Exam 1 Flashcards
What are dental caries caused by
Focal demineralization of tooth structure (enamel and dentin) by acidic metabolites of fermenting sugars that are produced by bacteria
What is the significance of fluoride with teeth
It is incorporated into crystalline structure of enamel, forming fluoropatite, which contributes to the resistance to degreaton by bacterial acids
What are the features of dental plaque
Sticky, colorless, biofilm that collects btw and on the surface of teeth; contains bacteria, salivary proteins, and desquamated epithelial cells; if not removed, becomes mineralized to form calculus (tartar)
What age group is gingivitis most prevalent in
Adolescence
What is periodontitis
Inflammatory process that affects supporting structure of teeth (periodontal ligaments) alveolar bone, and cementum; can lead to destruction of ligament (loosens and loss of teeth)
What is periodontal dz associated with
Shift in types and proportions of bacteria along the gingiva; *faculative gram + bacteria usually colonize oral mucosa, but in periodontitis, anaerobic and microaerophilic gram - colonize it
Which bacteria are associated with periodontitis
Aggregatibater (actinobacillus) actinomycetemcomitans, porphyromonas gingivalis, and prevontella intermedia
What diseases can periodotitis be a component of
AIDS, leukemia, Crohn dz, DM, downs, sarcoidosis, and syndromes associated w/ defects in neutrophils (chediak-higashi, agranulocytosis, and cyclic neutropenia); *can also be the origin of systemic dz such as endocarditis and pulm/brain abscesses
What are aphthous ulcers
Canker sores; common, recurrent, superficial oral mucosal ulceration of unknown etiology; most common in first 2 decades; associated with immuno disorders; single or multi, shallow, hyperemic ulceration covered by thin exudate (first mononuclear, but w/ secondary bacterial infection results in neutrophilic) and rimmed by erythema; resolve in 7-10 days unless immmunocompromised
What is an irritation fibroma
Aka traumatic fibroma and focal fibrous hyperplasia; fibrous proliferative lesion; submucosal exophitic smooth nodular mass of fibrous connective tissue that occurs on buccal mucosa along bite or gingiva line; reactive proliferation cause by repetitive trauma; surgical excision
What is a pyogenic granuloma
Type of fibrous proliferative lesion; found typically in children, young adults, and pregnant women (pregnancy tumor), ulcerated and red to purple in color; growth can be rapid; histo: vascular proliferation or organizing granulation tissue; can regress, mature into dense fibrous masses, or develop into peripheral ossifying fibroma; can be hemorrhagic; needs surgical excision
What is a peripheral ossifying fibroma
Common gingival growth that is reactive in nature rather than neoplastic; can develop from pyogenic granuloma or de novo from cells of the periodontal ligament; red, ulcerated, nodular; peak incidence in young and teenage females* ***recurrence rate of 15-20% so need to excise down to periosteum
What is a peripheral giant cell granuloma
*uncommon lesion of oral cavity (usually gingiva); reactive/inflammatory response; not neoplastic; covered by intact gingival mucosa, but can be ulcerated; histo: aggregation of multinucleate, foreign-body like giant cells separated by fibroangiomatous stroma; not encapsulated but easily excised; should be diff from neutral giant cell tumors within the jaw and “brown tumors” seen in hyperparathyroidism (histo is similar)
When do primary infections of HSV 1 usually occur
Btw 2-4 y/o; often asymptomatic; in 10-20% of cases, can present as acute hermetic gingivostomatitis w/ abrupt onset of vesicles and ulceration of oral mucosa (gingiva); accompanied by LAD, fewer, anorexia and irritability
What is the morphology of HSV-1 vesicles
Can be few mm or large bullae; at first filled w/ clear serous fluid, but rapidly rupture to yield painful, red-rimmed, shallow ulceration; histo: intra and intercellular edema (acantholysis), creating clefts that can become transformed into macroscopic vesicles; individual epidermal cells in margins of vesicle develop eosinophilia intranuclear viral inclusions or can fuse to produce giant cells (multinucleate polykaryons) *demonstrated by Tzanck test; clears in 3-4 wks
What is viral reactivation of HSV-1 called
Recurrent hermetic stomatitis; occurs at the site of primary inoculation or in adjacent mucosa associated w/ the same ganglion
What other viral infections can involve the oral cavity and head and neck region
Herpes zoster, EBV (mono, nasopharyngeal carcinoma, lymphoma), CMV, enterovirus (herpangina, hand-foot-mouth dz, acute lymphonodular pharyngitis) and rubeola (measles)
What is the most common fungal infection of the oral cavity
Candida albicans (normal flora in 50% of people)
What are the forms of oral candidiasis
Pseudomembranous (most common - thrush), erythematous, and hyperplastic
What are the characteristics of the pseudomembraneous type of oral candidiasis
Superficial, gray to white inflammatory membrane composed of matted organisms enmeshed in fibrinosuppurative exudate that can be scraped off to reveled underlying erythematous base; remains superficial unless immunocompromised
What infectious diseases can cause oral manifestations
- scarlet fever: raspberry (fiery red tongue) or strawberry tongue (white coated w/hyperemic papillae)
- Measles: spotty enathema in oral cavity often precedes skin rash; ulceration in buccal mucosa (koplik spots)
- mono: pharyngitis and tonsillitis can cause gray white membrane; palatal petechiae
- diphtheria: dirty white, fibrinosuppurative membrane over tonsils
- HIV: candida and kaposi sarcoma; hairy leukoplakia
What dermatologic conditions can have oral manifestations
Lichen planus, pemphigus, bullous pemphigoid, erythema multiforme
What hematologist disorders can cause oral manifestations.
Pancytopenia (oral infections), leukemia (oral lesions), monocytic leukemia (leukemic infiltration and enlargement of gingiva w/ periodontitis)
What diseases can cause melanotic pigmentation
Addison’s, hemochromatosis, fibrous dysplasia of bone (Albright syndrome), peutz-jaghers syndrome (GI polyposis)
What oral manifestation can rendu-osler-Weber syndrome cause
AD; multiple congenital aneurysmal telangiectasias beneath mucosal surfaces of oral cavity and lips
Which fungi can cause deep fungal infections in the oral cavity, head and neck
Histo, blasts, coccidioidomycosis, cryptococcosis, zygomycosis and aspergillosis
What is hairy leukoplakia
Oral lesion on lateral border of the tongue caused by EBV; white confluent patches of fluffy hyperkeratotic thickening; cannot be scraped off; histo: hyperparakeratosis and acanthus is w/ balloon cells in upper spinous layer; stains can show RNA transcripts of EBV; can have superimposed candida infection on top
What is leukoplakia
White patch or plaque that cannot be scraped off and cannot be characterized as any other dz; reserved for oral cavity; can be premalignant so until proven otherwise, considered precancerous
What is erythroplakia
Less common and more ominous than leukoplakia; red, velvety, rodeo area in oral cavity that remains level or depressed in relation to surrounding mucosa; epithelium is atypical and risk of malignant transformation is higher
What are speckled leukoerythroplakia
Intermediate forms btw leukoplakia and erythroplakia
What population are leukoplakia and erythroplakia most commonly seen in
Age 40-70; males; use of tobacco is common antecedent
What is the histo of erythroplakia
Severe dysplasia, carcinoma in situ, or minimally invasive carcinoma
What is the most common cancer of the head and neck
Squamous cell carcinoma; 2nd is adenocarcinoma of salivary gland
What are the causes of squamous cell carcinoma of the head and neck
- tobacco and alcohol abusers
- actinic radiation (sunlight) - lower lip
- younger than 40, if not infected w/ HPV, unknown
What is the survival rate dependent on for squamous cell carcinoma of the head and neck
-early stage of smoking and alcohol is about 80%
-HPV positive better prognosis than HPV negative
Development of multiple tumors decreases survival; secondary tumors are increased prevalence than any other malignancy *field cancerization or can be intraepithlial Mets
Which mutations are commonly involved in SCC
P53, p63, NOTCH 1; overexpress p16
Where can SCC occur in the oral cavity
Ventral surface of tongue, floor of mouth, lower lip, soft palate, gingiva; early stages: raised, firm, pearly plaques or irregular roughened areas of mucosal thickening; dyplastic lesions may or may not develop to full thickness dysplasia before invading (in cervical cancer, usually develops before invasion); can be well diff keratinizing or anaplastic tumors -> not related to behavior; met to cervical LN or mediastinal LN, lungs, liver, and bones
What are odontogenic cysts
Derived from remnants of odontogenic epithelium present in jaw; epithelial lined cysts;classified as either inflammatory or developmental
What are dentigerous cysts
Originates around crown of unerupted tooth; result of fluid accumulation btw developing tooth and dental follicle; associated w/ impacted wisdom teeth; histo: lined by stratified squamous epithelium; complete removal is curative
What are odontogenic keratatocysts (OKC)
Aka keratocystic odontogenic tumor; *aggressive; most common btw 10-40 yo males in posterior mandible; unilocular or multilocular; histo: keratinized stratified squamous epithelium w/ basal cell layer; needs complete removal; high rate of recurrence for incomplete removal; most are solitary lesions
What should you test for if someone has multiple OKCs
Nevoid basal cell carcinoma syndrome (gorlin syndrome); associated w/ mutations in PTCH (tumor suppressor) on chrom 9q22
What is a peripheral cyst
Inflammatory; common - found on apex of teeth; develop as a result of pulpitis (inflammation of teeth); complete removal
What are odontogenic tumors
Group of lesions w/ diverse histo appearances and clinical behavior; some are true neoplasms and other are hamartomas; derived from odontogenic epithelium, ectomesenchyme or both
What are the two most common odontogenic tumors
- ameloblastoma: arises from odontogenic epithelium and shows NO ectomesenchymal differentiation; commonly cystic, slow growing, and locally invasive but has indolent course in most cases; tx: resection
- odontoma: most common type*; arises from epithelium but shows extensive depositions of enamel and dentin; hamartomas rather than true neoplasms; cured by local excision
What are the inflammatory odontogenic cysts
Perioapical, residual, paradental
What are the developmental odontogenic cysts
Dentigerous, odontogenic keratocyst, gingival cyst of newborn and adult, eruption cyst, lateral periodontal, glandular odontogenic, calcifying epithelial odontogenic (gorlin)
What are the benign and malignant tumors of odontogenic epithelium
- Benign: ameloblastoma, calcifying epithelial odontogenic tumor (pindborg), squamous odontogenic tumor, adenomatoid odontogenic
- Malignant: ameloblastic carcinoma, malignant ameloblastoma, clear cell odontogenic carcinoma, ghost cell odontogenic carcinoma, primary intraosseous squamous cell carcinoma
What are the tumors of odontogenic ectomesenchyme
Odontogenic fibroma and my soma, cementoblastoma
What are the benign and malignant tumors of odontogenic epithelium and ectomesenchyme
Benign: ameloblastic fibroma, ameloblastic fibro-odontoma, adenomatoid odontogenic tumor, odontoameloblastoma, complex odontoma, compound odontoma, calcifying cystic odontogenic tumor, denitogenic ghost cell tumor
Malignant: ameloblastic fibrosarcoma
What drugs is xerostomia commonly a side effect of
Anticholinergic, antidepressant, antipsychotic, diuretic, anti-HTN, sedative, m relaxant, analgesic, and antihistamine
How can xerostomia present
Dry mucosa or atrophy or papillae of the tongue, with fissuring and ulceration
What are complications of xerostomia
Dental caries, candidiasis, difficultly swallowing and speaking
What is sialadenitis
Inflammation induced by trauma, viral or bacterial infection or autoimmune dz; mucoceles- most common type of inflamm salivary gland lesion; most common form of viral sialadenitis is pumps
What are mucocele
Most common lesion of salivary glands; results from either blockage or rupture of salivary gland duct w/ leakage of saliva into surrounding connective tissue; most often found on lower lip and are result of trauma; most common in toddlers, young adults and elderly; present as fluctuate swellings that have blue translucent hue; lesion can change in size (w/ eating); histo:; pseudocysts lined by granulation tissue - cystic spaces filled w/ mucin nad macrophages; excision of cyst and minor salivary gland needed
What is ranula
Epithelial lined cysts that arise when the duct of the sublingual gland has been damaged; can become so large it develops into plunging ranula which is cyst that has dissected through connective tissue, connecting the two bellies of the mylohyoid m
What is nonspecific bacterial sialadenitis
Most often involves major salivary glands (submandibular); common; secondary to ducal obstruction produced by stones (sialolithiasis); common offenders are S aureus and Strep. Viridans; can be obstructed by impacted food Debris as well; decreased salivary production can be underlying cause as well (ppl on phenothiazines) or dehydration (leads to bacterial suppurations parotitis in elderly w/ recent hx of thoracic or ab surgery); unilateral involvement of single gland
What are the most common benign tumors of the salivary gland
Pleomorphic adenoma (mixed), warthin tumor, oncocytoma, basal cell adenoma, canalicular adenoma, Ductal papilloma
What are the most common malignant tumors of the salivary glands
Mucoepidermoid carcinoma, adenocarcinoma, acinic cell carcinoma, adenoid cystic carcinoma, malignant mixed tumor, squamous cell carcinoma, other carcinoma
Which salivary gland do tumors most frequently occur
Parotid
Which salivary glands are more likely to house malignant tumors
Sublingual is most likely, then minor salivary then submandibular **likelihood of salivary gland tumor being malignant is inversely proportional to size of the gland
What population do salivary gland tumors occur in
Mostly adult females
Which salivary gland tumor appears more in males than females
Warthin tumors; *smoking is predisposing factor
When do the benign vs malignant salivary gland tumors occur
Benign: 5th-6th decade; malignant: later
Are malignant or benign tumors of the salivary gland detected quicker
Malignant because grow faster
What are pleomorphic adenoma
Benign tumors that consist of ductal (epithelial) and myoepithelial cells (mesenchyme); most common in parotid; contain myxoid, hyaline, chondroid and osseous tissue; radiation exposure increases risk; some are assoc w/ PLAG1 rearrangements (overexpression)
What is the morphology of pleomorphic adenoma
Round, well demarcated masses; encapsulated (in some areas - palate - not fully)blue translucent areas of chondroid; histo: heterogeneity
How do pleomorphic adenoma present
Painless, slow growing mobile, discrete masses
What is carcinoma ex pleomorphic adenoma
Malignant mixed tumor; usually takes form of adenocarcinoma or undifferentiated carcinoma;very aggressive
What is a warthin tumor
Aka papillary cystadenoma lymphomatosum; benign; second most common salivary gland neoplasm; arises almost exclusively in parotid; more common in males; 10% are b/l; smokers are increased risk
What is the morphology of warthin tumor
Round to oval encapsulated masses; pale gray; filled w/ mutinous or serous secretions; histo: lined by double layer of neoplastic epithelial cells and sometimes bear germinal centers; numerous mitochondria present (oncocytic)
Where else have warthin tumors been found to originate
cervical LN *dont mistake w/ Mets
What are mucoepidermoid carcinomas
Composed of squamous cells, mucus-secreting cells, and intermediate cells; occur most often inparotid; associated w/ balanced (11;19) (q21;p13) translocation that creates a fusion gene MECT1-MAML2 gene; most common form of primary malignant tumor of salivary glands
What is the morphology of mucoepidermoid carcinomas
No capsule; infiltrative at margins; pale and gray-white; contain mucin-containing cysts; histo: cords, sheets, or cystic configurations of squamous, mucous or intermediate cells
What is the clinical course of mucoepidermoid carcinomas
Depends on grade; low grade rarely met; high grade: difficult to excise so recur and met )=
What is adenoid cystic carcinoma
Uncommon tumor; found in minor salivary glands, in particular palatine glands; cribriform pattern on histo; spaces btw often filled w/ hyaline; slow growing and invade perineural spaces; highly recurrent; disseminate widely; *minor salivary glands have poorer prognosis than parotid glands
What is acinic cell carcinoma
Compose of cells that resemble the normal serous acinic cells of the salivary glands; uncommon; most arise in parotid, rest in submandibular; rarely involves minor glands; can be b/l; clear cytoplasm; miccrocystic, glandular, follicular, or papillary patterns on histo; recurrence is uncommon but can met to LN
An atresia, fistula or duplication of the GI tract would be discovered early on if located where?
When in the esophagus, discovered shortly after birth (regurgitation)
Esophageal atresia is what kind of obstruction
Mechanical
Where does esophageal atresia most commonly occur
At bifurcation of trachea; usually associated with a fistula connecting the upper or lower esophageal pouches to a bronchus or trachea; fistula can also be present w/o atresia
What are developmental abnormalities of the esophagus associated with
Congenital heart defects, GU malformations, neuro dz
What does intestinal atresia most commonly involve
Duodenum; less common than esophageal atresia
What is imperforate anus
Most common form of congenital intestinal atresia; caused by failure of cloacal diaphragm to involute
What is stenosis
Incomplete form of atresia; congenital forms or acquired as consequence of inflamm scarring (GERD, irradiation, systemic sclerosis, caustic injury); esophagus and SI are most commonly affected
What is a diaphragmatic hernia
Occurs when incomplete formation of the diaphragm causes ab viscera to herniate into thoracic cavity; can cause pulmonary hypoplasia that can be incompatible w/ life
What is an omphalocele
When closure of the ab mm is incomplete and ab viscera can herniate into ventral membranous sac; can be repaired surgically; assoc w/ other defects
What is gastroschisis
Similar to omphalocele except involves ALL layers of ab wall from peritoenum to skin
What is the most frequent site of ectopic gastric mucosa
Upper third of esophagus - referred to as inlet patch
Where can ectopic pancreatic tissue be found
Stomach or esophagus; most often asymptomatic but produce damage and local inflammation sometimes; when present in pylorus can lead to obstruction; can mimic invasive cancer
What can gastric heterotopia present with
(Small patches of ectopic gastric tissue in small bowel or colon); blood loss due to peptic ulceration of adjacent mucosa
What causes Merkel diverticulum
Failed involution of vitelline duct (connects lumen of developing gut to yolk sac)
What are the features of Merkel diverticulum
Extends from antimesenteric side of bowel; occurs in 2% of pop, present w/in 2 feet of ileocecal valve; 2 inches long, twice as common in males, most often symptomatic by age 2 (only 4% are ever symptomatic)
What symptoms can Merkel diverticulum have
If has gastric tissue, ulceration and blood loss; can resemble acute appendicitis or obstruction
What is the difference between meckel’s and other diverticulum
Meckel’s is congenital and has all 3 layers of bowel wall; acquired diverticula either lack musculature entirely or have attentuated muscularis propria *most common site of acquired is sigmoid colon
What are the features of pyloric stenosis
Congenital is More common in males; high rate of concordance in monozygotic twins; also increased risk of siblings; Turner syndrome and trisomy 18 have increased risk; erythromycin and azithromycin exposure in first 2 weeks of life linked to increased incidence
When does congenital hypertrophic pyloric stenosis present
Btw 3rd and 6th week of life as projectile, nonbilious vomiting after feeding and frequent demands for refereeing; PE reveals firm ab mass; can have abnormal left to right hyperperistalsis during feeding and before vomiting; results from hyperplasia of pyloric muscularis propria; surgical splitting of muscularis (myotomy) is curative
What causes acquired pyloric stenosis
Antral gastritis or peptic ulcers close to pylorus; carcinomas of distal stomach and pancreas can also cause this
What other dz is hirschprung dz associated with
Downs
What is another name for hirschsprung dz
Congenital aganglionic megacolon; abnormal NC migration from cecum to rectum; distal intestinal segment lacks both Meissen submucosal and auerbach myenteric plexus
What are the underlying mechanisms that cause hirschsprung dz
Genetic component present in nearly all cases; heterozygous LOF mutations in RET (RTK) account for most familial cases and some sporadic cases; mutations in endothelium and its receptor have also been described; *more common in males, but when present in females involves longer aganglionic segments
What stain can you use to diagnose hirschsprung
Stain for acetylcholinesterase (used to identify ganglion cells)
What are the clinical features of hirschsprung
Failure to pass meconium; obstruction and constipation, bilious vomiting; can pass stool if only affects few centimeters of rectum; *threats to life are enterocolitis, fluid and electrolyte disturbances, perforation, and peritonitis
What cause acquired megacolon
Chagas dz, obstruction by neoplasm or inflammation, toxic megacolon complicating UC, visceral myopathy, functional psychosomatic disorders; *chagas is the only one associated with loss of ganglion cells
What does the esophagus develop from
Cranial portion of foregut; recognizable by 3rd week gestation
What is a functional obstruction
Disruption of peristalsis
What is nutcracker esophagus
High amplitude contractions of distal esophagus that are due to loss of normal coordination of inner circular layer and outer longitudinal layer smooth m contraction
What is diffuse esophageal spasm
Repetitive simultaneous contractions of distal esophageal smooth m
What is hypertensive lower esophageal sphincter
Absence of altered patterns of esophageal contraction
What can esophageal dysmotility ultimately lead to
Development of small diverticulum (epiphrenic diverticulum - located above lower esophageal sphincter) or zenker (pharyngoesphageal) caused by impaired relaxation and spasm of cricopharyngeus m after swallowing
When do zenker diverticulum develop
Usually after 50; *halitosis
How do mechanical obstructions of the esophagus present
Progressive dysphagia that begins with inability to swallow solids; develops slowly
What is benign esophageal stenosis
Narrowing of lumen; caused y fibrous thickening of submucosal and atrophy of muscularis propria and secondary epithelial damage; usually able to maintain diet and weight (malignant strictures associated with weight loss)
What are esophageal mucosal webs
Idiopathic ledge like protrusions of mucosa; uncommon; occur in women older than 40 and associate w/ GERD, chronic graft vs host dz, or blistering skin dz; in upper esophagus, can cause iron deficiency anemia, glossitis, and cheilosis (Paterson-Brown-Kelly or Plummer-Vinson syndrome); main symptom is non progressive dysphagia assoc w/ incompletely chewed food
What are esophageal rings
Aka schatzki rings; circumferential rings that include mucosa, submucosal and hypertrophic muscularis propria; when present in distal esophagus, termed A rings and are covered by squamous mucosa; when located at squamocolumnar junction of lower esophagus, B rings and can ha be gastric cardia-type mucosa
What is achalasia
Incomplete LES relaxation, increased LES tone, aperistalisis of esophagus; NO and vasoactive polypeptide from inhibitory neurons and interruption of cholinergic signaling usually allows LES to relax (doesn’t happen here); sx: dysphagia for solids and liquids, difficulty belching, chest pain; some risk for esophageal cancer, but not great enough for screening
What is primary achalasia
Result of distal esophageal inhibitory neuronal generation; degenerative changes in vagus n or dorsal motor nucleus of vagus can also occur; cause unknown
What is secondary achalasia
Can be caused by chagas (trypanosomiasis cruzi causes destruction of myenteric plexus, failure of peristalsis and esophageal dilation)
What can cause achalasia-like dz
Diabetic autonomic neuropathy, malignancy, amyloidosis, sarcoidosis, lesions of dorsal motor nuclei (polio), Downs, Allgrove (triple A syndrome -> AR disorder characterized by achalasia, alacrity, and ACTH resistant adrenal insufficiency; can also be driven by autoimmune destruction of inhibitor esophageal neurons
What are treatments for primary and secondary achalasia
Laparoscopic myotomy and pneumatic balloon dilation; Botox to inhibit cholinergic neurons can also be effective
What are Mallory-Weiss tears
Longitudinal mucosal tears near GE jxn; assoc w. Vomiting or retching secondary to acute alcohol intoxication; relaxation of GE musculature usually precedes vomiting -> fails here; do not require surgery, healing is rapid
What is boerhaave syndrome
Less common than Mallory Weiss syndrome; more serious; trans mural tearing and rupture of distal esophagus; produces severe mediastinitis and requires surgery; present w/ chest pain, tachypnea and shock and can be confused with MI
What is odynophagia
Pain on swallowing
What causes esophageal chemical injury in children and adults
Children: accidental ingestion of cleaning items; adults: suicide attempts
What is pill-induced esphagitis
When pill get stuck and dissolves in esophagus vs stomach
What are esophageal infections usually due to
Very uncommon in healthy individuals; due to HSV, CMV, or fungi (candida, muco, and aspergillosis)
What is the morphology of esophagitis
Neutrophils present but can be absent following chemical injury (necrosis); candidiasis can cause gray-white pseudomembranes of fungal hyphae on esophageal mucosa; HSV causes punched out ulcers, CMV causes shallower ulceration and nuclear and cytoplasmic inclusions, graft vs host dz show basal epithelial cell apoptosis, mucosal atrophy w/o inflammatory infiltrates
What is the most common cause of esophagitis
Reflux; most common outpatient GI diagnosis as well
What causes GERD
LES relaxation due to gastric dissension, mild pharyngeal stimulation that does not trigger swallowing, and stress; increase in ab pressure (coughing, straining, or bending), alc and tobacco use, obesity, CNS depressants, pregnancy, hiatal hernia, delayed gastric emptying, increased gastric volume
What is the morphology of GERD
Usually unremarkable in mild GERD; more severe: eosinophils recreated followed by neutrophils; basal zone hyperplasia
What are the clinical features of GERD
Most common > 40; heartburn, dysphagia, regurgitation of sour tasting contents; rx w/ PPI; complications: ulcer, hematemeis, melena, stricture, Barrett
What is hiatal hernia
Can resemble GERD; separation of diaphragmatic courage and protrusion of stomach into thorax
What are the symptoms of eosinophilic esophagitis
Food impaction, dysphagia in adults; feeding intolerance or GERD like sx in children; histo: large intraepithlial eosinophils; reflux NOT prominent and PPIs provide no relief; most are atopic and many have atopic dermatitis, allergic rhinitis, asthma, or peripheral eosinophilia; tx: modify diet to remove food allergens or corticosteroids
Besides alcoholic liver dz, what is the next most common cause of esophageal varies
Hepatic schistosomiasis
Where are the esophageal varices found
Submucosal of distal esophagus and proximal stomach
How do you treat variceal hemorrhage
Inducing splanchnic vasoconstriction or sclerotherapy (injection of thrombotic agents), balloon tamponade, or variceal ligation
What are risk factors for variceal hemorrhage
Large varices, elevated hepatic venous pressure gradient, previous bleeding, advanced liver dz; treat prophylactically w/ beta blockers to reduce portal blood flow
What population is Barrett esophagus most common in
White males btw 40 and 60
What is the most common cancer of the esophagus worldwide
SCC; adenocarcinoma in US
What is the most common benign tumor of the esophagus
Leiomyomas
What can reduce the risk of adenocarcinoma of the esophagus
Diets rich in fresh fruits and vegetables, some serotypes of H pylori (reduced gastric acid secretion nand reflux)
What population is adenocarcinoma of the esophagus most common in
White males
What mutations are seen in the progression from Barrett esophagus to adenocarcinoma
TP53, downregulation of CDKN2A (p16/INK4a) detected at early stages (hypermethylation and alleluia loss); later stages - amplification of EGFR, ERBB2, MET, cyclin D1, Cyclin E
What part of the esophagus is usually affected by adenocarcinoma
Distal 1/3; can invade gastric cardia
What are the clinical features of esophageal adenocarcinoma
Difficulty or pain on swallowing, progressive weight loss, hematemesis, chest pain, vomiting; by time sx appear, usually spread to submucosal lymph vessels; not a good prognosis
Where is squamous cell carcinoma most commonly found in the esophagus?
Mid-esophagus
What population is usually affected by squamous cell carcinoma of the esophagus
Males; tobacco use, poverty, caustic esophageal injury, achalasia, tylosis, Plummer-Vinson syndrome, diets deficient in fruits and veggies, frequent consumption of hot beverages *African Americans
What mutations have been found to cause esophageal squamous cell carcinoma
Amplification of SOX2 (transcription factor); over expression of cyclin D1 and LOF of TP53, e-Cadherin, and NOTCH1
What is the in situ lesion before squamous cell carcinoma called
Squamous dysplasia
Where does squamous cell carcinoma of the esophagus spread
Upper 1/3: cervical LN
Middle 1/3: mediastinal, paratracheal and tracheobronchial
Lower 1/3: gastric and celiac nodes
What is commonly the first symptom of SCC of esophagus
Aspiration of food b/c of tracheoesophageal fistula
What lines the cardia and antrum of the stomach
Mucin-secreting foveolar cells that form small glands
What glands are found in the body and fundus
Chief cells (produce pepsin)
What is acute gastritis
Mucosal inflammation when neutrophils are present
What is gastropathy
When inflammatory cells are rare or absent; includes diverse set of disorders marked by gastric injury or dysfunction; *NSAIDs, alcohol, bile, and stress induced injury; acute mucosal erosion or hemorrhage (ie: curling ulcers or lesions following disruption in blood flow) can also cause gastropathy
What is hypertrophic gastropathy
Specific group of diseases exemplified by menetrier dz and zollinger Ellison syndrome
What protects the gastric mucosa from the acidity of the lumen
Mucin forms layer of mucus and phospholipids that prevents large food particulates from directly touching epithelium and has a neutral pH b/c of bicarbonate secretion from surface epithelial cells; replacement of foveolar cells every few days is needed to maintain this
Disruption of which protective mechanisms can lead to gastropathy, acute gastritis, and chronic gastritis
- NSAIDs inhibit COX dependent synthesis of prostaglandins E and I which stimulate mucus, bicarbonate, and phospholipid secretion, mucosal blood flow, and epithelial restitution while reducing acid secretion; greatest risk w/ nonselective inhibitors (aspirin, ibuprofen and naproxen); COX 2 only are celecoxib
- gastric injury in uremic patients and H pylori infxn: inhibits gastric bicarbonate transporters
- reduced mucin and bicarbonate secretion
- decreased oxygen delivery at high altitudes
What is the morphology of gastropathy and acute gastritis
Surface epithelium intact but foveolar cell hyperplasia w/ corkscrew profiles and epithelial proliferation are typical; not many immuno cells; presence of neutrophils above BM is abnormal in all parts of GI tract and signifies active inflammation (gastritis NOT gastropathy)
Can you distinguish gastritis and gastropathy by clinical sx
No
When does stress related mucosal dz occur
Patients w/ severe trauma, burns, intracranial dz, major surgery, serious medical dz; result of local ischemia
What are stress ulcers
Most common in individuals w/ shock sepsis or severe trauma
What are curling ulcers
Occur in proximal duodenum and are associated w/ burns and trauma
What are Cushing ulcers
Gastric, duodenal, and esophageal ulcers in ppl w/ intracranial dz; *high incidence of perforation
What causes stress-related mucosal dz
Hypotension, reduced blood flow by stress induced splanchnic vasoconstriction, upregulation of NO synthase and increased release of endothelin-1 (constricts); *increase in COX-2 is protective
What are gastric lesions associated with intracranial injury though to be caused by
Direct stimulation of vagal nuclei -> causes hypersecretion of gastric acid; will see systemic acidosis
What is the difference between acute stress ulcers and peptic ulcers
Stress ulcers are found anywhere in stomach and most often multiple; stress ulcers do not have scarring and blood vessel thickening that characterize chronic peptic ulcers
What is dieulafoy lesion
Caused by submucosal artery that does not branch properly w/in the wall of the stomach; results in artery 10 times the size of capillaries; most commonly found around lesser curvature near GE jxn
What is GAVE
Gastric antral vascular ectasia; responsible for upper GI bleeding; longitudinal stripes of edematous erythematous mucosa that alternate w/ less severely injured paler mucosa *watermelon stomach; stripes are created by ecstatic mucosal vessels; histo: reactive gastropathy w/ dilated cap containing fibrin thrombi; most idiopathic, but some assoc w/ cirrhosis and systemic sclerosis
What is the most common cause of chronic gastritis
Infection w/ H. Pylori (bacillus)
What is the most common cause of diffuse atrophic gastritis
Autoimmune gastritis
What kind of atrophic gastritis can H. Pylori cause
Multifocal rather than diffuse
Is hematemesis common with chronic gastritis
No
What is risk of h.pylori infection associated with
Poverty, household crowding, limited education, AA or Mexican, residence in rural areas, birth outside of US; transmitted via fecal/oral route
How does H pylori present
Antral gastritis w/ normal or increased local acid production; hypergastrinemia (gastric in serum) is very uncommon; can progress to involve body and fundus (multifocal atrophic gastritis) which is assoc w/ reduced parietal cell mass and acid secretion, intestinal metaplasia and increased risk of gastric adenocarcinoma; inverse relationship in duodenal ulcer and adenocarcinoma
What contributes to the virulence of h pylori
Flagella; urease, adhesins (enhance adhesion to surface foveolar cells), and toxins (CagA - cytotoxin-associated gene A) which is involved in progression
What is associated with increased risk of gastric cancer with h pylori infection
Cag A expressing strains
What pays a role in outcome of h pylori infection
Genetic polymorphism that leads to increased expression of TNF and IL-1beta or decreased expression of IL-10 are associated with development of pangastritis, atrophy and gastric cancer; iron deficiency is also a risk for development of cancer
What stain is used to view h pylori
Warthin starry silver stain
Besides biopsy, how else can h pylori infection be diagnosed
Serum test for abs, fecal bacterial detection, urea breath test
What is the treatment for h pylori
Abx and PPI
What are the features of autoimmune gastritis
Spares the antrum and is associated with hypergastrinemia; characterized by abs to parietal cells and IF (detected in serum in gastric secretions), reduced serum pepsinogen I, endocrine cell hyperplasia, vit B12 def, and defective gastric acid secretion (achlorhydria)
What is the inflammatory infiltrate found in h pylori vs autoimmune gastritis
H pylori: neutrophils and subepithelial plasma cells
Autoimmune: lymphocytes and macrophages
What is the gastrin level in h pylori vs autoimmune gastritis
H pylori: normal or decreased
Autoimmune: increased
What other lesions are seen w/ h pylori vs autoimmune gastritis
H pylori: hyperplastic and inflammatory polyps
Autoimmune: neuroendocrine hyperplasia
What would you find in the serology w/ h pylori vs autoimmune gastritis
H pylori: abs to h pylori
Autoimmune: abs to parietal cells, H+, K+ ATPase, IF)
What can happen down stream as a result of h pylori vs autoimmune gastritis
H pylori: peptic ulcer, adenocarcinoma, MALToma
Autoimmune: atrophy, pernicious anemia, adenocarcinoma, carcinoid tumor
What other conditions are associated with autoimmune gastritis
Autoimmune dz, thyroiditis, DM, graves dz, Addison, primary ovarian failure, primary hypoparathyroidism, vitiligo, myasthenia, lambert-Eaton syndrome
What do parietal cells secrete
IF and gastric acid
What is the pathogenesis of autoimmune gastritis
Loss of parietal cells -> loss of acid -> gastrin release stimulated -> hyperplasia of antral gastrin producing G cells; chief cell destruction -> loss of pepsinogen I
What is the principal agent of injury in autoimmune gastritis
CD4 T cells directed against parietal cell components (H+, K+ ATPase); no autoimmune rxn to chief cells (lost through gastric gland destruction); gastric stem cells survive so if treated, glands can repopulate
What is the morphology of autoimmune gastritis
Rugal folds lost; endocrine cell hyperplasia demonstrated by immunostains for chromogrannin A
What is the age of diagnosis of autoimmune gastritis
Median: 60; progression is slow; more women than men
Are there any HLA genes linked to autoimmune gastritis
No
What is the clinical presentation of autoimmune gastritis
Sx of anemia; b12 def can cause atrophic glossitis (tongue becomes smooth and beefy red), epithelial megaloblastosis, malabsorptive diarrhea, peripheral neuropathy, spinal cord lesions, and cerebral dysfunction
What is eosinophilic gastritis
Characterized by eosinophils in the mucosa and muscularis in antral or pyloric regions; assoc w/ peripheral eosinophilia and increased IgE; caused by allergic rxn and immune disorders (systemic sclerosis and polyomyositis), parasite infxn and H pylori
What are the characteristics of lymphocytic gastritis
Primarily affects women; nonspecific ab sx; idiopathic; assoc w/ celiac; affects entire stomach; referred to as varioliform gastritis b/c shows thickened folds covered by nodules w/ central aphthous ulceration
What is the most common cause of granulomatous gastritis
Crohns; also caused by sarcoidosis and mycobacterium, fungi, CMV, and H pylori infxn
What is the most common form of peptic ulcer dz
H pylori induced antral gastritis; results in increased gastric acid and decreased bicarbonate
What is PUD w/in the body or fundus assoc w/
Not suceptible to antral or duodenal ulcers b/c dont produce enough gastric acid
What are the risk factors for peptic ulcer dz
H pylori, cigarettes, COPD, illicit drugs, NSAIDs, alcoholic cirrhosis (duodenal), psych stress, endocrine cell hyperplasia, zollinger Ellison (stomach, duodenum and jejunum), viral infxn (CMV, HSV)
What is diff about the margins of ulcers and cancer
Ulcers: level w/ mucosa
Cancer: heaped up margins
How can perforation be detected
Free air under diaphragm on radiology
What are the clinical features of peptic ulcers
Pain 1-3 hrs after meals, worse at night, relieved by alkali or food; N/V/belching and bloating; referred to back, LUQ or chest (mistaken for MI)
What are the complicating of PUD
Bleeding, perforation, obstruction (w/ pyloric channel ulcers; rarely causes total obstruction)
What is intestinal metaplasia
Chronic gastritis of body and fundus can lead to loss of parietal cells (oxyntic atrophy) which can be assoc w/ metaplasia, which includes presence of goblet cells -» increased risk of gastric adenocarcinoma (greatest in autoimmune gastritis)
How can you tell the difference between dysplasia and reactive epithelial cells (regenerative epithelium)
Dysplasia remains immature, but reactive epithelial cells mature
What is gastritis cystica
Reactive epithelial proliferation associated with entrapment of epithelial lined cysts; found in submucosal (gastritis cystica polyposa) or deeper layers of gastric wall (gastric cystica profunda) *trauma induced (assoc w/ gastrectomy and gastritis); can mimic adenocarcinoma
What are hypertrophic gastropathies
Uncommon* giant cerebriform enlargement of rugal folds due to epi hyperplasia w/o inflammation; *excessive growth factor release
What are the 2 examples of hypertrophic gastropathies
Menetrier and zollinger Ellison
What is menetrier dz
Rare; assoc w/ excessive secretion of TGF alpha; diffuse hyperplasia of foveolar epithelium of body and fundus and hypoproteinemia due to protein losing enteropathy; secondary sx: weight loss, diarrhea, peripheral edema; sx in children similar to adults but children is self limited and often follows resp infxn; risk of gastric adenocarcinoma increases in adults
What is the treatment for menetrier dz
Supportive; IV albumin, parenteral nutritional supplements; gastrectomy needed if severe; TGF alpha blockers
Are there any risk factors of menetrier dz
No
What is zollinger Ellison syndrome
Gastrin secreting tumors found in SI or pancreas; duodenal ulcers, diarrhea; doubling of oxyntic mucosal thickness due to increase in number of parietal cells; gastrin also induces hyperplasia of mucous neck cells, mucin hyperproduction, and proliferation of endocrine cells (can produce carcinoid tumors)
What is the treatment of zollinger Ellison
PPI
Are gastrinomas malignant
60-90% of the time they are
What is associated with non-sporadic zollinger Ellison
MEN I; treat w/ stomatostatin analogues
What inflammatory infiltrate is seen in zollinger Ellison
Neutrophils
Is zollinger Ellison assoc w/ adenocarcinoma
No
What are the majority of gastric polyps
Inflammatory or hyperplastic
What are the features of inflammatory and hyperplastic polyps
Most common btw 50 and 60 y/o; usually develop in assoc w/ chronic gastritis (h pylori); polyps can regress after tx of h pylori
Which polyps should be resected and examined
Polyps larger than 1.5 cm; dysplasia correlates with size
What are fundic gland polyps
Occur sporadically and in ppl w/ familial adenomatous polyposis (FAP); has increased recently b/c of PPIs (inhibit acid which leads to increased gastrin and oxyntic gland growth); asymptomatic or assoc w/ N/V/epi pain
Where do fundic gland polyps form
Fundus and body; smooth surface; can be single or multiple; inflammation absent; composed of dilated glands lined by parietal, chief and foveolar cells
Do sporadic fundic gland polyps have a cancer risk
No
Do males or females get gastric adenomas more frequently
Males
Who is at an increased risk of developing gastric adenomas
FAP
What is the morphology of gastric adenomas
Usually solitary lesions in the antrum; composed of columnar epithelium that exhibits dysplasia; high grade dysplasia will show glandular budding and gland within glad (cribriform) structures; premalignant *cancer transformation is much higher in gastric adenomas than intestinal adenomas
What are the two types of gastric adenocarcinoma
Intestinal: form bulky masses
Diffuse: infiltrates wall, thickens it and is composed of signet rings
What are the most common sites of metastasis of gastric adenocarcinoma
Supraclavicular node, periumbilical (sister Mary joseph), left Axillary LN (iris node), ovary (krukenberg tumor) or pouch of Douglas (blumer shelf)
What groups are more likely to get gastric adenocarcinoma
Low SES, ppl w/ multifocal mucosal atrophy and intestinal metaplasia; NOT PUD, but ppl who have partial gastrectomy due to PUD are at increased risk (due to hypochlorhydria, bile reflux and chronic gastritis)
Cancer of what part of the stomach is on the rise
Cardia; related to Barrett esophagus and may reflect increased GERD
What mutations is familial gastric cancer associated with
LOF in CDH1 (tumor suppressor; encodes E-Cadherin) -> also present in sporadic forms *loss of E-cadherin is key step in development of diffuse gastric cancer; CDH1 mutation also common in familiar lobular carcinoma of breast which tends to infiltrate as single cells (like diffuse gastric cancer); ppl w/ BRCA2 at increased risk of gastric cancer
What mutations are associated with only the sporadic intestinal type gastric cancers
Mutations that result in increased WNT signaling; LOF of APC (adenomatous polyposis coli) and GOF in gene encoding beta-catering; LOF of TGF beta signaling, BAX, and CDK2A; *FAP have increased risk of intestinal type gastric cancer (more common in Japan)
Where are gastric adenocarcinoma most often found
Lesser curvature; antrum
What is the difference in the morphology of gastric tumors with an intestinal morphology and diffuse infiltrative growth pattern
Intestinal morph: bulky, composed of glandular structures; dont usually penetrate; form exophytic mass or ulcerated tumor; contain mucin
Diffuse: composed of singet ring cells; dicohesive cells; mucin vacules that expand cytoplasm and push nucleus to periphery which creates signet ring cells; mistaken for inflammatory cells
What diagnostic clue is helpful in diagnosing diffuse gastric cancer
Evoke desmoplastic reaction that stiffens the gastric wall; when large areas of infiltration, rugal flattening and thickened wall can impart leather bottle appearance *linitis plastica
What are the geographic locations of diffuse vs intestinal gastric cancer
Diffuse: equal across all countries, no precursor lesions, similar rate in M and F
Intestinal: high risk areas, precursor lesions, more likely in males
What are the most useful prognostic indicators in gastric cancer
Depth of invasion and extent of nodal and distant Mets; local invasion to duodenum, pancreas, and retroperitoneum is common; surgical resection is preferred rx
Where is the most common location of extranodal lymphomas
GI tract; particularly stomach
What is the most common site of EBV + lymphoproliferations in hematopoietic stem cell and organ transplant pts
Bowel; most likely because of oral immunosuppressive agents
What is the most common primary lymphoma in the stomach
Extranodal marginal zone B cell lymphomas (MALTomas)
What translocations are associated with MALTomas
(11;18)(q21;q21) -> brings together apoptosis inhibitor 2 (API2) w/ mutated in MALT lymphoma (MLT), (1;14)(p22;q32) and (14;18)(q32;q21) -> increased expression of intact MALT1 and BCL-10 proteins respectively
What is the pathogenesis of MALToma as a result of the translocation
Increased activation of NFkB; requires both BCL-10 and MLT
When is eradictation of h pylori effective vs ineffective in treatment of MALTomas
If doesn’t contain translocation, effective; if does have translocation or has required other mutations (p53 or p16), ineffective
What is the morphology of MALTomas
Dense lymphocytic infiltrate in lamina propria; infiltrates gastric glands vocally to create diagnostic lymphoepithelial lesions; express CD19 and 20, do not express CD5 or 10, but are positive for CD43 in some cases
What are the common presenting features of MALTomas
Dyspepsia and epigastric pain; hematemesis, melena and weight loss can be present
Where are most carcinoid tumors found
Aka well differentiated neuroendocrine tumors; most found in SI, then tracheobronchial tree and lungs
What are gastric carcinoid tumors associated with
Endocrine cell hyperplasia, autoimmune chronic atrophic gastritis, MEN I, and zollinger Ellison
Where do carcinoid typically arise in the stomach
Within oxyntic mucosa; overlying mucosa can be intact or ulcerated; in intestines can invade deeply to involve messengers; yellow or tan in color and very firm (can cause kinking and obstruction)
What is the histo of carcinoid tumors
Islands, trabeculae, strands, glands, or sheets of uniform cells w/ scant pink cytoplasm and stippled nucleus; minimal pleomorphism; positive for synaptophysin and chromogranin A
What are the clinical features of carcinoid tumors
Peak incidence in 6th decade; sx determined by hormones produced; ie: ileal tumors cause carcinoid syndrome (cutaneous flushing, sweating, bronchospasm, colicky ab pain, diarrhea, and right sided cardiac valvular fibrosis)
What is carcinoid syndrome associated with
Metastasis in the liver b/c vasoactive products released directly into circulation (if in intestine, goes through first pass effect)
What is the most important prognostic factor for GI carcinoid tumors
Location
What are the features of foregut carcinoid tumors
Stomach, duodenum proximal to lig of treitz and esophagus; rarely met; cured by resection; gastric carcinoid tumors w/o predisposing factors more aggressive
What are the features of midgut carcinoid tumors
Arise in jejunum and ileum; often multiple and aggressive; greater depth of local invasion, increased size, necrosis and mitosis associated w/ worse outcome
What are the features of hindgut carcinoid
Arise in appendix and colorectum; discovered incidentally; in appendix, benign; rectal produce polypeptide hormones and present w/ ab pain and weight loss (met uncommon)
Where do a majority of GI carcinoid form
Jejunum and ileum
Hat do stomach carcinoid produces
Histamine, somatostain, serotonin; causes sx of gastritis, ulcer
What produces do duodenum carcinoids produce
Gastrin, somatostatin, CCK; sx: peptic ulcer, biliary obstruction, ab pain; assoc w/ zollinger Ellison and NF-1
What are the products of jejunal and ileal carcinoids
Serotonin, substance P, polypeptide YY; sx: obstruction ,Mets; aggressive
What is the most common mesenchymal tumor of the abdomen
GI stromal tumor (GIST); more than half occur in stomach; arises from interstitial cells of Cajal
What is the chromatin structure seen with carcinoid tumors usually described as
Salt and pepper pattern
What is the carney triad
Nonhereditary syndrome of unknown etiology seen mostly in young females that includes gastric GIST, paraganglioma, and pulmonary chondroma
What dz is associated with an increased incidence of GIST
NF-1
What mutations are seen in GIST
GOF in KIT (RTK) and PDGFRA (overrepresented in stomach GISTs); those w/out these mutations commonly have mutations in genes encoding components of mitochondrial succinctness DH complex (SDHA-D) - LOF cause increased risk of GIST and paraganglioma (carney-stratakis syndrome NOT triad); mutation of KIT or PDGFRA is early even in sporadic cases (insufficent for tumor production) - need deletion of chrom 14 and 22 or 9 p (poor prognosis if have increased numbers of chrom alterations)
What is the morphology of gastric GISTs
Can be large, usually form solitary fleshy mass covered by ulcerated or intact mucosa and can project outward; cut surface shows *whorled appearance; can met to abdomen but rare elsewhere; *spindle cell and epithelioid type
What is the treatment for GIST
Resection
What does the prognosis of GIST depend on
Tumor size, mitotic index, location (gastric less aggressive); recurrence is rare for small but common for mitotically active tumors larger than 10 cm
How can you treat unresectable GIST
If have mutations in KIT or PDGFRA, RTK inhibitor imatinib; w/o these mutations associated w/ drug insensitivity
What is the most common site of GI neoplasia
Colon
Where in the GI tract does obstruction most often occur
SI
What is the most frequent cause of obstruction world wide
Hernias
What kind of hernias is obstruction most commonly associated with
Inguinal; pressure at pouch impairs venous drainage and resultant stasis increase the bulk of loop leading to permanent entrapment (incarceration) and strangulation
What can cause adhesions
Surgery, infection, peritoneal inflammation (endometriosis)
What is an internal hernia
Does not protrude into external pouch; ie: as a result of adhesions
What is the most common cause of intestinal obstruction in the US
Adhesions
Where do volvulus most often occur
Sigmoid colon
What is intussesception
When segment of intestine that is constricted by peristalsis telescopes into distal segment; pushed by peristalsis and pulls mesentery with it; can lead to obstruction and compression of mesenteric vessels
What is the most common cause of intestinal obstruction in children younger than 2
Intusseception; usually otherwise healthy; has been associated with rotavirus vaccine (reactive hyperplasia of Peyers patches)
What can be used diagnostically and therapeutically for idiopathic intussesceptoin in infants and children
Contrast enemas or air enemas; but if a mass is present, needed surgery (generally adults)
What causes transmural infarction
Typically acute vascular obstruction; mural and mucosal can be either acute or chronic
What are causes of acute arterial obstruction
Atheroscerosis, AAA, hypercoagulable states, OCP, embolization of cardiac vegetation’s or aortic atheromas
What is intestinal hypoperfusion associated with
Cardiac failure, shock, dehydration or vasoconstrictive drug use; systemic vasculitides (polyarateritis nodosa, Enoch-school Erin purpura, or granulomatosis w/ poly Angie is (wegener granulomatosis); mesenteric venous thrombosis (caused by cirrhosis, inherited hypercoag states)
What are the two phases of the intestinal response to ischemia
- hypoxia injury: epithelial cells lining intestine resistant to transient hypoxia
- repercussion injury: damage; can trigger multi organ failure; leakage of gut lumen bacterial products systemically
What are the watershed zones of the intestines
Splenic flexure (where SMA and IMA terminate) and sigmoid colon and rectum (where IMA, pudendal and iliac end); if see focal colitis of splenic flexure think ischemic dz
What part of the intestine is susceptible to infarction
Surface epithelium moreso than crypts; surface epithelium atrophy or necrosis/sloughing with normal or hyper proliferative crypts is signative of ischemic intestinal dz
What is the morphology of transmural infarction
Well demarcated line btw ischemia and normal; ischemic bowel is congested and dusky to purple-red; later blood-tinged mucus or accumulates in lumen and wall become edematous and rubbery; coagulation necrosis of muscularis propria in 1-4 days
What is the morphology of chronic ischemia
Fibrous scarring of lamina propria
Who does ischemic dz of the colon occur more frequently in
> 70 y/o female; drugs, cardiac dz, PVD, endothelial damage from CMV or E. coli O157:H7, strangulated hernia
How does acute colonic ischemia present
Sudden onset of cramping, left lower ab pain, desire to defecate and passage of blood or bloody diarrhea
When should you consider surgical intervention for acute colonic ischemia
If peristaltic sounds diminish or disappear (paralytic ileus) or guarding and rebound tenderness develop
What increases the mortality of acute colonic ischemia
Patients with right sided colonic dz (b/c supplied by SMA which also supplies SI); COPD and persistence of sx for more than 2 wks indicate poorer prognosis
What can chronic ischemia present at
Can masquerade as IBD w/ episodes of blood diarrhea with periods of healing
What infection can cause ischemic GI dz
CMV; tropism for endothelial cells
What is radiation enterocolitis
When GI tract is irradiated, can cause vascular injury and can produce ischemic dz; *radiation fibroblasts w/in s tromp; acute enteritis manifests as anorexia, ab cramps, malabsorptive diarrhea; chronic can present as inflammatory enterocolitis
What is necrotizing enterocolitis (NEC)
Acute disorder of small and large intestines that can result in transmural necrosis; *most common acquired GI emergency in neonates (premature) and presents when oral feeding is initiated
What is Angiodysplasia
Lesion characterized by malformed submucosal and mucosal bv; occurs most often in cecum or right colon usually in 6th decade; thought to be caused by normal distinction and contraction which intermittently occludes submucosal v -> focal dilation of vessels -> wall tension; liked to meckel; tortuous veins, venules, and caps
What are the most commonly encountered chronic malabsorptive disorders in the US
Pancreatic insufficiency, crohns and celiac
What can cause malabsorption after allogeneic hematopoietic stem cells transplant
Intestinal graft vs host dz
What are the phases of nutrient absorption that, if disrupted, will lead to malabsorption
- intraluminal digestion: proteins, fats, carbs broken down
- terminal digestion: hydrolysis of carbs and peptides in brush border
- transepithelial transport
- lymphatic transport
What can inadequate absorption of vit and minerals lead to
Anemia and mucositis due to pyridoxine, folate, or B12 def, bleeding due to K, osteopenia and tetany (calcium, Mg, and vit D), peripheral neuropathy (A and B12)
What is the definition of diarrhea
Increase in stool mass, frequency or fluidity greater than 200 mg per day
What is dysentery
Painful, bloody, small volume diarrhea
What are the classes of diarrhea
- secretory: isotonic stool and persists during fasting
- osmotic: ie - lactase deficiency, due to excessive osmotic forces exerted by unabsorbed solutes; diarrhea fluid > 50 mOsm; abates w/ fasting
- malabsorptive: failure of nutrient absorption; assoc w/ steatorrhea; relieved by fasting
- exudative: due to inflamm dz; purulent, bloody stools that continue during fasting
Which diseases have defects in terminal digestion
Celiac, environmental enteropathy, autoimmune enteropathy, disaccharidase deficiency, viral gastroenteritis, bacterial gastroenteritis, IBD
Which absorption diseases have a defect in transepithelial transport
Celiac, environmental enteropathy, primary bile acid malabsorption, carcinoid syndrome, autoimmune enteropathy, abetalipoproteinemia, viral and bacterial gastroenteritis, parasitic gastroenteritis, IBD
Which malabsorptive disease have defects in intraluminal digestion
Chronic pancreatitis, CF, primary bile acid malabsorption, IBD
Which malabsorptive dz has a defect in lymphatic transport
Whipple dz
What causes malabsorption in CF
Problems with bicarbonate, Cl, Na, and water secretion -> defective luminal hydration -> pancreatic introductions concretions; exocrine pancreas dysfunction; failure of intraluminal phase of digestion
What part of gluten contains the disease-producing components
Gliadin
How is gluten digested
By luminal and brush border enzymes into AA and peptides, including alpha-gliadin that is resistant to degradation by gastric, pancreatic and SI proteases
What is the pathogenesis of celiac dz
Gliadin induces epithelial cells to express IL-15 which triggers activation of CD8 cells that express NKG2D (NK cell marker and receptor fo MIC-A); enterocytes that express MIC-A are attacked by these; this allows gliadin to access the lamina propria where they are Deaminated by tissue transglutaminase -> interact with HLA-DQ2 or 8 and can stimulate CD4 to produce cytokines
What diseases is Celiac assoc w
T1DM, thyroiditis, Sjogren, IgA nephropathy, neuro disorders (ataxia, autism, depression, epilepsy, downs, turner)
Which section should be biopsied for diagnosis of celiac
Second portion of duodenum or proximal jejunum
What is the histo of celiac
Increased intraepithlial CD8 cells, crypt hyperplasia, bullous atrophy; increased rates of epithelial turnover doesn’t allow maturation of absorptive enterocytes (dont express proteins for transepithelial transport); increased # of plasma, mast cells, and eosinophils
What do you need to diagnose celiac dz
Combo of biopsy and serology (ie: lymphocytic infiltration not only indicative of celiac)
What are the clinical features of celiac
Presents btw 30 and 60; can have silent (+ serology and atrophy w/o sx) or latent (+ serology w/o atrophy); diarrhea, bloating, fatigue, often asymptomatic; more in women (except pediatric - equal)
What can children with no classic sx of celiac present with
At older ages w/ ab pain, N/V/D, bloating, constipation; arthritis or joint pain, aphthous stomatitis, iron def anemia, delayed puberty and short stature; dermatitis herpetiformis(itchy,blister) in 10% of patients
What are the complications of a gluten free diet
Anemia, female infertility, osteoporosis and cancer
What do you test for in serology to diagnose Celiac
IgA abs against tissue transglutaminase; anti-endomysial abs can also be present; IgG anti-tissue transglutaminase present in ppl w/ IgA deficiency; HLA does NOT confirm diagnosis, but is useful to rule out
What is the most common celiac disease associated cancer
Enteropathy-associated T cell lymphoma; aggressive; also small intestinal adenocarcinoma more frequent; must consider cancer if have sx after gluten-free diet
What is environmental enteropathy
Tropical sprue; prevalent in areas with poor sanitation and hygiene; suffer from malabsorption, stunted growth, and defective intestinal mucosal immune fxn
What is autoimmune enteropathy
X-linked; severe persistent diarrhea and AI dz; mostly in young children; IPEX* familial form - immune dysregulation, polyendocrinopathy, enteropathy, and X-linkage due to mut in FOXP3; rx: w/ cyclosporine or hematopoietic stem cell transplant
What are the two types of lactase deficiency
- congenital: mutation in gene encoding lactase; AR; explosive diarrhea w/ watery and frothy stools; ab distinction upon milk ingestion; sx abate when exposure to milk is terminated; fatal prior to development of soy based infant formula
- acquired: down regulation of lactase gene expression; common among Native American, AA, and Chinese; can develop following viral or bacterial infxn an can resolve; diarrhea and flatulence
What is abetalipoproteinemia
AR; inability to secrete triglyceride rich lipoproteins; mutation in MTP (microsomes triglyceride transfer protein) which catalyze transfer of lipids to nascent apoplipoprotein B polypeptides w/in RER; results in intracellular lipid accumulation; failure of intraepithlial processing and transport; *highlighted by oil red-O stain particularly after fatty meal; presents in infancy (failure to thrive, diarrhea, steatorrhea; absence of plasma lipoproteins) *presence of ancanthocytic red cells (burr cells) on blood smears due to lipid membrane defects
How can enterocolitis present
Diarrhea, ab pain, urgency, perinatal discomfort, incontinence, hemorrhage
What is vibrio cholerae
Comma shaped, gram negative bacteria; non-invasive
What factors are important for the pathogenesis of cholera
Flagella, hemagglutinin and metalloproteinase important for shedding into stool
How does cholera toxin cause cholera
B subunit binds GM1 ganglioside on surface of intestinal epithelial cells and is carried by endoytosis into ER (retrograde transport); A subunit is reduced by disulfide isomerase, unfolded and released; A subunit refolds in cytosol to resist degradation and interacts w/ ADP ribosylation factors to ribosylate and activate Gsalpha -> opens CFTR and inhibits Cl and Na reabsorption by cAMP increase; no histo alterations
What are the sx of cholera
Massive rice water stool with fishy odor, dehydration, hypotension, Anuria, m cramping, shock, death; treat with oral rehydration
What is the most common bacterial enteric pathogen in developed countries
Campylobacter jejuni; assoc w/ improperly cooked chicken or contaminated water; *food poisoning
What is the pathogenesis of campylobacter
Virulence: motility, adherence, toxin, invasion; assoc with dysentery in small minority; enteric fever occurs when bacteria proliferate w/in lamina propria and mesenteric LN; *can result in reactive arthritis (in pts with HLA-B27), also can cause erythema nodosum and guillaine barre
What is the morphology of campylobacter
Gram negative; diagnosis by stool samples histo: non specific; crypt architecture preserved
Do you generally treat campylobacter
No - self limiting
What are the characteristics of shigella
Gram negative unencapsulated nonmotile faculative anaerobes; *bloody diarrhea; fecal-oral route or contaminated water; low ineffective dose b/c resistant to stomach acidity
What is the pathogenesis of shigella
taken up by M cells (microfold), proliferate, escape into lamina propria and phagocytosis by macrophages (induce apoptosis) -> access to basoateral membrane of colonic epithelial cells (where they invade); virulence: plasmid that encode type III secretion system (directly inject into host cytoplasm); also releases shiva toxin (inhibits eukaryotic protein synthesis)
What is the morphology of shigella
Most prominent in left colon,but ileum may also be involved; mucosa is hemorrhagic and ulcerated, pseudomembranes may be present; destruction of crypt architecture
What are the complications of shigella
Sterile reactive arthritis, urethritis, and conjunctivitis (HLA-B27 positive); hemolytic uremic syndrome (also associated with EHEC) if serotype 1 that secretes shiga toxin
Can you give anti-diarrheal medicine to someone with shigella
No; contraindicated b/c can prolong sx and delay shigella clearance
What are the characteristics of salmonella
Grade negative bacilli; S. Enteritidis most common in young children and older adults; peak in summer and fall; food poisoning in raw meat
Who is more suceptible to salmonella
People with atrophic gastritis or on PPI’s; also those w/ Th17 deficiency (limits response)
What is the pathogenesis of salmonella
Type III secretion system (transfers bacterial proteins into M cells and enterocytes), which activate host Rho GTPases and. Trigger actin rearrangement and bacterial endocytosis -> bacterial growth w/in endosomes; flagellin activates TLR5 and increases local inflamm response; LPS activates TLR4; also secretes molecule that induces epithelial cell release of eicosanoid hepoxilin A3, drawing neutrophils into lumen
What are the clinical features of salmonella
Stool can be either watery or dysenteric; abx not recommended b/c can prolong carrier state; risk of severe illness increased in ppl w/ malignancy, immunosuppression, alcoholism, CV dysfunction, sickle cell, and hemolytic anemia
What causes typhoid fever
S. Enterica (subtypes s. Typhi and s. Paratyphi) paratyphi associated more w/ travelers; assoc w/ travel to India, Mexico, Philippines and Haiti; transferred from person to person or via contaminated water; *gallbladder colonization
What is the pathogenesis of s typhi
Survive in gastric acid, taken up by M cells in small intestine and invade; bacteria engulfed by macrophages; *can disseminate via lymph and bv (s enteritidis cannot do this); cause reactive hyperplasia of lymphoid tissue throughout body
What is the morphology of s typhi
Peyers patches in terminal ileum enlarge to plateau like elevations; mesenteric LN enlarged; neutrophils in superficial lamina propria and plasma cells and macrophages as well; oval ulcers; spleen is enlarged and soft w/ pale red pulp, obliterated follicular markings; liver shows Fock of parenchyma necrosis in which hepatocytes replaced by macrophage aggregates (typhoid nodules) -> also present in BM and LN
What are the clinical features of s typhi
Anorexia, ab pain, bloating, N/V/bloody D, short asymptomatic phase follows then fever w/ flulike symptoms; blood cultures positive during febrile phase and abx can prevent further dz progression; rose spots (maculopapular lesions) on chest and abdomen; systemic dissemination can cause encephalopathy, meningitis, seizures, endocarditis, myocarditis, pneumonia, cholecystitis; *sickle cell = suceptible to osteomyelitis
Which yersinia infections affect the GI tract
Y. Enterocolitica and Y. pseudotuberculosis ; more common Europe and North America; linked to ingestion of pork, raw milk, and contaminated water; cluster in winter
What is the pathogenesis of yersinia
Invade M cells and use adhesions to bind to host cell beta1 integrity; encodes iron uptake system that mediates iron capture and transport *iron enhances virulence and stimulates systemic dissemination *reason why ppl w/ increase non-heme iron (chronic anemia or hemochromatosis) are more likely to develop sepsis
What is the morphology of yersinia
Invade ileum, appendix, and right colon; multiply extracellularly in lymphoid tissue; bowel wall thickening; ulceration can develop
What are the clinical features of yersinia
Ab pain, N/V/D; mimics appendicitis; pharyngitis, athralgia, erythema nodosum occur frequently; complications: reactive arthritis, urethritis, conjunctivitis, myocarditis, erythema nodosum and kidney dz
What are the features of E. coli
Gram negative; colonize healthy GI tract
What are the features of Enterotoxigenic E. coli (ETEC)
Traveler’s diarrhea; spread via contaminated water; produces heat label toxin and stable toxin (both induce Cl and water secretion and inhibit fluid absorption) LT similar to cholera; ST binds to guanylate Cyclase and increases cGMP; secretory, noninflammtory diarrhea, dehydration
What are the features of Enteropathogenic E. coli (EPEC)
Produce attaching and effacing (A/E) lesions where bacteria attach tightly to enterocytes apical membranes and cause local loss (effacement of microvilli) -> encoded by locus of enterocytes effacement including Tir (inserts into intestinal epithelium plasma membrane; receptor for intimin -encoded by espE- and is used for diagnosis of EPEC) type III secretion system
What are the features of Enterohemorrhagic E. coli (EHEC)
O157:H7 and non O157:H7 serotypes; undercooked beef; both produce shiga-like toxin; hemolytic uremia with O157:H7 strain as well as ischemic colitis; *NO abx b/c killing bacteria increases release of shiga-like toxin - increased risk of hemolytic uremic syndrome
What are the features of enteroinvasive E. coli (EAEC)
Unique pattern of adherence; attach via fimbriae and aided by dispersin (neutralizes negative surface charge of LPS); lesions only visible by EM; nonbloody diarrhea prolonged in ppl with AIDS
What is the pathogenesis of C diff
Toxins released cause ribosylation of GTPases such as Rho and lead to disruption of epithelial cytoskeleton, tight junction barrier loss, cytokines release, and apoptosis
What is the morphology of c diff
Epithelium is denuded and superficial lamina propria contains infiltrate of neutrophils and fibrin thrombi w/in caps; superficially damaged crypts distended by exudate that formed an eruption (volcano); these come to gather to form pseudomembranes
What are the clinical features of c diff
Fever, leukocytes is, ab pain, cramps, watery diarrhea, dehydration; protein loss can lead to hypoalbuminemia; fecal leukocytes; bloody diarrhea uncommon; diagnose by presence of toxin, not culture
How do you treat c diff
Metronidazole or vancomycin; if resistant, monoclonal abs against toxins A and B, and fecal microbial transplants can be effective
What is whipple dz
Rare, multivisceral and chronic; malabsorption, LAD, arthritis; caused by gram positive Tropheryma whippellii; organism laden macrophages accumulate w/in SI lamina propria and mesenteric LN causing lymph obstruction; malabsorptive diarrhea due to impaired lymph transport
Who is whipple dz most common in
White males; particularly farmers or exposure to animals and soil
What is the presentation of whipple dz
Diarrhea, weight loss, arthralgia; fever, LAD and neuro, pulm, or cardiac dz can exist before malabsorption
What is the morphology of whipple dz
Accumulation of distended foamy macrophages in SI lamina propria; PAS positive, diastase resistant granules stuffed with partially digested bacteria; *similar presentation in intestinal tuberculosis (tell the difference by acid fast staining); villous expansion causes shaggy gross appearance to mucosa; lymphatic dilation and mucosal lipid deposition; macrophages accumulate in mesenteric LN, synovial membranes, cardiac valves and brain
What organisms is the most common cause of acute gastroenteritis requiring medical attention
Norovirus; second to rotavirus in kids
What are the features of norovirus
Contaminated food or water, person-to-person; fomites; N/V/D (watery); abnormalities occur in SI including loss of BB, crypt hypertrophy, and lymphocyte invasion; self limited; immunosuppressed -> infxn can last for 9 months
What are the features of rotavirus
Encapsulated; dsRNA; 6-24 months more vulnerable; vaccination assoc w/ intussusception - also do not give to immunocompromised pts; destroys mature enterocytes in SI and villus surface is repopulate by immature secretory cells; damage mediated by NSP4 (nonstructural protein 4); osmotic diarrhea
What are the features of adenovirus
Common cause of pediatric diarrhea and immunocompromised pts
What is ascaris lumbricoides
Nematode; fecal-oral; ingested eggs hatch and invade intestinal mucosa; larvae migrate from splanchnic to systemic circulation and enter the lungs and grow in alveoli, coughed up and swallowed; mature into adults worms and include eosinophil rich Inflam reaction that can cause obstruction; larvae can form hepatic abscesses and cause ascaris pneumonitis; dx: eggs in stool
What is strongyloides
Live in fecally contaminated soil and penetrate through skin; migrate to lungs where they induce Inflam infiltrates and then reside in intestine as adult worms; hatch w/in intestine and release larvae that penetrate mucosa causing auto infection; peripheral eosinophilia
What is necator duodenal and ancylostoma duodenale
Hookworms; penetrate skin, develop in lungs, swallowed, in duodenum, attach to mucosa and suck blood and reproduce; *superficial erosions, focal hemorrhage, Inflam infiltrates and iron deficiency anemia; dx: eggs in feces
What is enterobius vermicularis
Pinworms; do not invade host tissue; live in lumen; fecal-oral; migrate to anal orifice at night, female deposits eggs which cause irritation; tape test
What is trichuris trichuria
Whipworms; infect young children; does not penetrate mucosa; rarely causes dz; heavy infection can cause bloody diarrhea and rectal prolapse
What is schistosomiasis
Adults worms residing in mesenteric veins; trapping of eggs in mucosa; immune rxn is granulomatous and can cause bleeding and obstruction
What are the intestinal cestodes
Diphyllobothrium, taenia solium, hymenolepsis nana; all tapeworms; enlarges by formation of proglottids; no peripheral eosinophilia; can grow very large; proglottids and eggs shed in feces; majority asymptomatic; D. Latium can cause B12 def b/c competes w/ host for dietary B12
What is entamoeba histolytica
Fecal-oral; causes dysentery and liver abscesses; cyst have chitin wall and four nuclei; resistant to gastri acid; cysts colonize epithelial surface of colon and release trophozoites that reproduce; affects cecum and ascending colon most often
What is the pathogenesis of entomoeba histolytica
Amoebae attach to epithelium, induce apoptosis, invade crypts and burrow into lamina propria; this recruits neutrophils causing tissue damage and creates flask-shaped ulcer; can penetrate vessels and go to liver (abscesses); bloody diarrhea; acute necrotizing colitis and megacolon can occur; parasites lack mitochondria and are obligate fermenters of glucose *use metronidazole (inhibits private oxidoreductase)
What is giardia lamblia
Aka G duodenalis or intestinalis; most common parasitic pathogen in humans; fecal-oral; flagellated Protozoa; cause decreased expression of BB enzymes; *secretory IgA and IL-6 combat infxn; trophozoites found in biopsy (pear shape and 2 nuclei); no invasion;
What is cryptosporidium
Causes chronic diarrhea in immunosuppressed; limited dz in competent; contaminated drinking water; C. Hominids and C. Parvum; releases sporozoites following activation by gastric acid; attaches to BB and causes changes in enterocyte cytoskeleton (engulfs parasite) leads to Na malabsorption, Cl secretion, and increased tight junction permeability; non bloody, watery diarrhea; most concentrated in terminal ileum and proximal colon; dx: oocysts in stool
What is IBS
Chronic, relapsing ab pain,bloating, changes in bowel habits; gross and micro appearance normal * it is a syndrome
What is the pathogenesis of IBS
Poorly defined; role of psychological stressors, diet, gut microbiome, enteric sensory responses, abnormal GI motility; ie: increased or decreased colonic contractions, excess bile acid synthesis (diarrhea predominant); SSRT, cannabinoid receptors, and TNF mediators; 5-HT3 antagonists, anticholinergic, opioids, and psychoactive drugs effective in diarrhea predominant
What are the clinical features of IBS
Mostly female; age 20-40; ab pain for at least 3 days per month over 3 months with improvement following defecation and a change in stool frequency or form; IBD must be excluded
What is IBD
Chronic condition resulting from inappropriate mucosal immune activation; *UC and Crohn
What is the difference between UC and Crohn
- UC: limited to colon and rectum and extends only into mucosa and submucosal, diffuse, no strictures, thin wall, presence of pseudopolyps, malignant potential, no recurrence after surgery
- Crohn (regional enteritis):may involve any area of the GI tract and is typically transmural, skip lesions, strictures, thick wall, deep knife like lesions, strong lymphoid reaction, serositis, granulomas, fistula, fat/vitamin malabsorption, malignant potential, recurrence is common after surgery, no toxic megacolon
When do UC and crohns typically present
Teens and early 20s; UC more common in females; both more common in whites and ashkenazi Jews; hygiene hypothesis
What is the believed pathogenesis of IBD
Combined effects of alterations in host interactions with intestinal microbiota, intestinal epithelial dysfunction, aberrant mucosal immune responses, and altered composition of gut microbiome
Does crohns or UC have more of a genetic component
Crohns
Some IBD genes overlap with genes involved in responses to what organism
Mycobacterium
Which genes are associated with crohns
Most strongly: NOD2 (nucleotides oligomerization binding domain 2) which encodes intracellular protein that binds to bacterial peptidoyglycan and activates NFkB pathway; confers only small risk of having the dz; also, ATG16L1 (autophagy related) and IRGM (immunity related GTPase M)
How does the mucosal immune response contribute to IBD
T helper cells activated in Crohn dz (Th1), Th17 most likely to contribute to pathogenesis (polymorphism in IL-23 receptor confer reduction in risk of Crohn and UC), AR mutations in IL-10 and its receptor are linked to severe, early onset IBD
What epithelial defects have been seen in IBD
- defects in intestinal epithelial tight junctions in crohn; assoc w/ NOD2 polymorphism
- polymorphism in EDM1 which inhibits MMP9 linked to UC but not Crohn; inhibition of MMP9 reduces severity of colitis
- polymorphism in HNFA (TF) associated with UC but not crohn; also assoc w/ maturity onset diabetes of the young (MODY)
What is the role of microbiota in IBD
- ab against bacterial protein flagellin are most common in crohn patients who also have dz assoc NOD2 variants, stricture formation, perforation, and small bowel involvement; uncommon in UC
- microbial transfer studies can reduce dz in IBD
What is the morphology of crohn dz
Most common at terminal ileum, ileocecal valve, and cecum; earliest lesion: aphthous ulcer may progress and multiple lesions often coalesce into elongated serpentine ulcers; cobblestone appearance; fissures develop btw mucosal folds and can become fistula tracts; wall is thickened and rubbery; mesenteric fat extends around serosal surface (creeping fat)
What is the histo of crohn dz
Neutrophils that infiltrate and damage crypts (crypt abscesses); epithelial metaplasia - often takes form of gastric antral-appearing glands and is called pseudopyloric metaplasia; paneth cell metaplasia may also occur in left colon; noncaseating granulomas (hallmark)* -> can form on skin (met crohn dz); but absence of granulomas does not preclude dx of crohn
What can disease reactivation of crohn be caused by
Physical or emotional stress, specific dietary items, cigarette smoking (strong risk for development of crohn dz)
What are some clinical features of crohn dz
Iron deficiency anemia (colonic), hypoalbuminemia (small bowel), fibrosing strictures (terminal ileum most common; need resection); strictures commonly recur; fistula between loops of bowel, bladder, vagina, and ab or perinatal skin; rx: anti-TNF abs
What are the extrainestinal manifestations of crohn
Uveitis, migratory polyarthritis, sacroilitis, ankylosis spondylitis, erythema nodosum, clubbing of fingers; pericholangitis and primary sclerosing cholangitis occur with higher frequency than those w/o crohn and is even more common in UC
What are the extraintestinal manifestations of UC
Overlap with crohn + skin lesions
What is disease of the entire colon called
Pancolitis
What is backwash ileitis
When there is inflammation of distal ileum in UC patients
What is the gross appearance of UC
Slightly red and granular and can have broad based ulcers; NOT serpentine; pseudopolyps which can fuse to create mucosal bridges; mucosal atrophy; serosal surface is normal; inflammation can damage muscularis propria and lead to colonic dilation (megacolon - risk of perforation)
What is the histo appearance of UC
Crypt abscesses, distortion, and pseudopyloric metaplasia
What are the clinical features of UC
Relapsing disorder; attacks of bloody diarrhea with stringy, mucoid material; low ab pain and cramps that are relieved by defecation; 30% require colectomy w/in first 3 years of presentation -> cures intestinal dz but extraintestinal manifestations can still occur; smoking can partially relieve symptoms
What is indeterminate colitis
Do not involve small bowel and have colonic dz in a continuos pattern that would typically indicate UC; however, it has patchy histo dz, fissures, and family hx of crohn dz, perianal lesions, onset after cigarettes can be seen; user sero studies (perinuclear anti-neutrophil cytoplasmic abs seen in UC but not crohns; also UC lack ab to saccharomyces cervisiae which is present in crohn)
What is the risk of dysplasia of UC and Crohn related to
- duration of dz: increases 8-10 yrs after onset
- extent: pancolitis at greater risk
- nature of inflamm response: greater frequency of presence of neutrophils increases risk
When are IBD patients screened for cancer
8 yrs after onset; unless have primary sclerosing cholangitis which are enrolled for surveillance at time of diagnosis
What does IBD associated high grade dysplasia indicate
May be associated with invasive carcinoma of that site or elsewhere in the colon and warrants colectomy
What is diversion colitis
Colitis that develops in the diverted segment created from an ostomy; * friable, development of numerous mucosal lymphoid follicles; treat with enemas containing short chain fatty acids or reanastomosis of the diverted segment
What is microscopic colitis
2 forms: collagenous colitis and lymphocytic colitis; both present with chronic non bloody watery diarrhea without weight loss; normal radio and endoscopic studies
What are the features of collagenous colitis
Middle aged and older women, characterized by dense subepithelial collagen layer, increased intraepithlial lymphocytes, and mixed inflammatory infiltrate w/in lamina propria
What are the features of lymphocytic colitis
Subepithelial collagen layer is normal thickness and increase in intaepithilal lymphocytes is greater than collagenous colitis; strong assoc w/ celiac and autoimmune dz (graves, RA, gastritis)
What is graft vs host dz
Occurs after hematopoietic stem cell transplant; small bowel and colon most often involved; donor T cells target antigens on Gi epithelial cells; but no lamina propria lymphocytic infiltration; epithelial apoptosis is most common finding; presents as watery diarrhea
What is diverticular dz
Generally refers to acquired pseudodiverticular outpouchings of colonic mucosa and submucosa (not all 3 layers); rare in ppl < 30 but increases > 60; generally multiple and the condition is referred to as diverticulosis; right-sided diverticula more common in western countries
What is the pathogenesis of colonic diverticula
Results from unique structure of colonic muscularis propria and elevated intraluminal pressure in sigmoid colon; where ns, vasa recta, and connective tissue sheaths penetrate inner circular m coat, focal discontinuities in m wall created; in other parts of intestine, these gaps are reinforced by external longitudinal layer of muscularis propria; increased intraluminal pressure is due to exaggerated peristaltic contractions (enhanced by diets low in fiber)
What are the clinical features of diverticular dz
Most are asymptomatic; some develop cramping, continuous lower ab discomfort, constipation, distinction, or sensation of never being able to completely empty the rectum; can experience altering constipation and diarrhea; when present, bleeding visible in stools
What are polyps with stalks called
Pedunculated
What is the most common neoplastic polyp
Adenoma
What are the classifications of nonneoplastic polyps
Inflammatory, hamartomatous or hyperplastic
What are colonic hyperplastic polyps
Benign epithelial proliferation typically discovered in 6th and 7th decades; thought to result from decreased epithelial turnover and piling up of goblet cells and absorptive cells; no malignant potential; *must be distinguished from sessile serrated adenomas that are histo similar
What is the morphology of hyperplastic polyps
Most common in left colon; smooth, nodular protrusions;usually multiple; composed of mature goblet and absorptive cells
What are inflammatory polyps
Ie: polyps that form as part of solitary rectal ulcer syndrome; patients present with triad of rectal bleeding, mucus discharge, and inflammatory lesion of anterior rectal wall; cause is impaired relaxation of anorexia sphincter that creates a sharp angle at anterior rectal shelf and leads to recurrent abrasion of overlying rectal mucosa;entrapment of polyp in fecal stream can lead to mucosal prolapse; *histo: erosion, epithelial hyperplasia w/ fibromuscular hyperplasia of LP
What are hamartomatous polyps
Occur sporadically or as components of genetic or aquired syndromes; mutations in tumor suppressor or oncogenes; can be pre-malignant
What are juvenile polyps
Focal malformations of epithelium and LP; sporadic or syndromic; usually < 5yrs old; most located in rectum and present w/ rectal bleeding; intussusception, obstruction or polyp prolapse can occur
What is the difference between sporadic and syndromic juvenile polyps
Sporadic: usually solitary
Syndromic: AD; many hamartomatous polyps and may require colectomy to limit chronic and severe hemorrhage; some have polyps in stomach and bowel that can undergo malignant transformation; extraintestinal manifestations: pulm AV malformations
What is the morphology of juvenile polyps
Small; pedunculated, smooth, red; cystic spaces; glands filled w mucin
What causes juvenile polyps
Mucosal hyperplasia is initiating event; mutations: SMAD4 (most common), BMPR1A (kinase that is a member of TGF beta family); half of people will develop colonic adenocarcinoma by age 45
What is peutz-jeghers syndrome
Rare AD; present between age 10-15 with multiple GI hamartomatous polyps and mucocutaneous hyperpigmentation (dark blue-brown Manuel’s on lips, nostrils, buccal mucosa, palmar surface of hands, genitalia, and perianal region); can initiate intussusception which is sometimes fatal; *assoc w/ increased risk of several malignancies
What should peutz-jegher individuals have regular surveillance for
Beginning at birth for sex cord tumor of the testes, late childhood for gastric and SI cancers, and 2nd to 3rd decade for colon, pancreatic, breast, lung, ovarian, and uterine cancers
What is the pathogenesis of peutz jeghers syndrome
Heterozygous LOF mutations in STK11 (tumor suppressor; encodes a kinase that regulates cell polarization and acts as brake on growth and anabolic metabolism)
What is the morphology of peutz jeghers syndrome polyps
Most commonly found in SI; large and pedunculated w/ lobulataed contour; histo: arborizing network of CT, smooth m, LP, and glands lined by normal intestinal epithelium
Who are adenomas more prevalent in
Males
What are the features of Cowden syndrome as it relates to GI
Age of onset < 15 mutation in PTEN (PI3K pathway); causes hamartomatous/inflammatory intestinal polyps, lipomas, and ganglioneuromas; extraintestinal: benign skin tumors, benign and malignant thyroid and breast lesions, no increase in GI cancers
What is cronkhite-canada syndrome as it relates to GI
Age of onset > 50; nonhereditiary; unknown cause; causes hamartomatous polyps of stomach, SI, abnormalities in nonpolypoid mucosa; extraintestinal: nail atrophy, hair loss, abnormal skin pigmentation, cache is and anemia; fatal in 50%
What is tuberous sclerosis as it relates to GI
Mutation in TSC1 (hamartin) and TSC2 (tuberin) mTOR pathway; causes hamartomatous polyps; extraintestinal: mental retardation, epilepsy, facial Angiofibroma, cortical (CNS) tubers, renal angiomyolipoma
What are the types of familial adenomatous polyposis
Classic, attentuated, Gardner, turcot, MYH-associated polyposis
What is classic FAP
Onset 10-15; mutation in APC; causes multiple adenomas; extraintestinal: congenital RPE hypertrophy
What is attenuated FAP
Onset 40-50; mutation in APC; multiple adenomas; no other manifestations
What is Gardner syndrome
Onset age 10-15; mutation in APC; causes multiple adenomas; extraintestinal: osteomas, thyroid and Desmoid tumors, skin cysts
What is Turcot syndrome
Age of onset 10-15; mutation in APC; causes multiple adenomas; extraintestinal: medulloblastoma, glioblastoma
What is MYH-associated polyposis
Age of onset 30-50; mutation in MYH; causes multiple adenomas; no other manifestations
What sx do adenomas produce
Usually none; can produce bleeding or rare villous adenomas that cause hypoproteinemic hypokalemia by secreting large amounts of protein and potassium
What is the morphology of adenomas
Surface resembles velvet or raspberry; nuclear hyper chrom Asia, elongation, and stratification
How can adenomas be classified
Tubular: small, pedunculated composed of round or tubular glands, tubulovillous: mixture, or villous: larger and sessile, covered by villi; villous invade more frequently, but villous architecture along does not increase cancer risk when polyp size is considered
What are the features of sessile serrated adenomas
Overlap histo w/ hyperplastic polyps, but are more commonly found in right colon; lak cytology can features of dysplasia; serrated architecture through full length of glands and lateral growth
What is intramucosal carcinoma
Occurs when dysplastic epithelial cells breach the basement membrane to invade LP or muscularis mucosa; no metastatic potential (polypectomy is curative); invasion beyond muscularis mucosa constitutes invasive adenocarcinoma
What is the most important indicator of risk of malignancy in adenomas
Size
What is needed for a dx of FAP
100 polyps; colorectal adenocarcinoma develops in 100% of untreated FAP patients
What is the standard treatment for ppl w/ APC mutations
Colectomy; but still at risk for neoplasia at other sides, particularly adjacent to ampulla of vater in the stomach
What is the inheritance pattern of MYH-associated polyposis
AR; presence of few than 100 adenomas; also, serrated polyps with KRAS mutations often seen
What is hereditary non-polyposis colorectal cancer
HNPCC aka Lynch syndrome; *most common syndromic form of colon cancer; occur at younger ages and in the right colon; caused by inherited mutation in genes that encode proteins responsible for detection, excision, and repair of errors that occur during DNA replication (MSH2 or MLH1) - inherited AD but need 2nd hit; microsatellites are most common site of mutation
What is the most common malignancy of the GI tract
Adenocarcinoma of the colon; most dont occur before 50
What are the dietary risks assoc w/ adenocarcinoma of the colon
Low fiber and high carb/fat diets; low fiber reduces stool bulk and alters the comp of intestinal microbiota; high fat causes increased hepatic synthesis of cholesterol and bile acids which can be converted into carcinogens by intestinal bacteria
What has a protective effect against adenocarcinoma of the colon
NSAIDs; some c an cause polyp regression in FAP; inhibits COX-2 which is highly expressed in colorectal carcinomas; COX-2 is regulated by TLR4 which is overexpressed in adenomas and carcinomas
What is the classic adenoma-carcinoma sequence
Accounts for 80% of sporadic colon tumors and includes mutation of APC (both copies); APC is negative regulator of beta-catenin; APC usually ubiquinates beta catenin; beta catenin can now go to nucleus and cause transcription of MYC and cyclin D1; allows for mutation in KRAS (late event - found in bigger lesions); TP53 at late stages too; tumor suppressors silenced by methylation of CpG island
What is the histo of FAP
Tubular, villous, typical adenocarcinoma; no predominant site
What is the histo of MYH-asoc polyposis
Sessile serrated adenoma; mutinous adenocarcinoma
What is the histo of hereditary non polyposis colorectal cancer
(AD; Right side); sessile serrated adenoma, mutinous adenocarcinoma
What side predominates in sporadic colon cancer with APC mutation
left
Where does sporadic colon cancer with dNA mismatch repair defects predominant
Right side
Where does sporadic colon cancer with hypermethylation defects (MLH1 and BRAF) predominate
Right side
What mutation do a subset of micro satellite unstable colon cancers WITHOUT mutations in DNA mismatch repair demonstrate
CpG hypermethylation of phenotype (CIMP); MLH1 promotor region is hypermethylated reducing MLH1 expression; mutations in BRAF are common; KRAS and TP53 NOT mutated
What mutations are seen in a group of colon cancers that have increased CpG island methylation in the absence of micro satellite instability
KRAS; NOT TP53 or BRAF
What morphology is common in cancers with mismatch repair def and microsatellite instability
Sessile serrated adenomas
What do invasive carcinomas w/ microsatellite instability often have
Mucinous differentiation and peritumoral lymphocytic infiltrates; right colon
What is the difference in the morphology of adenocarcinoma in the proximal vs distal colon
Proximal: polyposis exophytic masses; rarely cause obstruction
Distal: annular lesions that produce napkin-ring constrictions and luminal narrowing
*most tumors composed of tall columnar cells; initiate desmoplasmic response which is responsible for their firm consistency; production of abundant mucin is assoc w/ poor prognosis
How do fecal and other right sided colon cancers present
Fatigue and weakness due to iron deficiency anemia
How do left sided colon cancers present
Occult bleeding, changes in bowel habits, cramping and left lower quadrant discomfort
What are the most important prognostic factors of adenocarcinoma
Depth of invasion (into muscularis propria) and present of LN Mets; can also met to lungs and bones but liver is most common site of met lesions (except for rectal cancer)
What lines the anal canal
Upper third: columnar rectal epithelium
Middle third: transitional epithelium
Lower third: stratified squamous epithelium
What patterns of differentiation can anal canal carcinomas have
Glandular, squamous, basaloid; basaloid present in tumors populated by immature cells derived from the basal layer of transition epithelium (cloacogenic carcinoma)
What causes hemorrhoids
Straining during defection and venous stasis of pregnancy; portal HTN
What is the difference between external and internal hemorrhoids
External: inferior venous plexus; below analrectal line
Internal: superior plexus
Who is acute appendicitis common in
Adolescents and young adults; males more than females
What can acute appendicitis be confused with
Ectopic pregnancy, salpingitis, mittelschmerz, meckel diverticulitis
What is the pathogenesis of acute appendicitis
Progressive increase in intraluminal pressure that compromises venous flow; can be caused by luminal obstruction
What is the characteristic morphology of acute appendicitis
*diagnosis requires neutrophilic infiltration of muscularis propria
What are complications of appendicitis
Rupture and suppurative peritonitis, pyelophlebitis, portal venous thrombosis, liver abscess, bacteremia
What is a mucocele
Dilated appendix filled w/ mucin; can be caused by mucinous cystadenoma/carcinoma; can be mistaken in women for ovarian tumors; in advanced cases, ab fills with semisolid mucin (pseudomyxoma peritonei)
What can cause peritonitis
- leakage of bile or pancreatic enzymes: sterile peritonitis
- perforation or rupture of biliary system; can be complicated by bacterial superinfection
- acute hemorrhagic pancreatitis: assoc w/ fat necrosis; may allow bacteria to spread to peritoneal cavity
- foreign material: foreign body type granulomas and fibrous scarring
- endometriosis: hemorrhage into peritoneal cavity
- rupture Dermoid cyst: releases keratin -> granulomatous rxn
- performation of ab viscera
Which bacterial are most often implicated in bacterial peritonitis
E. coli, strep, s aureus, enterococci, and c perfringens
When does spontaneous bacterial peritonitis develop
Cirrhosis and ascites; and children w/ nephrotic syndrome
What is sclerosing retroperitonitis
Aka idiopathic retroperitoneal fibrosis or ormond dz; characterized by dense fibrosis that can extend to involve mesentery; IgG4-related dz; frequently compresses ureters
What are primary malignant tumors than arise in the peritoneum
Mesotheliomas; almost always associated with asbestos exposure
What is the most common benign and malignant soft tissue tumor in the peritoneum
Round cell tumors; aggressive; children and young adults; resembles Ewing sarcoma; *translocation (11;22)(p13;q12) that results in EWS-WT1 fusion gene
What are the areas near the portal tract called
Periportal
What are the sinusoids lined by
Fenestrated endothelial cells; beneath these is the space of disse which contain hepatocyte microvilli and hepatic stellate cells
Where do the bile canniculi drain
Canals of hearing that connect to bile duct ulcers in periportal region; these ductules empty into the terminal bile ducts w/in portal tracts
What reversible changes can the liver go under
Steatosis and accumulation of bilirubin (cholestasis)
What happens during hepatoctye necrosis
Cell swells and ruptures; membrane bless carry cytoplasmic contents (w/o organelles) to extracellular compartment; macrophages cluster; *prominent mode of death in ischemic/hypoxia injury
What happens during hepatocyte apoptosis
Cell shrinkage, nuclear clumping, and fragmentation into acidophilic apoptotic bodies; referred to as councilman bodies or acidophil bodies (eosinophilic staining)
What is confluent necrosis
Seen when there is widespread parenchymal loss; severe, zonal loss of hepatocytes; filled with cell debris, macrophages and reticulin meshwork
What is bridging necrosis
Link central veins to portal tracts or bridge adjacent portal tracts
How do we measure hepatocyte integrity
Cytosolic hepatocellular enzymes: aspartame aminotransferase (AST), alanine aminotransferase (ALT), lactate DH (LDH)
How do we measure biliary excretory function
Substances normally excreted in bile: serum bilirubin, urine bilirubin, serum bile acids
Plasma membrane enzymes (damage to bile canaliculus): alkaline phosphatase, gamma glutamyl transpeptidase (GGT)
How do we measure hepatocyte synthetic function
Proteins secreted into blood: serum albumin, coagulation factors (PT and PTT)
Hepatoctye metabolism: serum ammonia and amino pyrine breath test
What are ductular reactions
In chronic injury when hepatocytes reach senescent, duct like s tractors develop from stem cells and contribute to the parenchymal restoration
Which cell type is involved in scar deposition
Hepatic stellate cell: in its quiescent form it is a lipid (vitamin A) storing cell; but during injury, the stellate cell is activated and is converted into highly fibrogenic myofibroblasts -> initiated by increase in expression of PDGFR beta and kupffer cells release cytokines that modulate genes in stellate cells (TGF beta, MMP-2 and TIMP-1); stellate cells release chemotactic and vasoactive factors and growth factors; stimulated by endothelin 1
What is the stimuli for stellate cell activation
- chronic inflammation with production of TNF, lymphotoxin and IL-1beta
- cytokine production by kupffer cells, endothelial cells, hepatocytes and bile duct epithelial cells
- response to disruption of ECM
- direct stimulation by toxins
- scar deposition often begins in space of disse q
Can scar formation in the liver be reversed
Yes; if stop damage, scars will be broken down by MMP
What is acute liver failure
Defined as acute liver illness assoc w/ encephalopathy and coagulopathy that occurs w/in 26 weeks of initial liver injury int he absence of pre-existing liver dz; caused by massive hepatic necrosis (often drugs or toxins or acute hepatitis A and B)
What is the morphology of acute liver failure
Livers are small and shrunken; if toxin mediated injury, no scar formation or regeneration
What is diffuse microvesicular steatosis
Seen in fatty liver of pregnancy or reactions to toxins (valproate and tetracycline); poisoning of liver cells w/o evidence of cell death; usually related to mitochondrial dysfunction, hepatocytes can’t perform met functions
How does acute liver failure manifest
N/V and jaundice first; then life threatening encephalopathy (disturbances in consciousness; rigidity, hyperreflexia and asterixis; *elevated ammonia) and coagulation defects (bleeding tendency; DIC); initially enlarged and then shrinks (liver enzymes increase then decrease); cholestasis (which increases risks of bacterial infection)
What are the features of portal HTN as it relates to acute liver failure
Not usually associated; but if occurs, obstruction is predominately intrahepatic and major clinical consequences are ascites and hepatic encephalopathy
What is hepatorenal syndrome
Form of renal failure occurring in ppl w/ liver failure in whom there are no intrinsic morph or functional causes for kidney dysfunction; sodium retention, impaired free water excretion and decreased renal perfusion/GFR are main abnormalities seen; begins w/ a drop in urine output and rising blood urea nitrogen and creatinine levels
What are the leading causes of chronic liver failure
Chronic hep B and C, non alcoholic fatty liver dz, and alcoholic liver dz
What is cirrhosis
Diffuse transformation of the entire liver into regenerative parenchymal nodules surrounded by fibrous bands and variable degrees of vascular shunting
Which chronic liver dz are not usually accompanied by cirrhosis
Primary biliary cirrhosis, primary sclerosing cholangitis, nodular regenerative hyperplasia, chronic schisto, ffibropolycystic liver dz
What is the child-Pugh classification of cirrhosis
- Class A: well compensated
- Class B: partially decompensated
- Class C: decompenated
What is cryptogenic cirrhosis
Cirrhosis with no clear cause
Biopsy specimens showing what features are more likely to have less portal HTN
Narrow, densely compacted fibrous septa separated by large islands of intact hepatic parenchyma; those with broad bands of dense scar and dilated lymph spaces with less intervening parenchyma are more likely to progress toward portal HTN
When are ductular reactions more prominent
In cirrhosis; 2 correlates of ductular reaction:
- role of liver s team cells in regeneration increases as preexisting hepatocytes undergo replication senescence after years of high turnover
- ductular reactions may incite some of the scarring and may be a negative effect on progressive liver dz
What are the clinical features of cirrhosis
Anorexia, weight loss, weakness and signs of liver failure; hepatic encephalopathy, bleeding from esophageal varices and bacterial infections are often terminal events
If cirrhosis regresses, is there still risk of HCC
Yes
What is the difference btw jaundice in acute and chronic liver failur
When chronic can lead to pruritus
What are features unique to chronic liver failure
Impaired estrogen metabolism -> hyperestrogenemia in male pts can lead to palmar erythema (local vasodilation) and spider angioplasty of the skin; hypogonadism (can also occur in women) and gynecomastia
What are the major prehepatic conditions that lead to portal HTN
Obstructive thrombosis, narrowing of portal v before it ratifies in liver, or massive splenomegaly w/ increased splenic blood flow
What are the main post hepatic causes of portal HTN
Severe right-sided heart failure, constrictive pericarditis, and hepatic v outflow obstruction
What is the dominant intrahepatic cause of portal HTN
Cirrhosis *accounts for most cases of portal HTN; other intrahepatic causes are schisto, massive fatty change, diffuse fibrosing granulomatous dz (sarcoidosis) and nodular regenerative hyperplasia
What is the pathophysiology of portal HTN
Involves resistance to flow in the sinusoids caused by contraction of vascular smooth m and myofibroblasts and formation of parenchymal nodules and increase in portal venous flow caused by hyper dynamic circulation caused b y arterial vasodilation in splanchnic circulation -> increased venous influx into portal system (NO is most significant mediator)
What causes the alterations in the sinusoidal endothelial cells that leads to the intrahepatic vasoconstriction seen in portal HTN
Decrease in NO and increased release of endothelin I, angiotensinogen and eicosanoids; sinusoidal remodeling and anastomoses btw arterial and portal system contribut to HTN by imposing arterial pressure on venous system
What are the 4 major consequences of portal HTN
Ascites, portosystemic venous shunts, congestive splenomegaly, hepatic encephalopathy
What is the composition of ascites
Usually serous; can contain few mesothelial and mononuclear cells; influx of neutrophils would suggest infxn; presence of blood cells points to disseminated intraabdominal cancer; can seep through trans-diaphragmatic lymphatics to produce hydro-thorax (more often on right side)
What is the pathogenesis of ascites
- sinusoidal HTN: alters starling forces and drives fluid into space of disse where it is removed by hepatic lymphatics; also promoted by hypoalbuminemia
- Percolation of hepatic lymph into peritoneal cavity: flow exceeds thoracic duct capacity; hepatic lymph is rich in proteins and low in triglyceraides (explains proteins in ascitic fluid)
- splanchnic vasodilation and hyper dynamic circulation: worsening vasodilation, HR and CO unable to maintain BP; triggers activation of renin and ADH
What are the consequences of splenomegaly caused by portal HTN
Thrombocytopenia or pancytopenia
What is hepatopulmonary syndrome
Seen in 30% of pts w cirrhosis and portal HTN; develop intrapulmonary vascular dilation -> blood flows rapidly giving inadequate time for oxygen diffusion which leads to ventilation-perfusion mismatch and right to left shunting manifesting as hypoxia and resulting dyspnea in upright position (exacerbated by gravity); poorer prognosis
What is portopulmonary hypertension
Pulmonary arterial HTN arising in liver dz and portal HTN; pulm vasoconstriction and vascular remodeling; most common clinical manifestations are dyspnea on exertion and clubbing of fingers
What is an example of acute on chronic liver failure
Ppl w/ Hep B who have a superinfection with hep D; ascending cholangitis in pt with primary sclerosing cholangitis or fibropolycystic liver dz; sepsis or acute cardiac failure or drug toxicity in chronic liver failure; also malignancy
What is the mnemonic for causes of acute liver failure
A: acetaminophen, hep A, autoimmune hepatitis
B: hep B
C: hep C; cryptogenic
D: hep D; drugs
E: hep E, esoteric causes (Wilson, budd-chiari)
F: Fatty change of microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)
What viruses can cause hepatitis (besides the hep viruses)
EBV,
CMV, HSV, adenovirus (newborn and immunosuppressed)
yellow fever: tropical countries
What is hep A
Usually benign and self limited; no chronic or carrier state; cause nonspecific symptoms (fatigue, loss of appetite and jaundice); noneveloped +RNA picornavirus (heptovirus) spread via contaminated water and foods; shed in stool for 2-3 weeks before and 1 week after jaundice; *not screened for in blood; measure IgM abs for acute infxn
What is hep B
Can produce acute hepatitis followed by recovery and clearance, nonprogressive chronic hepatitis, progressive chronic dz ending in cirrhosis, acute hepatic failure w/ massive liver necrosis, and an asymptomatic carrier state; *precursor to HCC even in absence of cirrhosis
What is the incubation period of HBV
2-26 weeks; remains in blood until and during active episodes of acute and chronic hepatitis
What family is HBV part of
Hepadnaviridae; DNA virus; Dane particle; partially ds circular w/4 open reading frames that code for: nucleocapside core protein, envelope glycoproteins (HBsAg - surface antigen), polymerase (pol) that has DNA and reverse transcriptase activity (DNA->RNA->DNA), and HBx protein (necessary for viral replication; implicated in pathogenesis of HCC)
What do specific serum markers indicate as far as the course of HBV infxn
- HBsAg appears before onset of symptoms, peaks during overt dz, and declines in 12 weeks
- Anti-HBs ab rises after acute dz is over; sometimes is not detectable for a few weeks after disappearance of HBsAg -> uses IgM anti-HBc ab to dx
- HBeAg, HBV-DNA and DNA pol appear soon after HBsAG and all signify active viral replication; HBeAg impt indicator of probable progression to chronic hep
- IgM anti-HBc ab detectable shortly before onset of sx and is replaced by IgG after a few months (but cannot measure IgG so implied by decline in IgM in face of rising total anti-HBc)
What is the best predictor of chronicity of HBV infxn
Age at the time of infxn; younger the age, more likely to develop chronicity; hard to treat because integrates into host DNA
What are the most common risk factors for HCV infxn
IV drug use, multiple sex partners, surgery w/in last 6 months, needle stick, multiple contacts w/ HCV person, employment in medical or dental fields, unknown
Is HBV or HCV more commonly transferred perinatally to children
HBV
What family is HCV a member of
Flaviviridae; small enveloped ssRNA virus; encodes for single poly protein w/ one open reading frame; very unstable; HCV exists as. Closely related genetic variants known as quasispecies (multiple detected in one individual)
What is the target for anti-HCV abs
E2 protein on the envelope *most variable region of the entire viral genome which allows it to escape immune system
Do anti-HCV IgG occurring after an active infection confer effective immunity
No
What is the incubation for HCV
4-26 wks; acute infxn asymptomatic; HCV RNA detected in blood for 1-3weeks; anti-HCV abs emerge after 3-6 weeks
Does chronic dz occur more often in HBV or HCV
HCV
How can HCV evade the immune system
Inhibits IFN mediated cellular antiviral response by inhibiting TLR signaling
What test is diagnostic for HCV
Serum HCV RNA; present even is presence of anti-HCV abs; also persistent elevation of serum aminotransferase
Associated with what is a unique feature of HCV infection
Association w/ metabolic syndrome; insulin resistance and nonalcoholic fatty liver dz
Is HCV curable
Potentially; pts with genotype 2 or 3 have best response; polymorphism in IL-28B gene assoc w. Better response to IFN alph and ribavirin
What is hep D virus
RNA; depends on B;
Confection: results in acute hep indistinguishable from hep. B; self limited, but higher risk of acute hep failure in IV drug users
Superinfection: results in severe acute hepatitis in a previously unrecognized HBV carrier or an exacerbation of preexisting chronic hep B infxn; chronic HDV infxn almost always occurs in these pts; may have 2 phases: acute w/ active HDV replication and suppression of HBV w/ high transaminase levels and chronic where HDV replication decreases, HBV replication increases, transferase levels fluctuate an dx progresses to cirrhosis and HCC
When is HDV RNA detectable
Before and in early days of acute sx dz; IgM anti-HDV ab is most reliable indicator of recent HDV exposure; confection best indicated by detection of IgM against HDAg and HBcAg
What is Hep E virus
Enterically transmitted, water borne infxn that occurs in young to middle aged adults; animal reservoirs; India; high mortality rate among pregnant women; not assoc w/ chronic liver dz unless immunocompromised; undeveloped, +RNA; hepevirus; shed in stool
What are the clinical syndromes of viral hepatitis
- acute asymptomatic infxn w/ recovery (serologic)
- acute symptomatic hep w/ recovery, anicteric or ictEric
- chronic hepatitis w or w/o progression to cirrhosis
- acute liver failure w/ massive to submassive hepatic necrosis
What is chronic hepatitis
Symptomatic, biochemical or serologic evidence of continuing or relapsing hepatic dz for more than 6 months
What are HBV carriers
Individuals w/ HBsAG, w/o HBeAg but with presence of anti-HBe; normal aminotransferase, low serum HBV DNA and liver biopsy shows lack of significant inflammation and necrosis; more likely to develop in endemic areas
Are there “healthy carrier” states of HCV
No
What are hepatitis viruses sometimes coinfected with
HIV
What is the morphology of acute viral hepatitis
Grossly appear normal or slightly mottled; histo: mononuclear infiltrate; spotty necrosis or lobular hepatitis
What is the defining histo feature of chronic viral hepatitis
Mononuclear portal infiltration; often interface hepatitis in addition to lobular hepatitis
What is the characteristic histo feature of hep B chronic hepatitis
Ground glass hepatocytes (cells w/ ER swollen by HBsAg)
What is the characteristic histo of hep C chronic hepatitis
Lymphoid aggregates or fully formed lymphoid follicles; fatty change of scattered hepatocytes; bile duct injury
What bacteria can infect the liver directly
S aureus in TSS, salmonella typi in typhoid fever, treponema pallium in secondary or tertiary syphillis; overgrowth of biliary tree bacteria -> ascending cholangitis
What are liver abscesses associated with
Fever, RUQ pain, and tender hepatomegaly
Which parasitic and helminthic infxn involve the liver
Malaria, schisto, strongyloidiasis, cryptosporidiosis, leishmaniasis, echinococcosis (hydatid cysts w/ calcification), amebiais, and liver flukes (fasciola hepatica, opisthorchis, and clonorchis sinensis) -> cause very high rate of cholangiocarcinoma;
What is autoimmune hepatitis
Chronic, progressive hepatitis; in Caucasians, associated with DRB1 alleles; female predominance; two types; type 1: more common in middle aged to older individuals; present of ANA, anti smooth m actin (SMA), anti-soluble liver antigen/liver-pancreas antigen (anti-SLA/LP) abs; type 2: seen in children and teenagers; ant-liver kidney microsome 1 (anti-LKM-1) directed against CYP2D6 and anti-liver cytosol 1 (ACL-1) abs
What is the morphology of autoimmune hepatitis
Same pattern of injury with viral hepatitis but early phase of severe parenchymal destruction followed by rapid scarring occurs; severe necroinflam activity (interface hep, perivenular or bridging necrosis), plasma cell predominance, rosettes*
What histo patterns are seen with autoimmune hepatitis
- very severe hep injury w. Confluent necrosis but little scarring; symptomatic
- mix of marked Inflam and some degree of scarring; seen in early or later stages
- burned out cirrhosis with little necroinflamamtory activity; years of subclinical dz
What are the classifications of drug toxic reactions
- predictable (intrinsic): ie: acetominophen
- Unpredictable (extrinsic): depend on the host; ie: chlorpromazine causes cholestasis in pts slow to metabolize it to halothane
What drugs cause cholestatic pattern of injury
Contraceptive and anabolic steroids, abx, HAART
What drugs cause cholestatic hepatitis pattern of injury
Abx, phenothiaazines, statins
What drugs cause hepatocellular necrosis
Methyldopa, phenytoin (spotty necrosis), acetominophen and halothane (massive necrosis) and isoniazid (chronic hepatitis)
What drugs cause fatty liver dz
Ethanol, corticosteroids, methotrexate, total parenteral nutrition; valproate, tetracycline, aspirin (reye syndrome), HAART, amiodarone (Mallory-denk bodies)
What drugs cause fibrosis and cirrhosis
Alcohol, methotrexate, Elanapril, vit A; causes perioporta and pericellular fibrosis
What drugs cause granulomas in the liver
Sulfonamides, amiodaron, isoniazid (noncaseating epithiliod granulomas) and allopurinol (fibrin ring granulomas)
What drugs cause vascular liver lesions
High dose chemo, bush teas (sinusoidal obstruction syndrome), OCP (budd-Chiari syndrome), anabolic steroids and tamoxifen (Peliosis hepatitis)
What drugs can cause neoplasms in the liver
OCP and anabolic steroids (hepatocellular adenoma), alcohol and thorotrast (HCC), thorotrast (cholangiocarcinoma), thorotrast and vinyl chloride (angiosarcoma)
What zone does alcoholic liver dz begin
Zone 3 and extends with increasing severity
What is the pattern of fibrosis seen in hepatic steatosis
Perisinusoidal Chicken wire
What is the morphology of alcoholic hepatitis (steatohepatitis)
- hepatocyte swelling and necrosis
- Mallory-denk bodies: clumped, amorphous, eosinophilic material in ballooned hepatocytes; made up of tangled skeins of intermediate filaments such as keratin (also present in wilsons and NAFLD)
- neutrophilic rxn
Where does fibrosis begin in alcoholic steotofibrosis
Sclerosis of central veins; perisinusoidal scar then accumulates in space of disse of centrilobular region in chicken wire fence pattern; eventually link to portal tracks and conduense into central-portal fibrous septa; if alcohol use continues w/o interuption, form Laennec cirrhosis
What factors influence the development and severity of alcoholic liver dz
- gender: women more susceptible although majority of pts are men; estrogen increases gut permeability to endotoxins which increases expression of LPS receptor CD14 in kupffer cells (increased proinflammatory cytokines)
- ethnic and genetics: AA at higher risk; ALDH*2
- comborbid conditions: iron overload and infx w HCV and HBV synergize w/ alch
What damage does alcohol cause
Steatosis, dysfunction of mitochondrial and cellular membranes, hypoxia and oxidative stress
What causes hepatocellular steatosis
- Shunting of normal substances away from catabolism and toward lipid biosynthesis as a result of increased generation of reduced NADH by alcohol DH and acetaldehyde DH
- impaired assembly and secretion of lipoproteins
- increased peripheral catabolism of fat, releasing FFA into circulation
What causes alcoholic hepatitis
- acetaldehyde induces lipid peroxidation and acetaldehyde protein aduct formation, disrupting cytoskelatal and membrane function
- ROS generated that react w proteins, membranes
- alch impairs hepatic metabolism of methionine which decreases glutathione levels
- alch causes release of bacterial endotoxin into portal circulation and endothelin from sinusoidal endothelial cells, causing vasoconstriction (decreased perfusion)
What are the clinical features of hepatic steatosis
Mild elevation of serum bilirubin and alkaline phosphatase; no severe hep dysfunction
What are the common lab findings of alcoholic hepatitis
Increased serum aminotransferase and alkaline phosphatase, hyperbilirubinemia, neutrophilic leukocytosis *AST tends to be higher than serum ALT (usually reverse for other chronic liver dz)
What are the lab findings in alcoholic cirrhosis
Elevated aminotransferase, hyperbilirubinemia, variable elevation of phosphatase, hypoproteinemia and anemia
What are the causes of death of end stage alcoholics
Hepatic coma, massive GI hem, intercurrent infxn, hepatorenal syndrome, and HCC
What is the “threshold” of developing alcoholic liver dz
80 gm/day
What is the most common cause of chronic liver dz in the US
NAFLD
Can NAFLD have a predisposition for HCC
Yes; and can do so in the absence of scarring
Who is at risk for NAFLD
Hispanics followed by AA and caucasians
What is the pathogenesis for NAFLD
Two hit hypothesis
- Insulin resistance gives rise to hepatic steatosis; high fructose corn syrup promotes this
- Hepatocellular oxidative injury resulting in liver cell necrosis and inflammation rxns to it
What occurs to the adipose tissue of ppl w/ insulin resistance and metabolic syndrome
Becomes dysfunctional: reduced production of adiponectin and increased production of inflamm cytokines (TNF and IL-6); promote hepatocyte apoptosis; diminished autophagy contributes to mitochondrial injury and formation of Mallory-deny bodies; kupffer cells activate stellate cells (also through SHH via NK cells) *level of hedgehog pathway correlates with stage of fibrosis in NAFLD
What is the criteria for metabolic syndrome
One of the following: DM, impaired glucose tolerance, impaired fasting glucose, insulin resistance
And Two of the following: blood pressure > 140/90, dyslipidemia, central obesity, microalbuminuria
What is pathologic steatosis
Involving more than 5% of hepatocytes
What is previously described “cryptogenic cirrhosis” now thought to. Be
Burned out NAFLD
What is different about the morphology of pediatric NAFLD
Children show more diffuse steatosis, portal rather than central fibrosis, and portal and parenchymal mononuclear infiltration rather than neutrophils
What is the most reliable took for NAFLD and NASH dx
Liver biopsy
What is a frequent cause of death in patients with NASH
CV dz
What is NOT seen in NAFLD that is seen in alcohol-related injury
Hepatocyte ballooning, Mallory-denk bodies, and neutrophilic infiltration
Where is the iron accumulation associated with hemochromatosis deposited
Liver, pancreas, heart, joints, and endocrine organs
What is secondary hemochromatosis
When iron accumulation occurs as a result of parenteral administration of iron (ie: transfusion)
What are the consequences of increased iron storage
- micronodular cirrhosis, DM, abnormal skin pigmentation
- in hereditary forms: slow and progressive injury, hence, sx usually appear in 4th-5th decades in men and later in women
- affects males more
What mutations cause hereditary hemochromatosis
Genes encoding HFR, transferrin receptor 2, or hepcidin; mutations of genes encoding HJV (hemojuvelin -> juvenile hemochromatosis); neonatal hemochromatosis develops in utero and is not hereditary
What can cause hemosiderosis (secondary hemochromatosis)
Long term dialysis, aplastic anemia, sickle cell, myelodysplasic syndromes, leukemia’s, iron-dextran injections, increased erythropoiesis (beta thalassemia, sideroblastic anemia, pyruvate kinase def), increased oral intake (African iron overload), congenital atransferrinemia, chronic liver dz, alcoholic liver dz, porphyria cutanea tarda, neonatal hemochromatosis
What are the NAFLD phenotypes
Isolated fatty liver (no risk of death compared to gen pop), non-alcoholic steatohepatitis (NASH) -> cirrhosis or HCC
What are the mechanisms of liver injury associated with hemochromatosis
- lipid peroxidation via iron-catalyzed free radical rxn
- stimulation of collagen formation by activation of hepatic stellate cells
- interaction of reactive oxygen species and iron with DNA; predisposition to HCC
- reversible with removal of exces iron
What proteins are involved in iron metabolism
- HJV: expressed in liver, heart, and skeletal m
- transferrin receptor 2: expressed in hepatocytes where it mediates uptake of transferrin bound iron
- HFE: product of hemochromatosis gene
- mutations in these cause hemochromatosis
What mutation almost always causes the adult form of hemochromatosis
HFE; encodes HLA class I like molecule that regulates hepcidin synthesis
What is the most common HFE mutation
Cysteine to tyrosine substitution at aa 282 (C282Y); other common mutation is H63 (histidine at position 63 to apartate) -> homozygous state and C282Y/H63D heterozygous mutation often only cause mild iron accumulation *C282Y confined to whites while H63D is any ethnicity
What is the morphology of hemochromatosis
- deposition of hemosidern in liver, pancreas, myocardium, pituitary, adrenal gland, thyroid and parathyroid, joints and skin; appear in liver as golden yellow granules in cytoplasm of periportal hepatocytes; no inflammation; liver is dense and chocolate brown in beginning; black later on
- cirrhosis
- pancreatic fibrosis; becomes pigmented; hemosiderin in both acinar and islet cells
- heart is enlarged; brown coloration
- skin pigmentation from increased melanin production -> slate gray color
- pseudogout from calcium pyrophosphate deposition
- testes small b/c of derangement in HP axis.
What are the clinical features of hemochromatosis
Hepatomegaly, ab pain, skin pigmentation, deranged glucose homeostasis or DM, cardiac dysfunction and atypical arthritis; significant cause of death is HCC
How do you treat hemochromatosis
Regular phlebotomy
What is neonatal hemochromatosis
Liver injury which leads to hemosiderin accumulation occurs in utero and is thought to be related to maternal alloimmune injury to fetal liver; dx with buccal biopsy; treat with supportive care and liver transplant
What is Wilson dz
AR; caused by mutation in ATP7B gene resulting in impaired copper excretion into bile and failure to incorporate copper into ceruloplasmin
How is copper usually absorbed
copper usually absorbed in duodenum or prox SI and is transported through portal circulation complexed to albumin and histidine; in liver, copper binds to alpha globulin (apoceruloplasmin) to form ceruloplasmin; excess copper is exported to bile; circulating ceruloplasmin is desalinated, endocytosed by liver and degraded w/in lysosomes and then copper excreted in bile
What is the pathogenesis of Wilson’s dz
Mutation in ATP7B gene on chrom 13; encodes transmembrane copper transporting ATPase o hepatocyte canalicular membrane; most are compound heterozygotes containing diff mutations on each ATP7B allele ; causes a decrease in copper excretion into bile, impairs its incorporation into cceruloplasm and inhibits ceruloplasmin secretion into blood
How does accumulated copper cause liver injury
- promoting formation of free radicals by Fenton reaction
- binding to sulfhydryl groups of cellular proteins
- displacing other metals from hepatic metalloenzymes
What is the morphology of Wilson’s dz
Fatty change mild to moderate; moderate to severe necrosis in severe dz; ballooning with Mallory Denk bodies; *demonstrated by rhodamine stain or orcein stain for copper associated proteins (most helpful for dx); dont use genetic testing
What part of the brain does Wilson’s usually target
Basal ganglia (putamen) which shows atrophy and cavitation
What is the clinical presentation of Wilson’s
Initial presentation with liver dz; neuro presents as movement disorders or rigid dystonia; can also have psych sx; hemolytic anemia
What are the tests used to dx Wilson
- decrease in serum ceruloplasmin
- increase in hepatic copper (most sensitive and accurate)
- increased urinary excretion of copper (most specific)
- serum copper levels dont tell you anything
What is alpha antitrypsin deficiency
AR disorder of protein folding; low levels of alpha antitrypsin (inhibits proteases, particularly neutrophil elastase, cathepsin G, and proteinase 3); causes liver dz and COPD; also causes cutaneous necrotizing panniculitis
What is the wild type form of alpha antitrypsin
PiMM
Which variants of antitrypsin show no detectable levels of the protein
Pi-null
What is the most clinically significant mutation that cause antitrypsin deficiency
PiZ; homozygotes for PiZZ have circulating alpha antitrypsin levels that are only 10% of normal *most commonly diagnosed inherited hepatic disorder in infants and children
What is the pathogenesis of antitrypsin deficiency
Defect in migration of protein from ER to Golgi (particularly of PiZ polypeptides resulting from Glu->Lys substitution); triggers UPR
What is the morphology of antitrypsin deficiency
Round cytoplasmic globular inclusions in hepatocytes which are acidophilic and stain strongly PAS and diastase resistant; periportal hepatocytes contain mutant proteins early on and with progression central hepatocytes become involved; not correlated with severity
What are the clinical features of antitrypsin deficiency
Neonatal hepatitis w/ cholestatic jaundice in 20% of newborns; adolescence: related to hepatitis, cirrhosis, or pulmonary dz; HCC develops in 2-3% of PiZZ adults; rx: liver transplant
What are the functions of hepatic bile
- emulsification of fat
- elimination of bilirubin, excess cholesterol, xenobiotics, and other insufficiently water-soluble products
How is bilirubin made
Heme oxygenate converts heme to biliverdin which is reduced to bilirubin by biliverdin reductase; bound to albumin; enters liver via carrier mediated uptake at sinusoidal membrane and is conjugated with glucuronic acid by UDP glycuronyl transferase (UGT1A1) in the ER and secretion into bile; deconjugated by gut and degraded to urobilinogens
What are bile salts
Conjugated bile acids with taurine or glycine
What are bile acids
Primary catabolic product of cholesterol; water soluble; *cholic acid and chenodeoxycholic acid ; reabsorpted from gut to liver (enterohepatic circulation)
What level of bilirubin causes evident jaundice
2-2.5 mg/dL
What can exacerbate physiologic jaundice of the newborn
Breastfeeding (contains bilirubin deconjugating enzymes)
What do mutations in UGT1A1 cause
Hereditary unconjugated hyperbilirubinemias: crigler-najjar I and II and Gilbert syndrome
What is the difference between crigler-najjar type I and II
I: severe; fatal around time of birth
II: some UGT1A1 activity; milder
What are Dubin Johnston and rotor syndrome
Deficiencies of canalicular membrane transporters; AR; leads to conjugated hyperbilirubinemia
What causes cholestasis
Impaired bile formation and bile flow that gives rise to accumulation of bile pigment in hepatic parenchyma; can be caused by extrahepatic or intrahepatic obstruction of bile channels or defects in hepatocyte bile secretion
How does cholestasis present
Jaundice, pruritis, skin xanthomas, or sx related to malabsorption; characteristic lab finding *elevated serum alkaline phosphatase and gamma glutamyl transpeptidase (present on apical membranes of hepatocytes and bile duct epithelial cells)
What is the morphology of cholestasis
Accumulation of bile pigment in hepatic parenchyma; elongated green-brown plus of bile visible in dilated bile canalicular; rupture leads to extravasation of bile and uptake by kupffer cells; in hepatocytes, takes o fine foamy appearance called feathery degeneration
What are the common causes of bile duct obstruction in adults vs children
Adults: extrahepatic cholelithiasis (gallstones), malignancies of. Biliary tree or head of pancreas, strictures from previous surgery
Children: biliary atresia, CF, choledochal cysts and syndromes in which there are insufficient intrahepatic bile ducts
What is ascending cholangitis
Secondary bacterial infection of biliary tree; promoted by subtotal or intermittent obstruction; common culprits: coliforms and enterococci; usually presents w/ fever, chills, ab pain and jaundice
What is the most severe form of cholangitis
Suppurative cholangitis: purulent bile fills and distends bile ducts; sepsis dominates
What is the histo hallmark of ascending cholangitis
Influx of periductular neutrophils directly into bile duct epithelium and lumen; if uncorrected secondary inflammation resulting from chronic obstruction can lead to feathery degeneration of periportal hepatocytes, Mallory-denk bodies (*periportal dominance: diff from alcohol), and formation of bile infarcts
Is intrahepatic or extrahepatic cholestasis amendable by surgery
Only extrahepatic; diseases of intrahepatic biliary tree or hepatocellular secretory failure may worsen in operative procedure
How does sepsis affect the liver
Direct effects of intrahepatic bacterial infxn, ischemia relating to hypotension, in response to circulating microbial products(*most likely to lead to cholestasis of sepsis, particularly if gram negative)
What is the most common form of cholestasis of sepsis
Canalicular cholestasis with bile plugs w/in primarily centrilobular canaliculi ; no hepatocyte necrosis
What is ductular cholestasis
Form of cholestasis of sepsis that is more ominous; dilated canals of hering and bile ductules at interface of portal tracts and parenchyma become dilated and contain bile plugs; accompanies septic shock
What is hepatolithiasis
Disorder of intrahepatic gallstone formation that leads to repeated bouts of ascending cholangitis, progressive inflammatory destruction of hepatic parenchyma and predisposes to biliary neoplasia *rare except for east Asia
What is the morphology of hepatolithiasis
Pigmented calcium bilirubinate stones in distended intrahepatic bile ducts; ducts show chronic Inflam, mural fibrosis, and peribiliary gland hyperplasia in the absence of extrahepatic duct obstruction*; biliary dysplasia may be seen can can evolve to invasive cholangiocarcinoma
What do the nodules of liver cells in biliary cirrhosis look like
Often not round (other forms of cirrhosis) but rather irregular like a jigsaw puzzle shape
What is neonatal cholestasis
Prolonged conjugated hyperbilirubinemia in the neonate; jaundice beyond 14-21 days after birth should be evaluated
What are the causes of neonatal cholestasis
- cholangiopathies
- primary biliary atresia
- neonatal hepatitis (toxic, metabolic, or infectious liver dz)
What is the importance of differentiating biliary atresia from nonobstructive neonatal cholestasis
Definitive treatment of biliary atresia requires surgical intervention (kasai procedure) whereas surgery can adversely affect the clinical course of a child with other disorders
What are the clinical features of neonatal cholestasis
Jaundice, dark urine, light or acholic stool, and hepatomegaly
Which infections can cause neonatal cholestasis
CMV, bacterial sepsis, UTI, syphilis
Which genetic disorders can cause neonatal cholestasis
Tyrosinemia, Neimann pick, galactosemia, defective bile acid synthetic pathways, alpha antitrypsin deficiency, CF, alagille syndrome
What are the morphological features of neonatal hepatitis
Lobular disarray with focal liver cell apoptosis and necrosis; panlobular giant cell transformation of hepatocytes; extramedullary hematopoiesis
What is biliary atresia
Complete or partial obstruction of the lumen of extrahepatic biliary tree within first 3 months of life; *most frequent cause of death from liver dz in early childhood
What are the 2 forms of biliary atresia
- fetal form: associated with other anomalies resulting from ineffective establisment of laterality of thoracic and ab organs during development (situs inversus malrotation of ab viscera, interrupted IVC, polysplenia and congenital heart dz)
- Perinatal form: more common; normally developed biliary tree is destroyed after birth; thought to be caused by viral infxn
What are the morph features of biliary atresia
Inflammation and fibrosing stricture of the hepatic or common bile ducts; if not corrected -> cirrhosis within 3-6 months of birth
What is the variability in the anatomy of biliary atresia
When limited to common duct (Type I) or right and/or left hepatic bile ducts (type II), surgically correctable; but most have type III where there is additionally obstruction of bile ducts at or above porta hepatis (not correctable)
What are the clinical features of biliary atresia
Present with neonatal cholestasis but exhibit normal birth weight and postnatal weight gain; more associated with females; normal stools change to acholic stools as dz evolves; if not treated, death w/in 2 years
What are the 2 main autoimmune disorders of intrahepatic bile ducts
Primary biliary cirrhosis and primary sclerosing cholangitis
What are the features of primary biliary cirrhosis vs primary sclerosing cholangitis
- primary biliary cirrhosis: median age: 50 yrs, mostly female, progressive, assoc w/ sjogren, scleroderma, and thyroid dz, serology shows AMA, ANA, or ANCA positivity, normal radiology, florid duct lesions and loss of only small ducts
- primary sclerosing cholangitis: median age: 30, mostly male, progressive, assoc w/ IBD, pancreatitis, and idiopathic fibrosing dz; serology shows ANCA (most), ANA, AMA; radiology -> strictures and beading of large bile ducts and pruning of smaller ducts; inflammatory destruction of extrahepatic and large intrahepatic ducts; fibrosis of medium and small intrahepatic ducts
What is primary biliary cirrhosis
Autoimmune dz characterized by non suppurative inflammatory destruction of small and medium sized intrahepatic bile ducts; does not commonly progress to cirrhosis
What are the most characteristic pathogenic findings in PBC
Antimitochondrial abs; recognize E2 component of pyruvate DH complex (PDC-E2)
What is the morphology of PBC
Interlobular bile ducts destroyed by lymphoplasmic inflammation w/ or without granulomas (florid duct lesion); patchy distribution *periportal bile accumulation assoc w feathery degeneration and ballooned bile stained hepatocytes with Mallory denk bodies; some pts proceed to portal HTN and will see nodularity w/o surrounding scar tissue (nodular regenerative hyperplasia) *hepatomegaly; does not shrink
When are most cases of PBC diagnosed
When asymptomatic; elevated serum alkaline phos and gamma glut. ; hypercholesteremia is common
How is PBC diagnosed
Liver biopsy *florid duct lesion
What pathways can PBC lead to if left untreated
Hyperbilirubinemia or portal HTN
How do you treat PBC
Oral ursodeoxycholic acid
What are the secondary features that may present with PBC
Skin hyperpigmentation, xanthelasmas, steatorrhea, and vit D malabsorption related osteomalacia/osteoporosis; may also have dry eyes and mouth, thyroiditis, RA, raynaud, and celiac
What is primary sclerosing cholangitis
Inflammation and obliterating fibrosis of intra and extrahepatic bile ducts with dilation of preserved segments; *beading on radiograph; assoc with UC
Ab targeting what are often found in PSC
Nuclear envelope protein
What is the difference in inflammation of the large vs small ducts in PSC
- Large: similar to UC; acute neutrophil infiltration of epithelium superimposed on chronic Inflam background; develop strictures
- smaller: little inflammation; show circumferential onion skin fibrosis around atrophic duct lumen leading to obliteration by a tombstone scar
- dx depends on large ducts
What are the clinical features of PSC
Fatigue, pruritus and jaundice; steatorrhea if chronic; chronic pancreatitis and cholecystitis also seen; distinctive type w. IgG4 levels in assoc with autoimmune pancreatitis has been recognized
What is the treatment for PSC
None; cholestyramine used for itching and endoscopic dilation with sphincterotomy or stenting used to relieve sx; need liver transplant
What are choledochal cysts
Congenital dilation (segmental or cylindrical)of common bile duct; present in children before age 10 as jaundice and recurrent ab pain; can occur in conjunction w/ cystic dilation of intrahepatic biliary tree (Caroli dz); more common in females; can take the form of diverticula of extrahepatic ducts (choledochoceles -> cystic lesions that protrude into duodenal lumen); predispose to stone formation, stenosis and stricture, pancreatitis; bile duct carcinoma risk increased
What is fibropolycystic dz of the liver
Group of lesions in which the primary abnormalities are congenital malformations of the biliary tree; found incidentally; most severe forms can manifest as HSM or portal HTN in absence of hepatic dysfunction in late childhood or adolescence
What are the three sets of pathological findings that can be seen in fibropolycystic disease of the liver
- von meyenburg complexes: small bile duct hamartomas; occasional complexes common in normal individuals; when diffuse, signify dz
- single or multiple intra or extrahepatic biliary cysts: when in isolation may be symptomatic and are referred to as caroli dz; when occurs along with congenital hepatic fibrosis called caroli syndrome
- congenital hepatic fibrosis: portal tracts enlarged by irregular broad. Bands of collagenous tissue forming septa that divide the liver into irregular islands; not truly cirrhotic bu can have portal HTN
What are ductal plate malformations
Associated with persistence of periportal ductal plates from fetal development
What does fibropolycystic liver dz often occur with
AR polycystic renal dz; involved gene encodes a protein called polycystin which is expressed i fetal kidney as well as liver; increased risk of cholangiocarcinoma
When is hepatic artery thrombosis most likely to cause infarction
Transplanted liver -> leads to infarction of major ducts of the biliary tree b/c their blood supply is entirely arterial
What does occlusive dz of the portal v cause
Abdominal pain, portal HTN; ascites is NOT common because block is presinusoidal; splenomegaly, intestinal congestion’s
What can impaired intrahepatic blood flow c abuse
Ascites, esophageal varices, hepatomegaly, elevated aminotransferase
What can hepatic outflow obstruction cause
Ascites, hepatomegaly, elevated aminotransferases, jaundice
What can cause extrahepatic portal v obstruction
- subclinical occlusion of portal v, from neonatal umbilical sepsis or umbilical v catheterization; presents as variceal bleeding and ascites years later
- intraabdominal sepsis caused by acute diverticulitis or appendicitis -> leads to pyelophlebitis in splanchnic circulation
- hypercoagulable disorders (polycythemia Vera)
- trauma
- pancreatitis and pancreatic cancer -> splenic v thrombosis
- HCC invasion of portal v
- cirrhosis
What causes intrahepatic portal v obstruction
Acute thrombosis; doesn’t cause ischemic infection but instead causes sharply demarcated area of red-blue discoloration called infarct of zhan; no necrosis, just severe hepatocellular atrophy and stasis in distended sinusoids
What are small portal v branch diseases
Noncirrhotic HTN with portal fibrosis and obliteration of small portal v branches; *most common cause is schistosomiasis
What is the most common intrahepatic cause of blood flow obstruction
Cirrhosis
What diseases are associated with physical sinusoidal occlusion
Sickle cell, DIC, eclampsia, and diffuse intra sinusoidal metastatic tumor; can lead to massive necrosis and acute hepatic failure
What is peliosis hepatis
Sinusoidal dilation that occurs in any condition in which efflux of hepatic blood is impeded; liver contains blood filled cystic spaces
What organism has been seen in the sinusoidal endothelial cells of AIDS associated peliosis
Bartonella
Administration of what can cause peliosis
Sex hormone administration
What is budd chiari syndrome
Obstruction of two or more major hepatic veins produces liver enlargement, pain, and ascites; hepatic damage is result of increased intrahepatic BP; hepatic v thrombosis associated w/ polycythemia Vera, antiphospholipid ab syndrome, paroxysmal nocturnal hemoglobinuria and intraabdominal cancers (HCC)
What is the morphology of budd chiari syndrome
Liver is swollen and red-purple, has a tense capsule; severe centrilobular congestion and necrosis; fibrosis when thrombosis is slow
What is the mortality rate of untreated acute hepatic v thrombosis
Very high; need prompt surgical creation of portosystemic venous shunt permits reverse flow through portal v.; chronic form less lethal
What is sinusoidal obstruction syndrome
Originally described in jamaica; drinkers of pyrrolizidine alkaloid containing bush tea; named veno-occlusive dz; now occurs in 2 settings: following allogeneic hematopoietic stem cell transplant and in cancer patients on chemo; arises from toxic injury to sinusoidal epithelium
How do you dx sinusoidal obstruction syndrome
Histo but made mostly on clinical grounds b/c of risk with liver bx
How can you lower the risk of sinusoidal obstruction syndrome in patients receiving a hematopoietic SC transplant
Anticoagulants and ursodeoxycholate
What can cause passive congestion of the liver
Right sided heart failure; liver is enlarged, tense and cyanotic with rounded edges; congestion of centrilobular sinusoids
What does left sided heart failure cause in relation to the liver
Hypoperfusion and hypoxia -> ischemic coagulative necrosis in central region of lobule
What does the combination of hypoperfusion and retrograde congestion cause
Centrilobular hemorrhagic necrosis; nutmeg liver
What can develop with sustained chronic severe CHF
Cardiac sclerosis with centrilobular fibrosis
What is acute graft vs host dz
Occurs 10-50 days after hematopoietic stem cell transplant; do not lymphocytes attack eptihilial cells of the liver; results in hepatitis with necrosis of hepatocytes and bile duct
What is the histo of chronic rejection
Obliterative ateriopathy of small and large arteries leads to ischemic changes in liver parenchyma; destruction of bile ducts (vanishing bile duct syndrome)
What is the most common cause of jaundice during pregnancy
Viral hepatitis
Which infection runs a more serious course in pregnant patients
HEV
What is preeclampsia
Maternal HTN, Proteinuria, peripheral edema, and coagulation abnormalities
What is eclampsia
Preeclampsia with hyperreflexia and convulsions; life-threatening
What is the primary manifestation of preeclampsia
Subclinical hepatitis; hemolysis, elevated liver enzymes; low platelets (HELLP syndrome)
What is the morphology of preeclampsia
Periportal sinusoids contain fibrin deposits associated with hemorrhage into space of disse -> coagulative necrosis; blood under pressure can coalesce and expand to form a hepatic hematoma; dissection of blood under glissons capsule can lead to hepatic rupture in eclampsia
What are the features of acute fatty liver of pregnancy
Most present in latter half of pregnancy; dx: biopsy which shows diffuse microvesicular steatosis of hepatocytes; unknown cause but thought to be linked to def in mitochondrial LC 3-hydroxyacyl metabolites produced by fetus causing hepatic toxicity ; *Fetus causing metabolic dz in the mother
What is intrahepatic cholestasis of pregnancy
Onset of pruritus in 3rd trimester, followed by darkening of urine and light stools and jaundice; bile salts increased greatly -> leads to itching
What are examples of nodular hyperplasias of the liver
- focal nodular hyperplasia
- nodular regenerative hyperplasia
- common factor is alterations in hepatic blood supply arising rom obliteration of portal v radicle and compensatory augmentation of arterial blood supply
What is the morphology of focal nodular hyperplasia
Well demarcated but not encapsulated; lighter than surrounding tissue; central grey-white depressed stellate scar containing large. Vessels
What is the morphology of nodular regenerative hyperplasia
Liver entirely transformed into nodules; similar to micronodular cirrhosis but without fibrosis; plump hepatocytes surrounded by atrophic hepatocytes; can lead to portal HTN; occurs in association with conditions affecting intrahepatic blood flow (transplant, Vasculitis) and HIV ppl with RA or SLE
What are the most common benign liver tumors
Cavernous hemangioma; appear as red-blue soft nodules located beneath the capsules; can be mistaken radiologically for metastatic tumors
What are the complications of hepatocellular adenoma
Can rupture (emergency)
What are HNF1-alpha inactivated hepatocellular adenomas
Inactivating mutations of HNF1-alpha (encodes a TF) that are somatic (some have Germline mutations); heterozygous germline mutations responsible for AD MODY-3 (maturity onset diabetes of the young type 3); most common in women; OCP implicated in some
What are beta-catenin activated hepatocellular adenomas
Activating mutations in beta catenin; very high risk for malignant transformation; should be resected even when asymptomatic; associated with oral contraceptive and anabolic steroid use; found in men and women
What are inflammatory hepatocellular adenomas
Found in both men and women; assoc with NAFLD; small risk of malignant transformation and should be resected even when asymptomatic; activating mutations in gp130 (coreceptor for IL-6) that leads to JAK-STAT signaling and overexpression of acute phase reactants
What is the morphology of HNF1-alpha adenomas
Often fatty and devoid of atypical; liver fatty acid binding protein (LFABP) is expressed in all normal hepatocytes but is absent in these tumors (Dx*)
What is the morphology of beta catenin mutated adenomas
High degree of dysplasia and some areas of HCC; dx: nuclear translation of beta catenin; glutamine synthetase (which is usually only found in perivenular hepatocytes) is diffusely positive here (need molecular analysis for confirmation)
What is the morphology of inflammatory hepatocellular adenomas
Characteristically have addition areas of fibrotic stroma, mononuclear inflammation, ductular reactions, dilated sinusoids and telangiectatic vessels; most overexpress CRP and serum amyloid A
What is hepatoblastoma
Most common liver tumor of early childhood; rarely occurs over age of 3; 2 variants:
- epithelial type: small polygonal fetal cells or smaller embryonic cells forming acini, tubules or papillary structions
- mixed epithelial and mesenchymal type: foci of mesenchymal differentiation that consists of primitive mesenchyme, osteoid, cartilage, or striated m
What is the characteristic feature of hepatoblastomas
Frequent activation of WNT signaling, including mutations in APC (commonly seen in ppl with FAP)
What chromosomal abnormalities are seen with hepatoblastoma
FOXG1 (regulator of TGF beta) is highly expressed
Where are the highest incidences of HCC found
Asia and sub Sahara Africa
When is HCC seen in the US
After age 60 after cirrhosis already established; male predominance
Is cirrhosis a precursor lesion to HCC
No; occur in parallel
What organism produces aflatoxin
Aspergillosis
What diseases increases the risk of HCC
Hemochromatosis and alpha antitrypsin deficiency, NAFLD, DM, and metabolic syndroem assoc with obesity
What are the 2 most common early mutational events in HCC
Activation of beta catenin (less likely to be associated with HBV) and inactivation of p53 (more likely to be assoc with aflatoxin)
What are the precursor lesions of HCC
- hepatocellular adenoma
- in chronic liver dz: large cell change (marker of increased risk of HCC as a whole; in HBV directly premalignant) and small cell change (directly premalignant)
- dysplastic nodules in cirrhosis : increased arterial supply
What are the patterns of HCC
Unifocal, multifocal, and diffusely infiltrative
What is the most likely route for met of HCC
Vascular
What is fibrolamellar carcinoma
Variant of HCC; most occur under age of 35 w/o gender predication; presents as single large hard scirrhous tumor with fibrous bands; micro: well diff cells rich in mitochondria (oncocytes) growing in nests or cords
What is found in the serum of patients with addvanced HCC
Serum alpha fetoprotein
How can HCC be dx
Imaging; has distinct vascular pattern
What do people with HCC usually die from
Cachexia, GI or esophageal variceal bleeding, liver failure with hepatic coma, or rupture of tumor with fatal hemorrhage
What are the extrahepatic forms of cholangiocarcinoma
Extrahepatic: klatskin tumors; perihilar tumors located at right and left hepatic ducts; most are extrahepatic
What are the premalignant lesions for cholangiocarinoma
- Biliary intraepithlial neoplasias (BilIN-1,2,3); BilIn-3 causes highest risk
- mucinous cystic neoplasms
- intra ductal papillary biliary neoplasia
How do cholangiocarcinomas invade
Lymphovascular and perineural
What is the prognosis of angiosarcoma
Fatal
Which lymphomas are most common in the liver
B cell
What are the most common sources of metastatic liver cancer
Colon, breast, lung, and pancreas
What is the most common congenital anomaly of the GB
Folded fundus which creates a Phrygian cap
What populations are more likely to have cholesterol gallstones
Native Americans; more prevalent in America
What populations are most likely to have pigmented gallstones
Non-western populations; arise primarily in setting of bacterial infections of the biliary tree and parasitic infestations
What are the major risk factors associated with the development of gallstones
- middle age-older, higher in white females
- estrogen exposure (OCP and pregnancy) -> increases expression of hepatic lipoprotein receptors and stimulates HMG-CoA reductase -> increased cholesterol secretion
- GB stasis
- genes that encode ATP-binding cassette transporters (ABCG8)
What is the pathogenesis of cholesterol stones
When cholesterol concentration exceeds solubilizing capacity of bile, it nucleats into solid cholesterol mono hydrate crystals
-supersaturated, hypomotility of GB, accelerated cholesterol crystal nucleation, and hypersecretion of mucus in the GB cause this
What is the pathogenesis of pigmented gallstones
Mixture of calcium salts of unconjugated bilirubin and inorganic calcium salts; disorders assoc with increased unconjugated bilirubin (hemolytic anemia, ileal dysfunction, and bacterial contamination of biliary tree) increase risk; infxn w/ E. coli, ascaris lumbricoides or c sines is increases likelihood
When are pigmented gallstones brown vs black
Black: sterile; radiopaque
Brown: infected large bile ducts; soap like or greasy; radiolucent
What are the complications of gallstones
Empyema, perforation, fistula, inflammation of biliary tree, obstructive cholestasis, and pancreatitis
What is bouveret syndroem
Aka gallstone ileus; when gallstone erodes directly into adjacent loop of small bowel
What is acalculous cholecystitis
Cholecystitis without gallstones
What is the pathogenesis of acute calculus cholecystitis
Mucosal phospholipiases hydrolysis luminal lecithin to toxic lysolecithins; normal protective glycoprotein mucus layer is disrupted exposing it to direct detergent actin of bile salts; no bacterial infxn at this point; frequently occurs in diabetic patients who have symptomatic gallstones
What is the pathogenesis of acute acalculous cholecystitis
Ischemia; cystic artery is end artery with no collaterals; causes: GB stasis, accumulation of micro crystals of cholesterol (biliary sludge), viscous bile, GB mucus; risk factors: sepsis, immunosuppression, trauma and burns, DM, infxn
What is the morphology of acute cholecystitis
GB enlarged and tense; bright red or blotchy, green-black b/c of sub serosal hemorrhage; when exudate is pure pus: GB empyema
What can cause acute emphysematous cholecystitis
Invasion of gas forming organisms (clostridia and coliforms)
What does the presence of hyperbilirubinemia suggest in patients with gallstones
Obstruction of common bile duct
Is the risk of gangrene and perforation higher in calculus or acalculous cholecystitis
Acalculous
What are rokitansky-aschoff sinuses
Outpouchings of mucosal epithelium through the wall; seen in chronic cholecystitis
What is xanthogranulomatous cholecystitis
GB has massively thickened wall and is shrunken, nodular and chronically inflamed with foci of necrosis and hemorrhage; triggered by rupture of rokitansky-aschoff sinuses followed by accumulation of macrophages that ingest biliary phospholipids (xanthoma cells)
What are complications of both acute and chronic cholecystitis
- bacterial superinfection
- GB perforation and local abscess formation
- GB rupture with diffuse peritonitis
- biliary enteric (cholecystenteric) fistula, entry of air into biliary tree, gallstone induced intestinal obstruction
- aggregation of previous illnesses
- porcelain GB
What is the most common malignancy of the extrahepatic biliary tract
Carcinoma of the GB; more common in native Americans and women
Which oncoprotein is overexpressed in GB cancer
ERBB2
What patterns of growth do carcinomas of the GB show
- infiltrating: more common; poorly defined area of diffuse mural thickening and induration; deep ulceration can cause direct penetration into liver or fistula; scirrhous and firm
- exophytic: irregular cauliflower mass; invades underlying wall
Which carcinoma tumors of the GB have a better prognosis
Papillary
What is the most common reason for emergency cholecystectomy
Acute calculus cholecystitis
What do the islet cells secrete
Insulin, glucagon and somatostatin
What does the pancreas form from
Outpouchings of the foregut; body, tail and superior/anterior aspect of the head as well as accessory duct of santorini are derived from dorsal primordium; ventral primordium gives rise to the posterior/inferior part of the head of the pancreas and drains via papilla of vater
What is the most common congenital anomaly of the pancreas
Pancreas divisum; caused by failure of fusion of fetal duct systems of dorsal and ventral pancreatic primordium; results in pancreas drains into duodenum through the minor papilla; duct of wirsung only drains a small portion; predisposes ppl to chronic pancreatitis
What is an annular pancreas
Band-like ring of normal pancreatic tissue that completely encircles the second portion of the duodenum; can produce duodenal obstruction
What sites are common for ectopic pancreas
Stomach and duodenum, jejunum meckel and ileum
What causes pancreatic agenesis
Homozygous mutations in PDX1 (encodes homeobox TF critical for pancreatic development)
What are the protective mechanisms to prevent self-digestion of the pancreas
- most proenzymes activated by trypsin which is activated b y duodenal enteropeptidase in SI
- acinar and ductal cells secrete trypsin inhibitors including serine protease inhibitor Kazal type I (SPINK1)
What can cause acute pancreatitis
- metabolic: alcoholism, hyperlipoproteinemia, hypercalcemia, drugs
- genetic: mutations in genes encoding trypsin or calcium metabolism
- mechanical: gallstones, trauma, operative injury
- vascular: shock, atheroembolism, Vasculitis
- infections: mumps
What is the gender predisposition in acute pancreatitis
- in those caused by biliary tract dz: more females
- in those caused by alcoholism: more males
How can the activation of trypsin lead to acute pancreatitis
- activates prophospholipase: breaks down fat
- proelastase: breaks down elastic fibers of bv
- prekallikrein -> kinin -> activates factor XII
- inflammation and thrombosis
What can cause pancreatic duct obstruction
Gallstone (most common), periampullary neoplasms, choledochoceles (congenital cystic dilation of common bile duct), parasites (ascaris lumbricoides and clonorchis sinensis), and pancreas divisum; increases pressure; lipase destroys fat and sends danger signal
What can cause inappropriate activation of pancreatic enzymes
Calcium; regulates trypsin activation; when calcium low, trypsin inactivates itself
How can defective intracellular transport of proenzymes within acinar cells cause acute pancreatitis
-usually transported separately from lysosomal hydroplane; if delivered to lysosomal hydrolysis, activated and enzymes released
How does alcohol cause pancreatitis
Direct toxic effect on acinar cells; also causes contraction of sphincter of oddi
What drugs can cause pancreatitis
Furosemide, azathrioprine, dideoxyinosine, estrogens
What is the common characteristic of most forms of inherited pancreatitis
Defect that increases or sustains the activity of trypsin
What inheritance pattern does pancreatitis with a PRSS1 defect have
AD
What is SPINK1
Encodes trypsin inhibitor; LOF = hereditary pancreatitis; AR
What are ppl with hereditary pancreatitis at risk for
Pancreatic cancer
What other mutations cause hereditary pancreatitis
CASR (calcium sensing receptor), CTRC (chymotrypsin C), and CPA1 (carboxypeptidase A1)
What is acute interstitial pancreatitis
Milder form of pancreatitis; mild inflammation, interstitial edema, focal areas of fat necrosis
What is acute necrotizing pancreatitis
Necrosis of acinar and ductal tissue and Silat cells; vascular injury leads to hemorrhage; gross: pancreas is red-black and contains foci of yellow-white chalky fat necrosis; peritoneal cavity contains serous brown tinged fluid
What is hemorrhagic pancreatitis
Most severe form; extensive parenchyma necrosis accompanied by dramatic hemorrhage
Where does pain from pancreatitis radiate
Upper back and left shoulder; constant and intense
What systemic response can full blown acute pancreatitis cause
Leukocytosis, DIC< edema and ARDS; shock and acute renal tubular necrosis
What labs will you find with acute pancreatitis
Amylase during first 24 hours; followed by rising lipase level by 72-96 hours after the attack; glycosuria and hypocalcemia
How do you manage acute pancreatitis
Resting the pancreas by NPO and supportive therapy with IV fluids and analgesia
What is chronic pancreatitis
Prolonged inflammation associated with irreversible destruction of exocrine parenchyma, fibrosis and in the late stages, destruction of endocrine parenchyma
What population is most common in chronic pancreatitis
Middle aged males
What is the most common cause of chronic pancreatitis
Long term alcohol abuse
What conditions is chronic pancreatitis associated with
Long standing obstruction of pancreatic duct
Autoimmune injury
Hereditary pancreatitis
Which factors are uniquely produced in chronic pancreatitis rather than acute
Fibrogenic: TGF beta and PDGFRA; induce activation and proliferation of periacinar myofibroblasts -> deposition of collagen and fibrosis
What is autoimmune pancreatitis
Associated with presence of IgG4 secreting plasma cells; may mimic pancreatic carcinoma; *responds to steroid therapy
What is the morphology of chronic pancreatitis
Fibrosis, atrophy of acini, variable dilation of pancreatic ducts; gland is hard, ductal epithelium can show squamous metaplasia
What is the morphology of autoimmune pancreatitis
Duct centric mixed Inflam infiltrate, venue it is and increased # of IgG4 secreting plasma cells
What can cause attacks of chronic pancreatitis
Alcohol use, overeating, use of opiates and other dugs that increase the tone of the sphincter of oddi
How can you dx chronic pancreatitis
CT or US to show calcification; weight loss and edema due to low albumin from malabsorption can support dx
What are the congenital cysts that arise in the pancreas
Unilocular thin walled cysts; result from anomalous development of pancreatic ducts; lined by cuboidal epithelium or if intracystic pressure is high, by flatted and attenuated cell layer; often filled with serous fluid; can be sporadic or part of AD polycystic kidney dz and VHL dz
What are pseudocyts
Localized collections of necrotic and hemorrhagic material rich in pancreatic enzymes and lack an epithilial lining; *most common; arise usually following acute pancreatitis; lined by fibrin and granulation tissue
Where do pseudocyts usually develop
Mostly common: lesser o mental sac or retroperitoneum btw stomach and transverse colon in btw stomach and liver
What are the precursor lesions to pancreatic cancers
Pancreatic intraepithlial neoplasia (PanIN); epithelial cells in PanIN show dramatic telomere shortening
What is the most frequently altered oncogene in pancreatic cancer
KRAS (GTP binding protein); activates MAPK and PI3K/AKT pathways
What it’s he most frequently inactivated tumor suppressor gene in pancreatic cancers
CDKN2A
Which pathway has been shown to have increased activity in pancreatic cancer
SHH
What is the population at risk for pancreatic cancer
Age 60-80; black, Jewish
What is the strongest environmental risk factor associated with pancreatic cancer
Smoking
What conditions are at a higher risk of pancreatic cancer
DM and chronic pancreatitis
What accounts for some of the germline mutations that cause pancreatic cancer in Jews
BRCA2
What do germline mutations in CDKN2A lead to an increased risk of
Pancreatic cancer and observed in families with increased incidence of melanoma
What is the proposed timeline of mutations that lead to pancreatic cancer
Telomere shortening and KRAS mutations occur first -> CDKN2A mutations -> TP53, SMAD4, and BRCA2 later and higher grade lesions
Where do most pancreatic cancers arise
Head of the gland
Pancreatic carcinomas that arise where are more likely to be symptomatic
Head of the pancreas: obstruct distal common bile duct
Where can pancreatic cancer directly invade
Spleen, adrenals, transverse colon, and stomach
Which LN are common places of met from pancreatic cancer
Peripancreatic, gastric, mesenteric, omental, and portohepatic
Where are the sites of distant met for pancreatic cancer
Lungs and liver
What is the characteristic micro feature of pancreatic cancers
Elicit intense desmoplastic reaction with dense stromal fibrosis
What are the inherited predispositions to cancer
- peutz-jegher
- hereditary pancreatitis
- familiar atypical multiple mole melanoma syndrome
- strong family history
- hereditary breast and ovarian cancer (BRCA, PALP2)
- HNPCC (MLH1, MSH2)
What antigen is elevated in ppl with pancreatic cancer
CA19-9
What do people with acinar cell carcinoma sometimes develop
Syndrome of met fat necrosis caused by release of lipase into circulation
What are pancreatoblastomas
Children 1-15; distinct micro appearance: squamous islands mixed with acinar cells; survival is better than for adenocarcinoma
What do lymphocytes in people with IBD show reactivity to
Fecal antigens
Is bleeding more common in UC Or crohn
UC
What is the impact of smoking of the immuno response in the GI tract
Reduces mucosal cytokine production and promotes adhesion of leukocytes to endothelial cells; enhances small bowel permeability and colonic mucus production
What dietary factors are linked to IBD
Refined sugars risk factor for crohn but not UC; fat intake linked to UC; fiber decreases risk
What is early appendectomy linked to in terms of IBC
Reduced incidence of UC
What do nonfermentable fibers do in the GI tract
Serve as trophic factor for colonocytes
what environmental factors are linked to IBD
Drugs: OCP and NSAIDs increase risk, especially in IL-10 deficiency
more prevelant in higher class;more prominent in sedentary workers more common in women
Which genes are linked to IBD-1
CARD-15 (caspase recruitment domain family member)formerly known as NOD2; recognizes structures containing muramyl dipeptide (MDP) -> triggers activation of NFkB; expressed in macrophages
what kind of bacteria are found exclusively in the proximal GI tract
Aerobic and faculative anaerobic
What kind of bacteria are found in the distal GI tract
Obligate anaerobes; capable of producing short chain FA from carbs to be used for immuno processes
What are pathobionts
Microorganismas associated with chronic inflammatory conditions; usually suppressed by commensal bacteria via induction of Treg cells ad IL-10 and regenerating islet-derived protein 3gamma
How does microbiota induce tolerance to commensal bacteria
MAMP, PSA (polysac signaling), SCFA, expression of epithelial intestinal alkaline phos (IAP) which detoxifies LPS
What kind of bacteria trigger UC vs Crohn
UC: aerobic
crohn: anaerobic
what happens when salmonella infects with proper colonization of bacterioides
Attenuated response; induction of peroxisome proliferation activated receptor (PPAR) exports NFkB from nucleus so cannot exert its effects
What kind of T cell responses are seen in crohn and UC
Crohn: Th1 and 17 driven by IFN gamma and TNF and IL-17
UC: Th2; increased expression of IL-5 and IL-13 (NK cells)
what is the role of IL-6 and 23 in IBD
Released by APCs; IL-23 regulates Th1 response and activity of macrophages and DC; deficiency in IL-23 -> type IV delayed hypersensitivity; stimulates T cells tp produce IL-17
What do Th2 cells produce
IL-4,5,13
What are current tx options for IBD
TNF blockers (Risk of worsening heart dz, reactivation of infections and malignancy) Leukocyte adhesion inhibitors (risk of PML)
What is an example of the Vago-vagal reflex
Gastric receptive relaxation reflex
What are the parasympathetic innvervations to the GI tract
Vagus and pelvic nerves
What are examples of paracrine mediators in GI tract
Somatostatin and histamine
What are the features of gastrin
Secreted from G cells
Stimulated by: small peptides, distention of the stomach, vagal stimulation via GRP
Actions: increase gastric H+ secretion; stimulates growth of gastric mucosa
What are the features of CCK
Secreted by: I cells of duodenum and jejunum
Stimulated by: small peptides and aa; FA
Actions: increase pancreatic enzyme secretion and bicarbonate secretion; stimulates contraction of GB and relaxation of sphincter of oddi; stimulates growth of exocrine pancreas and GB; inhibits gastric emptying
What are the features of secretin
Secreted by: S cells in duodenum
Stimulated by: H+ in duodenum, FA in duodenum
Actions: increases pancreatic and biliary bicarbonate secretion; decreases H+ secretion; inhibits trophic effect of gastrin on gastric mucosa
What are the features of glucose-dependent insulinotropic peptide (GIP)
- Secreted by: duodenum and jejunum
- stimulated by: FA, AA, oral glucose
- Actions: increases insulin secretion (incretin affect); decreases H+ gastric secretion
What mediates the incretin effect
GIP and GLP-1 (glucagon-like peptide 1)
What is the effect of NE on salivary secretion
Increases it
What does vasoactive intestinal peptide (VIP)
Source: neurons of ENS
-relaxes smooth m, increases intestinal secretion and pancreatic secretion
What are the actions of gastrin releasing peptide (GRP)
Source: vagal neurons of gastric mucosa
-increases gastrin secretion
What are the actions of enkephalins
Source: neurons of ENS
-contraction of smooth m, decreases intestinal secretion
What are the effects of neuropeptide Y
Source: neurons of ENS
-relaxation of smooth m, decreases intestinal secretion
What are the actions of substance P
Co-released with ACh by neurons of ENS
-contraction of smooth m, increased salivary secreiton
Where do you see phasic contractions
Esophagus, antrum of stomach, SI, and all tissues involved in mixing and propulsion
Where do you see tonic contractions
Orad of stomach, lower esophagus, ileocecal; internal and external sphincters
What mediators increase vs decrease the amplitude of slow waves
Increases: ACh
Decrease: NE
What is the function of interstitial cells of cajal
Generate and propagate slow waves; occur spontaneously and spread via gap junctions; drives frequency of contractions (increases possibility of Ca2+ opening)
Describe the pharyngeal phase of slowing
Soft palate pulled up -> epiglottis moves -> UES relaxes -> peristaltic wave of contractions initiated by pharynx -> food propelled via open UES
Describe the esophageal phase
Controlled by swallowing reflex and ENS; primary and secondary peristaltic waves
What controls the involuntary swallowing reflex
Medulla; food in pharynx -> afferent sensory input via vagus -> swallowing center in medulla -> efferent input to pharynx
Which peristaltic wave can occur after vagotomy
Secondary
What is the opening of the LES mediated by
VIP and NO
How are large particles of undigested in the stomach emptied
Migrating myoelectric complexes (MMC): periodic bursting peristaltic contractions occurring in 90 min intervals; *motilin plays significant role; inhibited during feeding
What increases the rate of gastric emptying
- decrease in distensibility of the orad
- increased force of peristalsis contractions in caudad of stomach
- decreased tone of pylorus
- increased diameter and inhibition of segmenting contractions of the proximal duodenum
What decreases gastric emptying
- relaxation of orad
- decreased force of peristaltic contractions
- increased tone of pyloric sphincter
- segmentation contractions in intestine
What is the entero-gastric reflex
Negative feedback from duodenum will slow down the rate of gastric emptying
How does the enterogastric reflex work
- acid in duodenum -> stimulates secretin ->inhibits motility via gastric inhibition
- fat in duodenum -> stimulates CCK and GIP -> inhibits stomach motility
- hypertonicity in duodenum -> unknown
What are segmentation contractions
Produce no forward propulsive movement
What are peristaltic contractions
Circular and longitudinal mm contract in opposition to complement each other; reciprocally innervated
Can slow waves initiate contractions in small intestine
No; need spike potentials to occur
What are the actions of the myenteric plexus vs submucosal plexus
Myenteric: regulates contraction of intestinal wall
Submucosal: senses lumen environment
What hormones can cause contraction of GI mm
Serotonin, prostaglandins, gastrin, CCK, motilin, and insulin (secretin and glucagon inhibit)
What is the rectosphincteric reflex
As rectum fills with feces, smooth m of rectum contracts and internal anal sphincter relaxes
What is the intestino-intestinal reflex
Short reflex; mostly inhibitory; involves only ENS; no ANS involvement (atropine has no effect); eg: ileocecal sphincter
What is the gastroileal reflex
Gastric distention relaxes ileocecal sphincter
What causes gastroparesis
DM, injury to vagus n; sx: N/V, early feeling of fullness, weight loss, ab bloating and discomfort
What is the composition of saliva in comparison to plasma
Increased K and HCO3; decreased Na and Cl
What can modify the composition of salvia
Aldosterone and vasopressin; decrease its Na concentration and increase its K concentration
What are the diff btw oxyntic and pyloric glands
Oxyntic: located in body and fundus; secretes acid
Pyloric: located in antrum; synthesizes gastrin
What do chief cells secrete
Pepsinogen
What is the most important stimuli for pepsinogen secretion
Vagus n stimulation; H+ triggers local cholinergic reflexes that stimulate chief cells to secrete pepsinogen
What makes the alkaline tide
Net secretion of H and absorption of HCO3 by gastric parietal cells
What does omeprazole inhibit
K/H exchanger
What does somatostatin inhibit
G cells from releasing gastrin
What GPCR do gastrin and ACh activate
Gq
What GPCR do somatostatin and prostaglandins activate
Gi; inhibit activation of H+/K+ ATPase
Histamine potentiates the actions of ______
ACh and gastrin
How is gastrin release stimulated
Vagal activation by releasing GRP and inhibiting the release of somatostatin
What is gastrin’s effect on somatostatin
Increased gastrin will have a negative feedback on itself by increasing release of somatostatin
What are the direct vs indirect pathways of vagus n stimulation of HCl release by parietal cells
- direct: ACh activates parietal cells to release HCl; *atropine will block this
- indirect: GRP released here which activates gastrin release -> parietal cells; *atropine will NOT block this
Why do you get steatorrhea with zollinger Ellison
Low duodenal pH inactivates pancreatic lipase
What are the phases of pancreatic secretion
Cephalic: mediated by vagus; produces mainly enzymatic secretions
Gastric: initiated by distention of stomach; mediated by vagus; produces mainly enzymatic secretions
Intestinal: accounts for most secretion; enzymatic and aqueous
How are bile salts take up across the basolateral membrane in the hepatocytes
- Na+ dependent transport protein, sodium taurocholate cotransporting polypeptide (NTCP)
- Na+ independent transport protein, organic anion transport proteins (OATPs)
How are bile salts taken up into the bile canaliculi
Bile salt excretory pump (bsep) and MDRP2
What is the mutation in dubin johnson
Mutation in MRP2; cant secreted conjugated bilirubin into bile; liver has black pigmentation
What is the mutation in rotor syndrome
Building of unconjugated and conjugated bilirubin; mutations in OATP1B1; cant transport bilirubin into liver
What kind of carbs can be absorbed by enterocytes
Only monosaccharides: glucose, galactose and fructose
What GLUT transporter does fructose use
GLUT 5
What is the function of colipase
Lipase is usually inactivated by bile salts; colipase binds to lipase and displaces bile salts
What can cause a deficiency in bile salts
Ileal resection, SI bacterial overgrowth caused by decreased gastric acid secretion and SI dysmotility (deconjugate bile salts); cannot form micelles and interrupts fat absorption
What are the things highly absorbed in the duodenum
Carbs, proteins, lipids, calcium, iron, folate
