretory diarrhea loss of intestinal fay that is isotonic with plasma and persists during fasting Osmotic diarrhea secondary to excessive osmotic forces exerted by unabsorbed luminal solutes; the diarrhea fluid is over 50mOsm more concentrated than plasma and it abates with fasting. Exudative diarrhea purulent bloody stool (inflammation of the mucosa and/or hemorrhage) that continue during fasting

Viruses: e.g. rotavirus; toxin- mediated: E.coli (need time for toxin to build up); preformed toxin: SA (rapid effect)

Lactase def, Lactulose therapy: used for constip, hepatic encephalopathy, Sorbitol: used to tx constip., Gut lavage b/f endoscopy, antacids

Infections causing tissue damage: Shigella, Salmonella, Entamoeba histolytica; Infections causing both tissue damage and toxins: clostridium difficile; with antibiotic therapy, leading to pseudomembranous colitis Idiopathic IBS Anemia: iron, folate and B12 nutrient absorption: 1. def, vit K def, Osteopenia: Ca & Intraluminal digestion proteins vit D def; Amenorrhea, and fats broken down into forms impotence, infertility; suitable for abs; 2.Terminal Purpura: vitamin K def; digestion hydrolysis of carbs & Dermatitis: vit A def; peptides in the brush border of SI; Peripheral neuropathy: folate 3. Transepithelial transport - and B12 def, vit A transported into and processed by epi; 4.Lymphatic transport of absorbed lipids malabsorption syndromes: 1. Defective intraluminal digestion: pancreatic insuff, defective bile secretion; 2. Mucosal abn: Disaccharide def (lactose intolerance); 3. Reduced surface area: Gluten-sensitive enteropathy (Celiac disease) , Surgical resection; 4. Infections: Tropical sprue?, Whipple disease

Malabsorption present as a chronic diarrhea characterized by defective absorption of fats (steatorrhea), fat and water- soluble vitamins, proteins, carbohydrates, electrolytes minerals and water; may be diarrhea, flatus, abd pain and wt; Diarrhea abates with fasting

types of malabsorption diseases: DISEASE CAUSES Celiac Disease AKA celiac sprue, nontropical sprue or gluten-sensitive enteropathy; An immune mediated enteropathy precipitated by gluten, a protein in wheat, rye barley in genetically susceptible people; MC in European ancestry; prevalence is 0.5- 1%

CLINICAL FEATURES sx due to loss of epithelium resulting in decreased surface area for absorption and immature enterocytes replacing injured cells; Dermatitis herpetiformis - ~10% , an itchy blistering skin lesion in which IgA antibodies to gliadin cross react with reticulin in the skin --> pic

PATHOGENESIS MORPH/HISTO LAB Immune reaction to gliadin, an Biopsy from duodenum or proximal Diagnosis based on histology in amino acid produced by intestinal jejunum: intraepithelial combo w/ serology; most digestion of gluten lymphocytes, villous atrophy, sensitive tests are IgA antibodies Two mechanisms of cellular crypt hyperplasia, Increased plasma to tissue transglutaminase or IgA damage: Gliadin induces epithelial cell, mast cells and eosinophils in or IgG antibodies to deamidated cells to express IL-15 ultimately the lamina propria gliadin; Antiendomysial results in cytotoxic T-cells killing antibodies are highly specific but enterocytes; Deamidated gliadin less sensitive than above interacts with HLA-DQ2 or HLA- DQ8 on antigen-presenting cells which are presented to CD4+ T cells which then produce cytokines causing tissue damage; Other immune diseases assoc w/ celiac disease may be type1 diabetes, thyroiditis and Sjogren syndrome

DX/PROG Increased risk for enteropathy-associated T- cell lymphoma and small intestinal adenocarcinoma

TX Treatment is gluten free diet pic --> left normal, right is celiac

tropical sprue

Idiopathic celiac-like disease found almost exclusively in people living in or visiting the tropics Rare disease caused by Presents with malabsorption, Trophermyma whipplei (gram diarrhea, weight loss positive rod-shaped bacilli) May involve any organ but typically affects intestine, CNS, and joints; MC Caucasian male age 30-50 yo

Micro: loss of villi similar to celiac disease

Whipple Disease

Micro: small bowel lamina propria with numerous macrophages filled with PAS-positive granules which are lysosomes stuffed with partially digested microorganisms

broad spectrum antibiotics is effective which would seem to indicate an infectious etiology diff from mycobacterium Prompt response to infection --> this will stain antibiotics w/ acid fast stain, and whipple's disease will not

Lactase deficiency

Congenital:AR disorder caused by a mutation in the gene encoding lactase; Unable to digest lactose in milk which is osmotically and leads to an explosive diarrhea w/ watery, frothy stools and abd distention

Acquired:Down regulation of lactase gene expression after childhood, MC in Native American, African-Americans and Chinese Enteric viral or bacterial infections

Infectious Enterocolitis

Global problem Types: More than 12,000 deaths per Viral day among children in Bacterial developing countries, and Parasitic constituting one half of all deaths before age 5 worldwide; In industrialized nations these infections have attack rates of one to two illnesses per person per year, second only to the common cold in frequency. Mainly associated with contaminated food and water

Viral Gastroenteritis Symptomatic human infection is caused by several distinct groups of viruses: Rotavirus Calciviruses (Norwalk-like viruses, Sapporo-like viruses), DISEASE CAUSES CLINICAL FEATURES Rotavirus With the loss of absorptive function and excess of secretory cells, there is net secretion of water and electrolytes, compounded by an osmotic diarrhea from incompletely absorbed nutrients

PATHOGENESIS MORPH/HISTO 6-24 months of age; MC cause of severe childhood diarrhea and diarrheal mortality worldwide Fecal-oral mode of transmission w/ estimated minimal infective inoculum of 10 viral particles; Selectively infects and destroys mature enterocytes in the small intestine, without infecting crypt cells; Surface epithelium of the villus is repopulated by immature secretory cells; the classic Caliciviruses (Sapporo- like viruses) and the Norwalk-like viruses (small round structured viruses); Sapporo-like viral infection is rare Norovirus (previously known as Norwalk-like viruses) is responsible for half of nonbacterial food-borne epidemic gastroenteritis worldwide and a common cause of sporadic gastoenteritis in developed countries (infections spread easily in schools, hospitals, nursing in SI, adenoviral infection causes atrophy of the villi and compensatory hyperplasia of the crypts similar to rotavirus; The virus can also cause colitis Identifying nuclear viral inclusions helps in making the diagnosis

LAB

DX/PROG

TX

Calicivirus

Enteric Adenovirus

Outbreaks occur following exposure of multiple individuals to a common source; incubation period of 1 to 2 days followed by 12 to 60 hours of N/v/ watery diarrhea, and abd pain cause a moderate gastroenteritis with diarrhea and vomiting, lasting for a week to 10 days after an incubation period of approximately 1 week

Self-limited disease

Numerous types of adenovirus Subtypes (enteric serotypes) Ad40, Ad41, and Ad31 appear to be responsible for enteric infections and are a common cause of diarrhea among infants

Can be distinguished from Self-limited disease adenoviruses that cause respiratory disease by their failure to grow easily in culture

astrovirus

Diarrhea, anorexia, headache, Named after its starlike and fever appearance; Primarily affects children worldwide

Bacterial Enterocolitis Symptomatic human Rapid onset of diarrhea, infection is caused by abdominal discomfort numerous bacteria; AKA food poisoning

mech: Ingestion of preformed toxin (Present in contaminated food, Major pathogens: SA, Clostridium perfringens, Vibrio cholerae, other vibrio spp., Bacillus cereus (yesterdays rice)), Infection by toxigenic orgs, Infection by enteroinvasive orgs Comma shaped gram negative bacteria, Non-invasive with preformed enterotoxin causing disease (encoded by a virulence phage), Flagellar proteins involved in motility and attachment necessary for bacterial colonization;Hemagglutinin (metalloproteinase) imp for bacterial detach/shedding in stool Enterohemorrhagic-O157:H7 serotype seen in inadequately cooked ground beef. Shiga-like toxins. Bloody diarrhea and hemolytic uremic syndrome (HUS) Enteroaggregative-adhere to epithelial cells, travelers diarrhea, non-bloody Cholera toxin incorporated into the cell resulting in increased cAMP opening the cystic fibrosis transmembrane conductance regulator, CFTR, which releases chloride ions into the lumen -> causes secretion of bicarbonate, sodium and water with massive diarrhea; only minimal alterations of S.B mucosa. Mortality 50% without treatment but over 99% survival with fluid replacement. IV fluid replacement

Cholera

Incubation period - 1 to 5 days; Endemic in Ganges Valley of India Most exposed individuals are and Bangladesh; Contaminated asymptomatic or develop only drinking water and sporadic cases mild diarrhea; Abrupt onset of of seafood-associated disease in voluminous watery diarrhea North America; Vibrio (rice water stools); 1 liter per parahaemolyticus-most common hour; Dehydration, shock with cause of seafood-associated death in 24 hours for severe gastroenteritis in N. America; cases. Enterotoxigenic-MC cause of travelers diarrhea, secretory diarrhea with production of heat- labile and heat-stable toxin. Enteroinvasive- invade epithelial cells, bloody diarrhea, acute self- limited colitis

E. Coli

self-limited, no need for Abx

Salmonella (typhoid and non- Vomiting, profuse diarrhea or S. enteriditis causes most typhoid Salmonella) dysentery, abdominal pain nontyphoid Salmonella infection -> I million cases a year in US; Contaminated beef and chicken, poultry, eggs and milk DISEASE Typhoid fever CAUSES CLINICAL FEATURES PATHOGENESIS Invades intestinal epithelial Week1: fever, chills, septicemia cells and tissue mps; systemic (90% with + blood cultures); illness caused by S. typhi or S. Week 2: rash (Rose spots on paratyphi (Humans are the chest and abd), abd pain (may sole reservoir of both) mimic appendicitis), exhaustion; Week 3: ulceration of Peyers patches in ileum, intestinal bleeding, shock. Perforation may occur; - Typhoid nodules, macrophage aggregates,may develop in liver, BM, lymph nodes and phagocyte hyperplasia in spleen; gallbladder colonization assox w/gallstones and chronic carrier state MORPH/HISTO LAB DX/PROG

do not use Abx; Self- limited,abx not recomm. since it prolongs carrier state or even cause relapse and does not shorten diarrhea durat. TX

Shigella

May produce Shiga toxin Hemolytic uremic syndrome Causes dysentery with a high mortality rate in the developing world (10% of diarrheal illness and ~75% of deaths) Very low infective dose

Invades intestinal epithelial cells but do not go beyond lamina propria and are phagocytosed by mp and induce apoptosis. The ensuing inflamm process damages surface epithelium and allows the Shigella to have access to the colonocyte basolateral membrane (left colon prominent site of infection but ileum may be involved) Reservoir- Chickens, sheep, pigs, cattle; Transmission poultry, milk, water Complications- arthritis, Guillain-Barre (rare)

Campylobacter jejuni Flagellated, gram-negative, Colon is affected GI site; comma-shaped organsims Watery or bloody diarrhea Most common bacterial enteric infection in developed countries and a cause of travelers diarrhea. Yersinia Yersinia enterocolitica and Abd pain/F/D and may mimic pseudotuberculosis cause GI appendicitis; extra-intestinal sx disease; Northern and central of pharyngitis,arthralgia, and Europe; Affected GI sites- erythema nodosum may occur Ileum, appendix, right colon.

Reservoir- pigs; Transmission- pork, milk, water; org multiplies extracellularly in lymphoid tissue with hyperplasia of Peyers patches and lymph nodes left: entamoeba histolytica, middle: giardia, right: cryptosporidia --> lots of mp

Complications- arthritis, myocarditis, thyroidits, GN

parasites

Entamoeba histolytica: oral- fecal transmission, invasive, amebic colitis and amebic liver abscesses Giardia lamblia: oral-fecal spread, contaminated water or food (cysts are not killed by chlorination) , noninvasive, duodenum and jejunum, diarrhea and malabsorption Cryptosporidium: self-limited diarrhea in immunocomp Pseudomembranous AKA antibiotic associated diarrhea, fever, abdominal pain Colitis colitis; Acute colitis with adherent inflamm exudate (pseudomembrane) overlying sites of mucosal injury, usually after broad spectrum antibiotics which favor the overgrowth of Clostridium difficile over other gut bacteria SI tumors: Uncommon site for benign or malignant tumors CAUSES CLINICAL FEATURES

Classically assoc w/ clindamycin usage but also seen with cephalosporins; makes a toxin

Gross: yellow-white or yellow- green mucosal plaques or 'pseudomembranes Micro: karyorrhectic debris and neutrophils that adheres to denude mucosal surface Neutrophils emanating from crypt is like volcanic eruption

TX: oral vancomycin or metronidazole

DISEASE

PATHOGENESIS

MORPH/HISTO

LAB

DX/PROG

TX

Carcinoid tumor

Neuroendocrine tumors Majority are found in the GI tract with 40% of these in SI; next MC site are the bronchi and lungs

Peak incidence 60s; sx depend These tumors arise in the GI tract upon the hormone secreted, from endocrine cells which i.e. gastrin secreting tumor secrete hormones which causes Zollinger Ellison coordinate gut function syndrome; Carcinoid syndrome caused by vasoactive compounds rarely occurs in GI tract carcinoids due to first pass effect thru the liver unless they are metastatic

Gross: Intramural or submucosal nodule, Firm, yellow-tan Micro:Islands, trabeculae, glands or sheets of uniform cells, round to oval nucleus with salt and pepper nuclei with scant ,pink granular cytoplasm; Usually minimal pleomorphism Prognosis depends on location with those in the jejunum and ileum the most aggressive

Leiomyosarcoma of very rare small bowel Inflammatory Bowel Chronic bowel disease More common in females disease resulting from inapp Presents in 20s and 30s activation of mucosal More common in Caucasians immune response; Due to Most common in N. America, reduced frequency of enteric northern Europe and Australia infections, the immune Hygiene hypothesis response to pathogens is poorly regulated resulting in an overwhelming immune response and chronic inflamm disease in those who are susceptible; Acute infectious gastroenteritis has preceded onset of IBD in some individuals Crohns disease- may involve any area of the mild D/F/abd pain; may GI tract and is transmural presents w/ RLQ pain, bloody D/F; sx free periods occur; Attacks can be precipitated by physical or emotional distress, specific dietary items; Cigarette smoking assoc w/ Crohns and disease onset has occurred w/ initiation of smoking but stopping does not cause remission

Idiopathic but Not considered an autoimmune disease; results from a combo of defects in host interactions with intestinal microbiota, intestinal epithelial dysfunction and aberrant mucosal immune responses Genetic factors more dominant in Crohns than ulcerative colitis

TRANSMURAL INVOLVEMENT morph: Skip lesions areas of micro: Noncaseating granulomas Complications: Most commonly involved sites are disease interspersed with normal a hallmark of Crohns seen in Malabsorption, Fibrosing terminal ileum, ileocecal valve, areas; 35% in active or uninvolved strictures req surgical and cecum but may involve any Mucosa has cobblestone regions involving any layer of resection; freq recurs at area of the GI tract --> this will appearance (disease tissue is wall and may occur in mesenteric the anastomotic site; involve entire bowel wall depressed below the normal nodes; cutaneous granulomas Fistulae formation mucosa); Mucosal ulcers may may occur (metastatic Crohns); involving adjacent loops of coalesce in elongate serpentine Neutrophils infiltrating crypt epi bowel or strictures such as ulcers oriented along the axis of the and may form crypt abscesses bladder, vagina skin; bowel; Mucosal fissures which may with crypt destruction; Mucosal Colonic disease has develop b't mucosal folds and ulcerations with intervening increased risk of colonic extend thru the wall become fistula normal mucosa adenocarcinoma w/long- tract or sites of perforation; Distortion of mucosal standing colonic disease; Strictures are common: Wall is architecture with bizarre Extraintestinalmanifestati thickened and rubbery due to branching and orientation of ons of disease include transmural edema, inflamm, normally straight and parallel uveitis, migratory submucosal fibrosis and glands; Metaplastic change - polyarthritis, sacroiliitis, hypertrophy of the muscularis Pseudopyloric metaplasia and ankylosing spondylitis, propria which contribute to Paneth cell metaplasia in left erythema nodosum, stricture formation; Creeping fat- colon clubbing; Pericholangitis Mesenteric fat may extend around and sclerosing cholangitis the serosal surface may occur but are more common in ulcerative colitis

DISEASE CAUSES CLINICAL FEATURES Ulcerative colitis disease involves the mucosa and submucosa and is limited to colon and rectum (unlike crohn's); relapsing disorder characterized by attacks of bloody D with mucoid material, lower abd pain and cramps temporarily relieved by defecation;

PATHOGENESIS Factors which may trigger initial episode are infectious enteritis, stress and cessation of smoking; Always involves the rectum and extends proximally with no skip lesions (sometimes focal appendiceal or cecal lesions are seen); 1. Pancolitis entire colon is involved;2. Left sided disease extends no further than the crypt abscess and destruction -- transverse colon; 3. Limited distal > pic disease ulcerative proctitis or ulcerative proctosigmoiditis; 4. Backwash ileitis distal ileum may have mild inflammation with a severe pancolitis

MORPH/HISTO LAB morph: Colonic mucosa may be red and granular or may have broad based ulcers; Pseudopolyps regenerating mucosa which bulges into the lumen with tips fusing to form mucosal bridges; Mucosal atrophy may occur w/ chronic disease; NO strictures, mural thickening or serosal involvement; histo: Inflamm infiltrates, crypt abscesses, architectural crypt distortion and epi metaplasia which is diffuse and limited to the mucosa Ulcerations may occur and involve the submucosa; w/ healing- mucosal atrophy, submucosal fibrosis and distorted mucosal architecture may or may have normal mucosa after a prolonged remission; NO granulomas

DX/PROG TX Extra-intestinal diseases similar to Crohns with 2.5% to 7.5% of ulcerative colitis patients with primary sclerosing cholangitis; Increase risk of colon adenocarcinoma; complication: Toxic megacolon may occur - severe colonic dilation due to damage to muscularis propria causing abn neuromuscular fxn

difference:

Crohn disease: Small bowel (particularly terminal ileum) and colon (mostly right side); Patchy involvement; Transmural inflammation, fistulas, strictures, serositis; Non-caseating granulomas; Poor response to surgery; Increased risk for cancer

ulcerative colitis: Colon only; Continuous involvement; Superficial inflammation; No granulomas; Good response to surgery; Increased risk for cancer

Indeterminate colitis Overlapping signs and symptoms of Crohns and ulcerative colitis Meckel diverticulum A blind pouch located in distal small bowel (ileum) ; MC congenital anomaly of SI; results from failure of the involution of the omphalomesenteric (vitelline) duct; ~1/2 contain heterotopic rests of gastric mucosa or pancreatic tissue; The rule of 2s: 2% of the population, 2 inches in length, 2 feet proximal to the ileocecal valve, 2 types of

most asymp; Overgrowth of bacteria that depletes vit B12 diverticulum are discovered leading to anemia; Ulcer and incidentally during surgical bleeding; Obstruction procedures; located in ileum

Overtime, features may develop that help establish diagnosis which may be important as new therapies evolveeckel's Most cases of M

Acute Appendicitis

Acute bacterial infection of periumbilical pain that the appendix assoc w/ migrates to right lower obstruction in 50-80% of quadrant, nausea/vomiting, cases usually by a fecalith and anorexia, tenderness (direct less commonly by a gallstone, and with rebound) at tumor, or ball of worms McBurneys point, leukocytosis (enterobius vermicularis)

Gross: fibrinopurulent exudate on serosa, prominent vessels; lumen may contain blood-tinged pus; may be areas of perforation, mucosal ulceration, fecalith or other obstructing agent;

Micro: mucosal ulceration; minimal (if early) to dense neutrophils in muscularis propria with necrosis, congestion, perivascular neutrophilic infiltrate; late - absent mucosa, necrotic wall, prominent fibrosis, granulation tissue, marked chronic nflamm infiltrate in wall, thrombosed vessels DX/PROG TX

DISEASE Angiodysplasia

CAUSES CLINICAL FEATURES Characterized by malformed submucosal and mucosal BV; Most freq locations: cecum or R colon; age > 60; Prevalence is < 1% in the adult pop, accounts for 20% of major episodes of lower GI bleeding (acute and massive or chronic and intermittent)

Diverticulosis

PATHOGENESIS MORPH/HISTO LAB Mechanical factors: Norm morph: Ectatic nests of tortuous distension and contraction of veins, venules, and capillaries, colon may lead to intermittent Separation of the vessels from the occlusion of submucosal veins bowel lumen may be only the causing surface vessels to b'c blood vessel wall and a layer of congested and overdistended w/ attenuated epit causing increased chronic dilation /tortuosity susceptibility to bleeding by only developing over time; minor trauma degenerative vascular changes related to aging; Dev component - angiodysplasia has been Diverticulum: blind pouch Only 20% develop symptoms Congenital: have all 3 layers of leading off alimentary tract, due to infection -> diverticulitis bowel wall (mucosa, submucosa, lined by mucosa that (may perforate) or cause and muscularis propria) communicates with gut bleeding Acquired: lack or have lumen attenuated muscularis propria due to focal weakness in wall and increased intraluminal P; assoc w/ Western diets (low fiber causes prolonged transit time and increased intraluminal pressure associated with low volume stools); rare in Asia, Africa, South America where high residue diet is common; Rare before age 30 Juvenile polyps (mostly rectal, present with bleeding); Peutz-Jeghers syndrome mostly in small intestines and associated with mucocutaneous hyperpigmentation Cowden syndrome and Bannayan- Ruvalcaba-Riley syndrome or PTEN hamartoma syndrome; Cronkite-Canada syndrome nonhereditary but unknown cause occurring in over 50 age group with polyps in stomach, SI and LI with cachexia, weight loss, diarrhea, with 50% fatal

Polyps

Inflammatory solitary rectal ulcer syndrome with clinical triad of rectal bleeding, mucus and inflammatory lesion of the anterior rectal wall; Hamartomatous polyps (hamartomas are tumor like growth composed of mature tissues that are normally present at the site in which they develop)

Peutz-Jegher polyps- MC in SI

Arborizing network of connective tissue, smooth muscle, lamina propria and glands which may have a complex structure lined by normal appearing epithelium

Increased risk fro numerous cancers such as colon, pancreas, breast, lung, gonads, etc. BUT the polyps themselves are NOT preneoplastic precursor lesions Morphologically indistinguishable from sporadic adenomatous polyp except FAP may also have flat or depressed adenomas these are precancerous; Standard therapy is Colorectal CA develops in prophylactic colectomy 100% of untreated patients before age 30; increase risk for stomach polyps and polyps adjacent to the ampulla of Vater

Familial adenomatous AD disorder in which multiple polyposis adenomatous colorectal polyps develop during teenage years; Mutation in adenomatous polyposis coli or APC gene in most with mutation of MUTYH gene in ~10%; Must have at least 100 polyps for the diagnosis and may have 1000s

FAP variants: 1. Gardner syndrome intestinal polyps and osteomas ofmandible ,skull and long bones, dentla abnormalities, desmoid tumors, thyroid tumors, epidermal cysts 2. Turcot syndrome intestinal adenomas and tumors of the CNS

DISEASE CAUSES CLINICAL FEATURES Hereditary Non- Occur at a younger age than polyposis Colorectal sporadic colon cancers and Cancer (HNPCC) often located in right colon;

PATHOGENESIS MORPH/HISTO Caused by inherited mutations in mismatch repair genes encoding proteins responsible for the detection, excision and repair of errors that occur during DNA replication; Majority of HNPCC involve MSH2 and MLH1 genes Possibly due to decreased epithelial cell turnover and delayed shedding of surface epithelial cell which then pile up; imp to distinguish from sessile serrated adenomas which Polyps are composed of mature goblet and absorptive cells w/ crowding that creates a serrated surface, the histo hallmark of these lesions (on the surface epithelium, not in crypts

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Hyperplastic polyps Common epithelial proliferation which are NOT preneoplastic; Mostly occur in the left colon and usually less than 5 mm; May be single but usually multiple

neoplastic polys Colonic adenomas are polyps characterized by the presence of epit dysplasia and they are precursor lesions to adenocarcinoma; No gender preference; Present in nearly 50% of adults in the Western world by age 50

Classification of colonic adenomas morph: Sessile or pedunculated based on architecture with a velvety or raspberry surface; 1)Tubular adenomas small Variable size with those less than 1 pedunculated polyps compose of cm less likely to harbor a small rounded or tubular glands malignancy; however, 40% of 2)Villous larger and sessile lesions large than 4 cm contain foci covered by slender villi and of cancer; epi dysplasia (usually contain foci of of invasion more noted at surface of polyp with the frequently than tubular adenomas epithelium on the stalk being Rarely secrete large amounts of benign) with nuclear stratification, protein and potassium and cause enlarged, elongated hyp0proteinemic hypokalemia hyperchromatic nuclei 3)Tubulovillous mixture of tubular and villous elements 4)Sessile serrated adenomas- Serrated architecture like hyperplastic polyp; however, serration also involves the crypts and is associated with lateral growth and crypt dilation. Does not have the usual app of dysplasia but are considered premalignant

these are precancerous, need biopsy; However, the majority of adenomas do not progress to adenocarcinoma

Colorectal adenocarcinoma

MC malignancy of the GI tract Most prevalent in developed countries; In US, ~130,000 new cases each year with ~55,000 deaths represent ~15% of all cancer deaths (2nd only to lung cancer); Colorectal cancer peaks at age 60 to 70 years and less than 20% of cases occur before age 50; Males slightly affected more often than females; Dietary factors assoc w/increased cancer risk with low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat; Aspirin or other NSAIDS may have protective effect

Insidious and may go undetected for long time; R- sided cancer may present with fatigue and weakness due to iron deficiency anemia; L-sided CA may have occult bleeding, changes in bowel habits or cramping of LLQ

Morphologic and molecular Morphologic and molecular changes in the adenoma- changes in the mismatch repair carcinoma sequence of the APC/B- pathway of colon carcinogenesis. catenin pathway accounting for These molecular alterations are 80% of sporadic colon tumors. common in sessile serrated 70% of FAP has a mutation in APC adenomas. Invasive carcinomas gene with microstaellite instability often have prominent mucinous differentiation and lymphocytic infiltrates and are frequently located in the right colon. Important to identify those with HNPCC because of increased of malignancy in other organs as well as increased risk for a second colon tumor.

morph: Overall, equal The most important distribution over the entire prognostic factors are length of colon, depth of invasion and Tumors of the proximal colon are presence or absence of frequently polypoid, exophytic lymph node metastases masses extending along one wall rarely causing obstruction because of large-caliber lumen, Tumors of the distal colon are frequently annular and may produce napkin ring lesions with luminal narrowing micro: Glandular diff w/ tall columnar cells resembling dysplastic cells in adenomas; Strong desmoplastic response with invasion; The less differentiated tumors have less gland formation ; Mucinous adenocarcinoma containing signet-ring cells and extracellular mucin pools

metastatic -->

anal cancer

Upper third lined by columnar rectal epi; Middle third by transitional epi; Lower third by stratified squamous epithelium

STOMACH DISEASE Pyloric stenosis

CAUSES Due to hypertrophy of the muscularis propria of the pylorus Causes gastric outlet obstruction

Carcinomas may have glandular or squamous differentiation or basaloid tumors may arise from the basal layer of transitional epithelium; These different tumor types may occur separately or be mixed together as well SCC of the anal canal is frequently CLINICAL FEATURES PATHOGENESIS MORPH/HISTO projectile vomiting beginning in Associated with Turner syndrome 2nd week of life, visible waves and Trisomy 18, high rate of of peristalsis, epigastric mass concordance in monozygotic (olive) twins

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Congenital losure of Defective c Diaphragmatic Hernia diaphragm, usually left sided (CDH) Hernia sac usually contains all/part of stomach Acute gastritis Transient mucosal inflamm Asymptomatic vs. sympt process; Factors predisposing (epigastric pain, n/v and rarely to gastritis: hematemesis) Excessive alcohol consumption, non-steroidal anti-inflammatory drugs (NSAIDS), radiation therapy, chemotherapy, decreased oxygen, uremia, ingestion of acids or alkali

Gastric pH is 1 with mucus secreted by foveolar cells protecting the gastric mucosa: 1. Mucus layer prevents large food particles from touching the epithelium; 2. promotes an unstirred layer of fluid over the epithelium, protecting it and also resulting in a neutral pH from bicarbonate ion secretion by surface epithelial cells; Rich vascular supply washes away acid that has back-diffused into the laminal propria in addition to supplying bicarbonate, oxygen and nutrients

Gross: Intact surface epithelium or with more severe damage, erosions and hemorrhage may occur;Histo: Very mild gastritis may only have edema and vascular congestion Surface epithelium may be intact with scattered neutrophils in direct contact with epithelial cells or in the mucosal glands (plasma cells and lymphocytes suggest chronic disease) Eroded superficial epithelium may occur with neutrophilic infiltrate, fibrin containing purulent exudate and/or hemorrhage

Acute gastric ulcerations

Acute gastric ulcerations occurring from severe physiologic stress or NSAID therapy; Stress ulcers shock, sepsis or severe trauma; Curling ulcers Proximal duodenal ulcers with severe burns or trauma; Cushing ulcers Gastric, duodenal and esophageal ulcers in persons with intracranial disease assoc w/ high incidence of perforation

Gross: range from shallow to deep ulcerations Rounded ulcer and less than 1 cm in diameter. Found anywhere in the stomach, usually multiple ulcerations but may be single; Micro:Sharply demarcated with normal adjacent mucosa, blood in the mucosa and submucosa with some inflamm, absent chronic features such as scarring

Prophylactic H2 antagonists or proton pump inhibitors mayprevent this complication in seriously ill patients Gastric mucosa can completely recover with resolution of precipitating illness

Chronic gastritis

MC cause: Helicobacter pylori; Autoimmune gastritis is less than 10% of pts but is the next MC cause; less common causes are radiation injury, chronic bile reflux, mechanical injury and systemic disease (i.e., Crohn disease, amyloidosis, or graft- versus-host disease) H. pylori -->

Antrum of the stomach is MC location; causes high acidity despite HYPOgastrinemia, Pangastritis may occur which is associated with LOW acidity, mucosal atrophy, intestinal metaplasia and increase risk of gastric adenocarcinoma

4 virulence factors in H. pylori: Gross: occurs MC in antrum but Flagella (motile in viscous mucus) also in the cardia (uncommon in Urease generates ammonia the acid producing fundus and from endogenous urea, elevating body) gastric pH; Adhesin enhance Infected mucosa may be red with bacterial adhesion to epithelium; coarse or nodular appearance; Toxins - cytotoxin-associated gene Micro: (usually antral biopsy) Spiral A (CagA) which may increase ulcer or curved bacilli within surface or cancer risk mucus overlying epithelial cells; Intraepithelial neutrophils and subepithelial plasma cells Long standing H.pylori gastritis may involve body and fundus with atrophic mucosa and lymphoid aggregates with potential to transform into a MALT lymphoma (MALT is mucosa-associated lymphoid tissue) MORPH/HISTO LAB Gross : Diffuse atrophy of the body and fundus with thinning of the mucosa and loss of rugal folds When atrophy is incomplete, islands of oxyntic (acid producing) cells give the appearance of small polyps; Micro: Loss of parietal and chief cells with lymphocyte, macrophage and plasma cell infiltrate (but not the superficial plasma cells of H.Pylori) and lymphocyte aggregates;Intestinal metaplasia Antral endocrine hyperplasia (best seen on special stains)

Histologic ID, Abx & PPI Serology for H. pylori antibodies Urea breath test (based on generation of ammonia by bacterial urease) Rapid urease test on biopsies DNA detection by PCR

DISEASE CAUSES Autoimmune gastritis Less than 10% of chronic gastritis but MC cause of atrophic gastritis; Characterized by: Antibodies to parietal cells and intrinsic factor (IF) Vitamin B12 deficiency (pernicious anemia)due to lack of IF Reduced serum pepsinogen I concentration (chief cell destruction also but no antibodies against chief cells) Defective gastric acid secretion (achlorhydria due to parietal cells destruction) Antral endocrine cell hyperplasia (lack of acid simulates gastrin release and subsequent inc in G cells)

CLINICAL FEATURES PATHOGENESIS Median age at diagnosis is 60 Despite presence of antibodies, Women slightly more than men this is not the mechanism for Clinical presentation- anemia, injury (transfer of antibodies to possibly atrophic glossitis other experimental animals does NOT manifestations of Vitamin B12 produce gastritis) deficiency, especially CD4+ T cells are directed against neurologic parietal cell components, Associated with other including the proton pump autoimmune disease such as (transfer of CD4+ T cells against Hashimoto thyroiditis, insulin- the proton pump into dependent diabetes, Graves experimental animals results in disease, vitiligo, myasthenia gastritis) gravis, etc. Chief cells are lost also in the Possible complications- gastric gastric gland destruction, even adenocarcinoma and carcinoid though there is no autoimmune tumors response against them

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Peptic ulcer disease (PUD)

Primary causes are H.pylori and NSAID use; Other causes are parietal cell hyperplasia, Zollinger-Ellison syndrome (gastrinoma), or other causes of increased acidity; Cigarette smoking, corticosteroid use associated with increased risk Duodenal ulcers more frequent in alcoholic cirrhosis, chronic obstructive pulmonary disease, chronic renal failure, and hyperparathyroidism (hypercalcemia stimulates gastrin production) Psychological stress may increase acid production

H.pylori-induced hyperchlorhydric Gross: Duodenal ulcer 4 X more chronic gastritis is associated with common than gastric PUD in 85 to 100% of duodenal Duodenal ulcer-1st part on anterior ulcers and 65% of gastric ulcers; wall; Gastric ulcers - lesser However, only 20% of H.pylori curvature near antrum/body infected people develop an ulcer; interface; Solitary in more than Location of MC in antrum of the 80%; stomach and1st part of Sharply punched out defect duodenum; (heaped-up margins are more May also occur in esophagus and characteristic of cancer which do a Meckels diverticulum not usually develop from PU); Micro: Active ulcers have fibrinoid debris with underlying neutrophilic infiltrate in the base; w/ peptic digestion of exudate, base of ulcer may be smooth and clean w/ prominent BV; Granulation tissue beneath base w/ mononuclear leukocytes and fibrous tissue or scar forms

Recurrence, Iron duodenal ulcer --> deficiency anemia from chronic bleeding, Acute severe hemorrhage, Perforation; bleeding accts for most deaths from ulcers; benign antral ulcer -->

May mimic infiltrative carcinoma or lymphoma of stomach on endoscopic and radiographic examination; 3 variants: 1. menetrier disease, 2. Hypertrophic- hypersecretory gastropathy, Menetrier Disease M:F~3:1; Middle-aged; epigastric discomfort, diarrhea, Gastric secretions have weight loss excess mucus and decreased acid (diff than ulcer disease epigastric discomfort/pain, Zollinger-Ellison Gastrinoma (typically in Associated with MEN1 syndrome duodenum or pancreas) diarrhea Increased acid secretion Duodenal, gastric, jejunal ulcers Gastric polyps Inflammatory/hyperplastic polyps (75% of gastric polyps Fundic gland polyps Gastric adenoma DISEASE CAUSES Inflammatory/hyperpl Age 50 to 60 years astic polyp Polyps associated with chronic gastritis CLINICAL FEATURES PATHOGENESIS Injury from gastritis stimulates reactive hyperplasia leading to polyp growth

Hypertrophic gastropathy

Gross: enlarged rugal folds Micro: marked foveolar hyperplasia with replacement of parietal and chief cells Gross: enlarged rugal folds Micro: gastric gland and parietal cell hyperplasia

Increased risk of mucosal metaplasia and gastric cancer

MORPH/HISTO LAB Gross: polyps usually smaller than 1 cm, frequently multiple, and smooth, oval with erosions; Micro: irregular, cystically dilated foveolar glands with edema, inflammation of lamina propria and possible surface ulceration Gross: Well circumscribed, smooth and may be multiple or single Micro: Cystically dilated glands lined by flattened parietal and chief cells with

DX/PROG TX Risk of dysplasia in polyps In H.Pylori gastritis, greater than 1.5 cm polyps may regress with Rx

Fundic gland polyp (PPI association)

5 X more common in women, average age of 50; NO inflammation

Sporadic or familial adenomatous polyposis; Increased occurrence with proton pump inhibitors (PPI) likely due to increased gastrin secretion due to acid inhibition stimulating glandular hyperplasia

Gastric adenoma

3 X more common in men, age 50 to 60 May occur in familial adenomatous polyposis

Adenomas occur in a background Gross: Usually solitary in the of chronic gastritis with atrophy antrum and intestinal metaplasia Micro: Intestinal type of columnar epithelium with dysplasia, high or low grade

Risk of adenocarcinoma increased in polyps greater than 2 cm (carcinoma may be present in up to 30% of adenomas)

gastric tumors Gastric adenocarcinoma

Most common malignancy of the stomach; Adenocarcinoma of the gastric cardia is increasing likely due to Barrett esophagus possibly reflecting increased obesity and GERD High incidence in Japan and some other countries Diffuse type of gastric CA has a uniform incidence across countries

Early Sx - dysphagia, dyspepsia and nausea Advanced stage weight loss, anorexia, anemia, hemorrhage

genetics: Familial gastric cancer Gross: Most involve the antrum, Germline mutations in CDH1 lesser more than greater curvature which encodes E-cadherin Exophytic mass or an ulcerated (adhesion promoter) tumor form with intestinal type Loss of E-cadherin function may Diffuse infiltrative tumor (linitis be key step in development of plastica or a leather bottle look) diffuse gastric CA with thickened stiff wall and loss of CDH1 mutations also common in rugae; Micro: (mucin lakes may lobular CA of breast with loss of E- occur in both types) cadherin (remember single file invasive lobular carcinoma) BRCA 2 mutations have increased gastric CA risk Sporadic cases may have CDH1 mutations and multiple other genetic abnormalites

Most important prognostic factors are depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis Over 5 year survival in the US is only 30% since most cases are advanced at Dx. Metastasis Left supraclavicular lymph node -> Virchow node One or both ovaries -> Krukenberg tumor Periumbilical -> Sister Mary Joseph nodule

intestinal type Males> females 2:1 Risk factors: diet (nitrites, smoked food), chronic gastritis (H. pylori), antral gastrectomy, smoking, diffuse type Similar frequency in males and females No well defined risk factors (no known relation to H. pylori)

Occurs in setting of intestinal metaplasia and mucosal atrophy

Glandular morphology; Neoplastic cells with apical mucin and glandular lumens filled with mucin

top is intestinal type composed of Signet ring cell morph in columnar, gland-forming desmoplastic stroma; Linitis infiltrating thru desmoplastic plastica (leather bottle stomach) stroma; bottom is signet-ring cell in diffuse type

Gastric Lymphoma

5% of gastric tumors are primary lymphomas Lymphomas of mucosa- associated lymphoid tissue (MALT) or MALTomas (B cell) H.pylori chronic gastritis is found in association with most gastric MALTomas gastric MALToma CLINICAL FEATURES PATHOGENESIS

Micro: Dense lymphocytic infiltrate in the lamina propria, lymphoepith lesions w/ neoplastic lymphocytes infiltrate the gastric glands Express B cell markers CD 19 and CD20 and are positive for CD43 in 25% of tumors; 3 diff chrom translocations have been IDed

May have complete remission w/ tx of H.pylori with abx (if not transformed to a higher grade lymphoma and the MALTomas is still localized)

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Gastrointestinal Most common mesenchymal Presenting symptoms may be GIST may arise from or share a stromal tumor (GIST) tumor of the abdomen with related to mass effect or common stem cell with the more than half affecting the anemia due to chronic blood interstitial cells of Cajal (cells in stomach loss from mucosal ulceration or the muscularis propria which act Slightly more common in an incidental finding as pacemaker cells for gut males with peak age at peristalsis); Mut of the c-KIT gene diagnosis ~60 years old or PDGFRA gene(platelet derived Slightly increase incidence in growth factor receptor alpha) w/ neurofibromatosis I their activity promoting tumor May occur in children as part cell prolif & survival which is of Carney triad (NOT to be usually sporadic w/ rare germline confused with Carney mutations complex of atrial myxomas) which is seen in females and includes GIST, paraganglioma, and pulmonary chondroma PERITONEUM The peritoneal cavity contains Peritoneal cavity Additionally , trauma, peritoneal the abdominal vsiceral organs Inflammatory diseases: dialysis, acute salpingitis may The peritoneal cavity is lined Peritonitis due to a variety of introduce bacteria into by a single layer of cuboidal causes, i.e. bile irritation due to peritoneum mesothelial cells covering the leakage or rupture of biliary Spontaneous bacterial visceral and the parietal system, pancreatitis, foreign peritonitis develops without surfaces material, endometriosis, obvious source and associated The peritoneum is formed by perforation with liver cirrhosis and ascites and the mesothelial cells Bacterial peritonitis typically in children with nephrotic overlying a thin layer of occurs with perforation of GI syndrome connective tissue lumen causing release of bacteria into peritoneal cavity associated with disease such as appendicitis, peptic ulcer, cholecytitis, diverticulitis, intestinal ischemia.

Gross: Solitary well circumscribed fleshy mass, covered with mucosa with possible ulcerations or may be direct outward and covered with serosa, ranges from a few cms to 30 or 40 cm, Mets multiple serosal nodules thruout peritoneal cavity, nodules in liver w/ spread outside abdomen uncommon; Micro: May be spindle cell type or epithelioid type or mixtures; CD 117 or c-KIT positive (normally binds stem cell factor)

Prognostic factors are spindle cell tumor --> tumor size, mitotic index and location (gastric GISTs are usually less aggressive than small intestine GISTs) Recurrence or metastasis is rare for gastric tumors less than 5 cm but common for mitotically active tumors greater than 10 cm

acute peritonitis

Gross: Tan to yellow exudate on serosal surfaces, Purulent fluid may collect; Micro: Neutrophils and fibrinous material, abscesses may form, w/ resolution, may have fibrous adhesions An uncommon cause of ureteral obstruction characterized by fibrous proliferative inflammatory process which encases retroperitoneal structures Causes include certain drugs (ergots, beta-blockers), adjacent inflammatory conditions such as diverticulitis or Crohns, malignant disease 70% are idiopathic (Ormond disease); may be assoc w/: Riedels fibrosing thyroiditis, other fibrosing diseases such as Riedels thyroiditis, mediastinal fibrosis and sclerosing cholangitis suggesting that the disorder is systemic, autoimmune etiology Microscopic exam shows fibrosis with a prominent infiltrate of lymphocytes, plasma cells and eosinophils

Sclerosing Retroperitonitis

Primary Tumors of peritoneum

Mesotheliomas also associated with asbestos exposure (swallowed asbestos fibers may penetrate the gut) Desmoplastic small round cell tumor in children and young adults (resembles Ewing sarcoma Pseudomyxomatous peritoneii (extensive mucinous ascites, cystic epithelial implants on peritoneal surfaces, adhesions) seen with ovarian mucinous tumors and appendiceal mucinous carcinomas CLINICAL FEATURES PATHOGENESIS MORPH/HISTO Failure of hepatocytes to Hepatic encephalopathy CNS perform homeostatic dysfxn due to inc. ammonia levels functions: (Alzheimer type II astrocytes); Jaundice, Hypoalbuminemia, Hepatorenal syndrome renal coagulopathy due to impaired failure w/no intrinsic renal defect synthesis of clotting factor; as a causative factor overall due Fetor hepaticus Musty body to dec. renal perfusion P; odor due to formation of Hepatopulmonary syndrome - mercaptans by action of GI chronic liver disease, hypoxemia bacteria on the sulfur and intrapulm vasc dilations containing methinonine and causing V/Q mismatch; enhanced subseq portosystemic shunting prod of NO is key mediator; Acute of blood; Dec. estrogen liver failure defined as acute liver metabolism w/ elevated illness assoc w/ encephalopathy estrogens felt to resp from w/in 6 mths after Dx (fulminant if spider angiomas, palmar within 3 months) erythema, male hypogonadism and gynecomastia LAB DX/PROG TX

Secondary tumors of direct spread or metastatic peritoneum seeding Pancreatic and ovarian adenocarcinoma are the most commonly tumors to produce serosal implants LIVER DISEASE Hepatic failure

CAUSES May be sudden and massive or result of prog chronic damage to the liver; Causes: drugs or toxins;may be acute infectious hepatitis, autoimmune hepatitis, unknown

Cirrhosis

12th MC cause of death in US aympt until late in course of Central pathogenic processes are: morph: Bridging fibrosis linking Trichrome Stain --> highlights w/ main causes of cirrhosis disease; Non-specific sx such as 1) Death of hepatocytes portal tracts to each other and collagen in fibrosis being alcohol abuse, viral anorexia, wt loss, weakness 2) Extracellular matrix (ECM) portal tracts to central veins; hepatitis C, and non-alcoholic and hepatic failure deposition: fibrosis due to prolif Parenchymal nodules steatohepatitis (NASH) and activation of hepatic stellate hepatocytes encricled by fiborsis cells into highly fibrogenic cells rangin from small or micronodular along with portal fibroblasts and (less than 3 mm ) to large other cells; 3) Vascular reorg w/ (macronodular); disruption of impairment of blood supply to architecture of entire liver hepatocytes and impaired ability Parenchymal injury and fibrosis is of hepatocytes to secrete DIFFUSE, not just a focal injury --> substances into blood: new affects entire liver vascular channels in fibrotic septa connect vessels in portal region to the central vein, bypassing the parenchyma; collagen in the space of Disse results in loss of sinusoidal fenestration impairing the exchange of solutes b't hepatocytes and blood Increased resistance to portal Ascites clinically detectable Increased resistance to portal blood flow due clinically at 500 cc -> flow at sinusoidal level due to: predominantly to cirrhosis Sinusoidal HTN and Smooth mm contraction; hypoalbuminia (dec. oncotic disrupted blood flow from pressure) drives fluid into scarring; parenchymal nodules; space of Disse, then removed Increase in portal venous blood by hepatic lymphatics -> lymph flow due to increased splanchnic exceeds capacity of the arterial blood flow due to thoracic duct and leaks into vasodilation from increased NO peritoneal cavity; splanchnic production mostly (also vasodil & hyperdynamic circ prostacyclin and TNF); the theory lowers systemic P triggering is that NO prod is stim by red. activation of vasoconstrictors clearance of bacterial DNA and ADH -> increases perfusion absorbed form the gut, shunting P of interstitial capillaries and of blood from portal to systemic causes extravastion of fluid system bypasses Kupffer cells in into abd liver aka icterus; describes yellow discoloration of the skin, mucous membranes and eyes (conjunctiva over the sclera) due to retention of bilirubin; Bilirubin is the end-product of heme degradation Normal source of bilirubin: the breakdown of senescent red blood cells in the spleen releases heme that changes into bilirubin by specific enzymatic reactions clinical cont.Portosystemic shunts venous bypasses around the liver to get to systemic circ thru shared capillary beds: 1. Esophagogastsirc junction esophageal varices, 2. hemorrhoids, 3. retroperitoneal, 4. Falciform ligament (involves periumbilical and abd wall collaterals appearing as caput medusae, dilated SX veins extending from the umbilicus); Congestive splenomegaly may have thrombocytopenia or pancytopenia

death include progressive liver failure, comp related to portal HTN or dev of hepatocellular carcinoma f death include progressive liver failure, complications related to portal hypertension or development of hepatocellular carcinoma

portal HTN

Jaundice

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TX

cholestasis

characterized by not only retention of bilirubin but of other components of bile; Impaired bile formation and bile flow, leading to accum of bile pigment in the hepatic parenchyma; caused by extrahepatic or intrahepatic obstr. of the biliary tree or by defects in hepatocyte bile secretion

include jaundice, pruritis, skin xanthomas or sx of intestinal malabs such as deficiencies of fat-soluble vitamins A, D, or K

Bile composed of bile salts (catabolic products of cholesterol are bile acids which conjugate with taurine or glycine to form bile salts), chol and bilirubin; purpose of bile is to emulsify dietary fat in the gut lumen and eliminate bilirubin, excess chol, xenobiotics and other waste products which are not water- soluble enough to be excreted in urine

accum of bile pigment in the GGT (gamma-glutamyl hepatic parenchyma; elongated bile transpeptidase) and serum plugs are visible in dilated bile alkaline phosphatase are canaliculi; characteristically elevated Rupture of canaliculi causes (plasma membrane enzymes extravastion of bile with ingestion from damage to bile canaliculus) by Kupffer cells; Bile droplets may accum w/in hepatocytes and have a fine foamy app (feathery degeneration); bile duct prolif in portal triads induced by bile stasis and back-pressure; bile lakes may occur with dissolution of hepatocytes; unrelieved obstruction leads to fibrosis and ultimately to biliary cirrhosis

Prompt dx of extrahepatic biliary obsruction is imp since it maybe amenable to surgical correction

bilirubin Conjugation is a function of the liver by adding glucuronic acid to bilirubin

Unconjugated: albumin bound, Insoluble in water, toxic; cannot be excreted in urine; Conjugated: Loosely bound to albumin, water soluble, non-toxic, excreted in urine

Hepatitis

Inflammation of Liver Viral, Alcohol, immune, Drugs & Toxins Acute, Chronic & Fulminant - types viral Heterotropic viruses Hepatitis A, B, C, D, E Systemic - CMV, EBV, yellow fever from a Flavivirus transmitted by mosquitos in the tropics acute hepatitis Asymp;acute infection may be found incidentally by elevated serum transaminases HAV and HVB may be asymptomatic in childhood and maybe found later on by 4 phases: Incubation period, Hepatocyte swelling (balloon Hepatocyte necrosis isolated cells sympt preicteric phase, sympt cells) and apoptosis (Councilmans or clusters: Piecemeal necrosis or icteric phase, convalescence bodies -> see arrows in pic on interface hepatitis Inflmmation right); inflammation Mixed siplees over from the protal tract to inflamm infiltrate in portal tracts, the adjacent heaptocytes (limiting mp aggregates in the lobule; plate), Bridging necrosis; Mild fatty change HCV; Cholestasis canalicular bile plugs; Regenerative changes hepatocyte regeneration Lymphoid aggregates, mp, occ. Scattered hepatocyte apoptosis, plasma cells and bile duct reactive Fibrosis Early fibrous expansion of changes in portal tracts; Inflamm portal tract, then septal fibrosis form portal tracts may spill into advancing to bridging fibrosis and adjacent parenchyma interface ultimately cirrhosis; ground glass hepatitis hepatocytes (in pic on right) HBV; mild fatty change HCV

Chronic Hepatitis

Fulminant Hepatitis

Hepatic insuff which progresses to hepatic encephalopathy with in 2-3 wks; most often due to drugs or chem; ~12% of cases are due to viral hepatitis (HAV or HBV); massive necrosis, shrinkage, wrinkled; entire liver or only random areas involved PATHOGENESIS

Collapsed reticulin network, only portal tracts visible; little inflammation acutely but if survival for several days, massive influx of inflammation occurs to begin phagocytic cleanup process After a week > regenerative activity

Complete recovery, cirrhosis, or death (mortality is 80% without a liver transplant and 35% with transplantation

DISEASE Hepatitis A virus

CAUSES CLINICAL FEATURES ssRNA virus (related to picornavirus); fecal-oral transmission(contaminated water and food); Incubation period: 2-6 weeks; Virus shedding: 2-3 weeks b/f and 1 wk after app of jaundice; 50% of population above age 50 are seropositive in USA, no carrier state dsDNA virus (Hepadnavirus); parenteral transmission (blood products, contam needles and IV drug abuse), sexual, perinatal transmission during childbirth (vertical transmission); Incubation 4- 26 weeks

MORPH/HISTO

LAB Because viremia is transient, no need to screen donated blood; Rarely causes massive hepatic necrosis and acute liver failure; fatal ~0.1% of cases

DX/PROG No increased risk for chronic hepatitis, or carcinoma

TX Effective vaccine available

Hepatitis B virus

Carrier state: yes, 400 million carriers around the world with 75% in Asia and Western Pacific rim;Usually subclinical disease, but may lead to fulminant hepatic failure, chronic liver disease and cirrhosis;

Effective vaccine available

Hepatitis C

ssRNA virus (Flaviridae); parenteral transmission, sexual (not common) and vertical transmission, 32% unknown; Incubation: 2-26 weeks; Genomic instability and antigenic variability have made dev of a vaccine diff; HCV IgG (appears in 3 to 6 weeks) after an active infection does NOT confer effective immunity; huge prob in US now!

Characteristic feature of infection is repeated bouts of hepatic damage due to reactivation of preexisting infection or emergence of an endogenous, newly mutated strain

US, the most common chronic bloodborne infection accounting for almost half of all US individuals with chronic liver disease Virus can evade host antiviral immunity (can inhibit interferon mediated cellular antiviral response)

Hepatitis D

A RNA virus (circular defective ssRNA, subviral particle Delataviridae family) that is dependent on HBV for its life cycle

Acute coinfection with HBV; Superinfection when a chronic HBV carrier contracts HDV; Helper- indep latent infection seen in liver transplants (HDV is in nuclei of grafted liver hours after transplant but HBV initially suppressed by Hep B immunoglobulin to prevent reinfection but eventually HBV escapes neutralization and coinfects the cell) Epidemics in certain populations; Indian subcontinent, sub-Saharan Africa, Mexico Self-limited infection (no chronic disease) but with higher mortality of approximately 20% in pregnant females

Hepatitis E

ssRNA virus, Calicivirus, waterborne; Zoonotic disease with animal reservoirs, such as mondeys, cats, pigs and dogs; incubation: 6 wks

Hydatid disease

caused by Echinococcus -> a tapeworm is not common in US but endemic in some parts of the world

DISEASE Autoimmune hepatitis

CAUSES CLINICAL FEATURES Female preponderance Clinical presentation may be (young and perimenopausal); acute (40%), w/ a fulminant Classified into type I and type presentation or may be asymp II based on patterns of and progress to cirrhosis w/o a circulating antibodies clinical dx Type I more common in US and associated with HLA-DR3 serotype

Ingestion of food (i.e. sheep)contaminated with eggs released by infected dogs (E. granulosis) or foxes (E. multilocularis, rare but most virulent) ->Eggs hatch in small intestine and release oncospheres which invade liver, lungs, bones and rarely brain ->Cysts form mostly in the liver with 5 to 15% in the lungs and the rest in bones, brain or other organs ->Cyst PATHOGENESIS MORPH/HISTO T cell-med autoimmunity due to histo: autoimmune hepatitis is genetic factors and possibly clusters of plasma cells at the triggered by viral infections or junction of the portal tract and certain drugs; assoc w/ other adjacent hepatocytes (interphase autoimmune diseases such as hepatitis); May progress to cirrhosis SLE, RA, celiac disease, thyroiditis, etc

LAB

DX/PROG TX Mortality of severe immunosuppressive untreated autoimmune drugs and transplant in hepatitis is ~40% within 6 end stage disease months of diagnosis with cirrhosis developing in 40% of survivors; 10 year survival in liver transplanted pts is 75% but disease recurs in 22 to 42%

Drug and toxin Drug induced liver injury is induced liver disease the MC cause of fulminant hepatitis; Genetic susceptibility; Predictable (intrinsic) or unpredictable (idiosyncratic); Predictable rxns occur with OD of acetaminophen, Amanita phalloides toxin, CCl4, alcohol but genetics does play a role in individual susceptibility;Idiosyncratic reactions may be assoc w/ abx ,allopurinol, anti-seizure meds Alcoholic liver disease Amount of alcohol to cause Other factors influencing the liver injury: 1.Short-term severity and risk of developing ingestion of 80 g (6 beers/8 alcoholic liver disease are ounces of 80-proof liquor) of gender (F>M), AA>C, Genetic ethanol over one to several factors; Co-morbid conditions days leads to reversible such as HCV or HBV steatosis; 2. Daily intake of 80 g or more leads to significant risk of severe hepatic injury;3. Daily ingestion of 160 g for 10-20 years consistently leads to severe injury

Injury results from: 1) Direct cellular toxicity to hepatocytes or biliary epithelial cells 2) Hepatic conversion of a xenobiotic to an active toxin 3) Immune mechs (drug or metabolite) acts as a hapten converting a cellular protein into an immunogen

Ethanol causes steatosis, Hepatic steatosis - reversible dysfunction of mitochondrial and Gross-yellow, greasy liver in severe cellular membranes, hypoxia and steatosis oxidative stress: 1. Acetaldehyde Micro-microvesicular lipid droplets (major intermediate metabolite of in hepatocytes becoming ethanol) disrupts cytoskeletal and macrovesicular globules w/chronic membrane function; intake ; Alcoholic hepatitis: 2.Cytochrome P-450 metab prod Hepatocyte swelling (ballooning) rxn 02 species; 3.Ethanol induces and necrosis, Mallory bodies cytochrome P-450 enzymes (clumps of cytokeratin complexed enhances conversion of other with other proteins) not specific for mallory bodies --> drugs to toxic metabolites;4. alcoholic hepatitis, Neutrophilic Steatosis results from shunting of reaction,Fibrosis (sinusoidal and substrates away from catabolism perivenular; occ. periportal); and toward lipid biosynthesis due Cirrhosis ~10 to 15% to excess red NADH+H prod as a result of alcohol metabolism by alcohol dehydrog & acetaldehyde dehydrog; 5. Impaired assembly/secretion of lipotrotein and inc. peripheral catabolism of fat 1) Hepatic fat accumulation 2) Hepatic oxidative stress: Oxid stress acts on the hepatic lipis, resulting in lipid peroxidation and release of lipid peroxides which can preduce reactive oxygen species PATHOGENESIS morph: Steatosis - macrovesicular and microvesicular steatosis, predominantly triglycerides; NASH has steatosis and multifocal parenchyma inflamm(neutrophils), Mallory bodies, hepatocyte death and sinusoidal, venular and/or portal fibrosis;May progress to cirrhosis MORPH/HISTO LAB steatosis -->

steatosis is reversible!!

Nonalcoholic fatty A group of conditions w/ liver disease (NAFLD) hepatic steatosis in person who do not drink alcohol; MC cause of chronic liver disease in the US;Diseases include simple hepatic steatosis, steatosis with minor, non- specific inflamm and non- alcoholic steatohepatitis DISEASE CAUSES CLINICAL FEATURES

DX/PROG

TX

Hemochromatosis

Characterized by excessive accum of iron mostly in the liver, pancreas, heart, joints, or endocrine organs (life long accumulation but presents in the 5th and 6th decades, M>F); Excess iron damages DNA, lipids and stimulates collagen formation (fibrosis)

Primary AR disorder caused by Micronodular liver cirrhosis, skin excessive iron absorption (HFE pigmentation (bronzing) , diabetes gene on chromosome 6); mellitus(pancreatic fibrosis) Secondary or Acquired ->called 200X increased risk for hemosiderosis (example would be hepatocellular carcinoma; Heart excessive blood transfusions involvement leading to CHF & causing excess iron) arrythmias, hypogonadism

Diagnosis: elevated serum ferritin, elevated serum iron, elevated tissue iron (quantitative hepatic iron content is gold standard) ; Early detection and therapy by phlebotomy and iron chelators lead to normal life expectancy

Wilson Disease

AR disorder characterized by neuropsychiatric The mut gene (ATP7B) is located accum of copper in liver, manifestations, acute and on chrom 13; the mutation leads brain, eyes, other organs chronic liver disease and Kayser-to failure to excrete copper into Fleisher rings in the cornea bile, , impairs its incorporation (green to brown deposits --> into ceruloplasmin and inhibits see pic) ceruloplasmin secretion in blood Fxn of alpha 1-antitrypsin is to inhibit proteases; def leads to liver disease (due to accum of the abn alpha 1-antitrypsin protein in hepatocytes) and emphysema due to uninhibited proteases; Alpha 1-antitrypsin def->MC dx genetic hepatic disorder in infants and children likely an autoimmune disease Insidious onset w/o sx for yrs; unknown with likely genetic and causing inflamm destruction present w/ fatigue and pruritis; environmental factors of med-sized intrahepatic bile HM, eyelid xanthelasmas; ducts; F>M, ages 40- 50; Hyperpigmentation due to Family members at inc risk melanin deposition and inflamm arthropathy; + anti- mitochondrial antibodies in 95% pts; Elevated alkaline phosphatase, gamma- glutamyltransferase and chol; Hyperbilirubinemia is a late dev usually signifying incipient hepatic decomp; due to prolonged obs of the extrahepatic biliary tree w/ cholestasis, then secondary inflamm initiating periportal fibrosis and eventual cirrhosis Some causes include: Choledocholithaisis, Malignancies, Congenital anomalies (bilialry atresis, May develop ascending cholangitis with partial obstruction Round to oval cytoplasmic globular eosinophlic inclusions in hepatocytes (PAS positive, diastase resistant); Most of the globule containing hepatocytes are around the portal tracts; # of globules are not correlated with severity of disease; Liver disease is variable - neonatal hepatitis to childhood cirrhosis to chronic inflam hepatitis Focal and variable disease - Pre-cirrhosis lymphocyte, plasma cell, mp infiltrates in the portal tracts with occ. eosinophil; Bile ducts infiltrated by lymphocytes and may have noncaseating gran. inflamm w/ (see pic --> ) prog destruction and obst.; Portal tracts upstream from damage bile ducts show bile ductular prolif, inflamm, necrosis; Cholestasis, liver may look green; fibrosis and cirrhosis develops Conjugated hyperbilirubinemia, inc: alkaline phosphatase, bile acids, GGT& chol

Clinical picture (mean age is 11.4 years), increased hepatic and urinary copper, and decreased serum ceruloplasmin (a copper binding protein)

copper chelation (D- penicillamine), liver transplantation if fulminant hepatitis or severe cirrhosis

Alpha 1-antitrypsin deficiency

Primary biliary cirrhosis (PBC)

May be assoc w/ many other autoimmune disorders; Increased risk for hepatocellular carcinoma

No specific therapy; tx w/ ursodeoxycholic acid (mechanism of action in PBC not well understood) may proved complete remission if started early and prolong survival in 25 to 30% of cases; Liver transplantation for end stage disease

Secondary biliary cirrhosis

Primary sclerosing cholangitis (PSC)

inflamm, fibrosis and strictures of the intrahepatic and extrahepatic biliary tree with dilation of preserved segments; assoc w/ IBS, UC (very comon), age 30-50, M>W

Asympt w/ persistent elevation Autoimmune etiology is likely as Concentric peri-ductal fibrosis or of alk phos; Fatigue, pruritis, evidenced by: Detection of T cells onion-skin fibrosis -> replaced by jaundice; can dev. in periductal stroma {T cells a solid, cordlike fibrous scar; Other cholangiocarcinoma activated in gut mucosa (normally portions of Bile ducts b'c ectatic reacting to gut antigens or and inflamed from downstream; bacterial antigens) travel to liver bstruction due to bile duct fibrosis; and cross react with bile duct Cholestasis; Eventual biliary antigens}; Numerous circulating cirrhosis autoantibodies (Anti-smooth

Inc. incidence of chronic pancreatitis and hepatocellular carcioma

Endoscopic dilation w/ stents or sphincterotomy Liver transplantation for end stage liver disease

BENIGN HEPATIC MASSES: DISEASE CAUSES CLINICAL FEATURES Nodular hyperplasias Not neoplastic, Single or multiple; due to alteration in blood supply (increase in arterial branches unaccomp by portal branches)

PATHOGENESIS MORPH/HISTO LAB Two main types: 1. Focal nodular Gross: well demarcated but poorly hyperplasia, assoc w/ long-term encapsulated nodule, lighter than use of anabolic hormones and OC; surrounding liver frequently with a 2. Nodular regenerative central gray-white stellate scar hyperplasia Micro: Central scar contains large vessels, usually arterial showing fibromuscular hyperplasia and narrowing or the lumen; Radiating fibrous septa have lymphocytic infiltrates and bile duct prolif; Hepatocytes between the septa are norm but lack normal sinusoidal plate architecture

DX/PROG

TX

Nodular regenerative Nodular regenerative hyperplasia hyperplasia occurs in conditions affecting intrahepatic blood flow such as solid-organ transplantation (particularly renal with azothioprine use) vasculitis, autoimmune disorders, hematologic malignancies, HIV Cavernous Hemangioma MC benign liver tumors and are soft red-blue nodules, usually less than 2 cm and frequently located directly beneath the capsule; Histology-vascular channels in fibrous CT

Gross: Liver entirely composed of spherical nodules with NO fibrosis (unlike above); Micro: Plump hepatocytes surrounded by rims of atrophic hepatocytes

Hepatic adenoma

benign neoplasms developing from hepatocytes; women using OC (may regress if stopped); Subcapsular adenomas may rupture, especially in pregnancy, causing life threatening hemorrhage

Hormones are assoc w/ their dev Gross: Usually solitary (but may be May be mistaken for but cause is unknown; Mut in multiple) nodule which is pale, hepatocellular CA genes encoding TF HNF1alpha and yellow-tan, possibly bile stained, May transform into B-catenin have been found; well demarcated but not always hepatocellular CA Multiple hepatic adenoma encapsulated located anywhere in syndromes can occur in maturity the liver (often beneath capsule) onset diabetes of the young with and may be up to 30 cm in size HNF1 mutations Micro:sheets and cords of hepatocytes which may be normal or have variation in cell and nuclear size with possible steatosis or presence of glycogen; Absent portal tracts with solitary arteries and veins in tumor

MALIGNANT TUMORS: Angiosarcomas

Hepatoblastoma

rare tumor assoc w/ vinyl chloride, arsenic or thorotrast with latency of several decades after exposure MC primary childhood liver tumor but still very rare

DISEASE Hepatocellular carcinoma(HCC)

CAUSES CLINICAL FEATURES Globally, 3rd most freq cause nonspecific sx, masked by the of cancer deaths mostly due underlying liver disease; to chronic HBV infection in dev world; Cirrhosis is absent Poor 5 year survival with most in half the cases; in US, HCC patients dead in 2 years usually assoc w/ cirrhosis in 75 to 90% of cases from various chronic liver diseases including HCV; M>F; Four major etiologic factors: 1. Chronic viral infection (HBV,HCV) 2. Chronic alcoholism 3. Non-alcoholic steatohepatitis (NASH) 4. Food contaminants (primarily aflatoxins)

Characteristic feature is activation of WNT/B-catenin signaling pathway; assoc w/FAP syndrome and Beckwith-Wiedmann syndrome PATHOGENESIS MORPH/HISTO Exposure to aflatoxins in peanuts gross: Unifocal, multifocal or and grain binds with DNA causing diffusely infiltrative w/ possible a specific mutation in liver enlargementi n all 3 patterns; p53;Repeated cycles of cell death More pale than surrounding liver or and regen such as seen in chronic may appear green if malignant hepatitis of any cause; Continuous hepatocytes are secreting bile; cycles of cell division may damage Strong propensity to invade vasc DNA repair mechanisms with structures w/metastases; subsequent accum of mut; Global Invasion of portal vein may cause gene expression studies show occlusion of portal circ or IVC; that 50% of HCC are assoc w/ can get lung and lymph mets late in activation of WNT or AKT disease; histo:Well-diff w/ pathways; HBV gene integration malignant hepatocytes in into cells DNA may activate trabecular or pseudoglandular protooncogenes architecture; varying from large giant cells to small cells to a spindled sarcomatous appearance

LAB

DX/PROG Elevated serum AFP -> seen in numerous disease states including non- neoplastic liver disease as well as norm preg and fetal neural tube defects.

TX Poor 5 year survival with most patients dead in 2 years

Fibrolamellar carcinoma

Variant of HCC (constitutes ~5% of HCCs); eq. both sexes in 20-40 yrs of age;NO underlying liver disease in most

Etiology is unknown

Gross Single large, hard tumor with fibrous bands coursing through it Histo: Well-differ polygonal cells with abundant eosinophilic cytoplasm and prominent nucleoli in nests or cords separated by parallel lamellae of dense collagen bundles

Better prognosis than conventional HCC

Cholangiocarcinoma Malignancy of intra- or (CCA) extrahepatic bile ducts; Risk factors: primary sclerosing cholangitis, congenital fibropolycystic disease of bile tract, HCV infection, Thorotrast exposure, chronic infection PANCREATIC NEOPLASMS: Acinar cell carcinoma prominent acinar cell diff (may have metastatic fat necrosis due to systemic lipase release) Pancreatoblastoma rare malignant neoplasms which occur in KIDS w/ admixed squamous elements and acinar cells Cystic neoplasms fewer than 5% Serous cystadenomas benign. W>M, arise in 7th decade are benign cystic neoplasms containing serous fluid cured by surgery Mucinous W>M, arise in body or tail with one third containing an invasive adenocarcinoma Intraductal papillary M>W, head of pancreas, may mucinous neoplasm be benign or malignant Solid-pseudopapillary young women, locally aggressive but may be cured with surgical excision. B- catenin/Adenomatous polyposis coli genetic pathway is altered DISEASE CAUSES CLINICAL FEATURES

Extrahepatic (80 to 90%): more fibrous look than other liver Klatskin tumors (50 to 60% of all cancers; pleomorphic CCAs) occur at the junction of the hyperchromatic nuclei R and L hepatic duct forming common hepatic duct; Distal bile duct tumors (20 to 30% of CCAs) Intrahepatic (~10%) occur in non- cirrhotic liver

All of dismal prognosis with survival rates of ~15% at 2 years; With intrahepatic CCA, median time from diagnosis to death is 6 months

PATHOGENESIS

MORPH/HISTO

LAB

DX/PROG

TX

Pancreatic adenocarcinoma (ductal)

MC; 80% of cases occur between ages of 60 and 80; Cigarette smoking is strongest environmental influence; other assoc are chronic pancreatitis and diabetes mellitus; Familial clustering in some cases

asympt until they invade adj structures; initial sx: pain but far advanced by then; Obstructive jaundice is seen in carcinomas of head of pancreas; Trousseau Sign, or migratory thrombophlebitis

Prog of precursor lesion called pancreatic intraepithelial neoplasia to infiltration carcinoma; KRAS gene (chromosome 12p) is most freq altered oncogene in pancreatic cancer (80 to 90% of cases); P16/CDKN2A gene (chrom 9p) - >most freq inactivated tumors suppressor gene;SMADR and p54 tumor suppressor genes also commonly inactivated

MC head>body>tail; diffusely involve entire pancreas; Gross: hard, stellate, gray-white, POORLY DEFINED MASSES; Most carcinomas of the head of the pancreas obstruct the common bile duct with marked distention of the biliary tree in ~50% who develop jaundice; Carcinomas of the body and tail do not impinge on the biliary tract and remain silent for some time and may be widely disseminated at dx; Invade into the retroperitoneum and invade the spleen, adrenals, vertebral column, transverse colon and stomach; Micro: poorly formed glands and secrete mucin; Highly invasive; intense desmoplastic response with a propensity for perineural invasion

Acute pancreatitis

due to biliary tract disease or Abdominal pain radiating to alcoholism; Gallstones are the back, N/V -> MC causes: present in 35% to 60% of Alcoholism , gallstones cases of acute pancreatitis, and about 5% of pts w/ gallstones develop pancreatitis; Obstruction of the pancreatic duct system, Drugs, Mumps, Metabolic disorders, Acute ischemia from shock, vascular thrombosis, embolism, etc Trauma (blunt trauma and iatrogenic); Inherited alterations in genes encoding pancreatic enzymes and their inhibitors, including germ line mutations in the cationic trypsinogen (PRSS1) and trypsin inhibitor (SPINK1) genes; Autodigestion of the pancreas because of inappropriately activated pancreatic enzymes

reversible lesions characterized by Gross: Swollen, edematous or Marked elevation of serum inflammation of the pancreas hemorrhagic/necrotic,Yellow- amylase in first 24 hours ranging in severity from edema white, chalky areas of fat necrosis, followed by rising serum lipase; and fat necrosis to parenchymal Mesenteric and omental fat Leukocytosis necrosis with severe hemorrhage necrosis; Micro: Diffuse interstitial edema due to microvascular leakage, Fat necrosis (fatty acids combine with calcium to form insoluble salts causing a granular appearance to fat cells); Severe pancreatitis will have necrosis of acinar, ductal, and islet cells ->Vascular damage and hemorrhage, neutrophils

serious comp: hypocalcemia -> due to precipitation of calcium soaps in necrotic fat

Chronic pancreatitis

MC cause:chronic ethanol Variable pain, sx of pancreatic abuse ->Repeated attacks of insufficiency (malabsorption, pancreatic inflamm w/ diabetes) irreversible destruction of exocrine pancreatic parenchyma, fibrosis and ultimately destruction of endocrine parenchyma;

Gross: hard firm white pancreas Micro: fibrosis, chronic inflamm , dilation of ducts with inspissation of eosinophilic material with preservation of islets at first

Complications: diabetes mellitus, pseudocyst

GALLBLADDER: DISEASE Gallstones (cholelithiasis)

CAUSES Heterotropic viruses Hepatitis A, B, C, D, E Systemic - CMV, EBV, yellow fever from a Flavivirus transmitted by mosquitos in the tropics

CLINICAL FEATURES PATHOGENESIS MORPH/HISTO freq have no sx; 70-80% are 2 types: chol and pigmented asymptomatic throughout their stones -> 1. chol: Western > lives; RUQ abdominal pain others, Advancing age, female, obese; Hyperlipidemia and bile stasis; 2. pigmented: Asian > Western Hemolytic anemia Biliary infection Gross: Enlarged, tense gallbladder with possible subserosal hemorrhage, May have serositis with fibrinopurulent exudate Wall is edematous, thickened and hyperemic; may have gangrene with green-black necrosis Micro - acute inflammation

LAB

DX/PROG TX comp: cholecystitis, Obstructive cholestasis or pancreatitis, cholangitis, empyema, perforaton, fistulas; Large stone may erode into bowel causing obstruction (gallstone ileus or Bouverets syndrome);

Acute cholecystitis Calculous: Acalculous:No stones Due to chemical irritation and Occurs in severely ill patients, inflamm of the obstructed severe trauma, burns, diabetics gallbladder precipitated 90% and sepsis, Likely due to of the time by obstructed ischemia cystic duct; Primary reason for emergency cholecystectomy

Chronic cholecystitis

Gross: variable thickening of gallbladder wall, variable adhesions Micro: Chronic inflam w/ Rokitansky-Aschoff sinuses on left (reactive prolif of the mucosa and fusion of the mucosal folds may give rise to buried crypts of epithelium within the wall); fibrosis; Dystrophic calcification MC women, ~72 yo; Rarely discovered at a resectable stage Frequently asymptomatic until advanced stage; RUQ abdominal pain, anorexia, N/v, jaundice Poor prognosis, 5 yr. survival ~ 5 to 12% Assoc w/ gallstones in 95% of cases

Gallbladder Cancer