GI  PATHOLOGY EXAM  IORAL  CAVITYDISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXGingivitis Gingiva  –  squamous  mucosa  

around  the  teeth;  Chronic  gingivitis  –  inflamm  of  gingiva  characterized  by  erythema,  edema,  bleeding;  May  occur  at  any  age  but  most  prevalent  and  severe  in  adolescence

Due  to  poor  oral  hygiene  resulting  in  build  up  of  plaque  and  calculus  around  and  on  the  tooth  surface  and  beneath  the  gumline;  Dental  plaque:  biofilm  composed  of  bacteria,  salivary  protein,  and  desquamated  epithelial  cellsCalculus  (tartar)  is  mineralized  plaque

reducing  accum  of  plaque  and  calculus  thru  brushing,  flossing,  reg  dental  visits

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

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

Inflamm/reactive  lesions

Most  common  fibrous  proliferative  lesions  of  the  oral  cavity

Fibroma  (61%) irritation  fibroma  seen  at  bite  line  on  buccal  mucosa  or  gingivodental  margin

fibroma

Peripheral  ossifying  fibroma  (22%

young  and  teenage  females  with  15  to  20%  recurrence  rate  after  excision

Pyogenic  granuloma  (12%)  

Highly  vascular  prolif  resembling  granulation  tissue  (may  have  alarming  rapid  growth)  

seen  in  kids,  young  adults  and  commonly  preg    (preg  tumor)

may  regress,  undergo  fibrous  maturation  or  develop  into  a  peripheral  ossifying  fibroma

Peripheral  giant-­‐cell  granuloma  (5%)

Aphthous  ulcers Common  superficial  ulcerations  (single  or  multiple)  of  oral  mucosa  which  are  painful  and  recurrent;  these  are  normal  mouth  ulcers

Mostly  seen  in  first  2  decades  of  life;  Cause  unknown

Resolve  in  7  to  10  daysRecurrent  may  be  assoc  w/  celiac  disease  and  IBS

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

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

Plummer  -­‐Vinson  syndrome  (or  Paterson-­‐Kelly  

syndrome)  

combo  of  iron-­‐deficiency  anemia  +  glossitis  +  esophageal  dysphagia  usually  due  to  a  web

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXGeographic  tongue The  tongue  develops  multiple  

areas  of  desquamation  (loss)  of  the  filiform  papillae  in  several  irregularly  shaped  but  well-­‐defined  areas.  The  smooth  areas  resemble  a  map,  thus  the  name  geographic  tongue.  

Over  a  period  of  days  or  weeks,  the  smooth  areas  and  the  whitish  margins  seem  to  migrate  across  the  surface  of  the  tongue  by  healing  on  one  border  and  extending  on  another  (migratory)F:M  =  3:1

Uncertain  cause,  some  foods  may  exacerbate  problem;  resolves  w/in  mths

no  proven  tx,  resolves  spont.

Fissured  tongue normal  variant;  its  cause  is  unknown;  Prevalence  of  2-­‐5%  of  population;    dorsal  surface  of  the  tongue  appears  to  have  deep  fissures  or  grooves  that  become  irritated  if  food  debris  collects  in  them

Melkersson-­‐Rosenthal  syndrome  is  a  rare  condition  consisting  of  a  triad  of  persistent  or  recurring  lip  or  facial  swelling,  intermittent  seventh  (facial)  nerve  paralysis  (Bell  palsy),  and  a  fissured  tongue  -­‐the  etiology  of  this  syndrome  is  also  unknown

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

Herpes  simplex  virus Initial  infection  is  usually  asympt  occurring  during  preschool  years  but  may  have  acute  herpetic  gingivostomatitis  in  10  to  20%;  Recurrent  infections  due  to  reactivation  of  latent  HSV-­‐1  residing  in  ganglia

Fever,  anorexia,  irritability,  lymphadenopathy  with  vesicles  and  ulcerations  thruout  the  mouth,  especially  of  the  gingiva;  recurrent:  Localized  group  of  small  vesicles  (1-­‐3  mm)  on  lips,  nasal  orifices,  buccal  mucosa,  gingiva  and  hard  palate;  may  predispose  to  reactivation  including  trauma,  allergies,  URI,  immunosupp

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

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

make  sure  kids  stay  hydrated

Oral  candidiasis may  be  a  normal  component  of  the  oral  flora  in  ~50%  of  ppl;  MC  form  is  pseudomembr.  form  or  “thrush”-­‐>superficial,  gray-­‐white  membrane  which  can  be  scraped  off  revealing  an  erythematous  base;  May  occur  in  those  with  immunosupp  due  to  diabetes,  transplant  recipients,  AIDS,  neutropenia;  may  also  occur  if  normal  oral  flora  eradicated  by  antibiotics

common  in  babies can  scrap  this  off

Hairy  leukoplakia Caused  by  EBV   Characterized  by  white,  confluent,  “hairy”  patches  on  the  lateral  aspects  of  the  tongue  due  to  hyperkeratosis  which  cannot  be  scraped  off  like  thrush

80%  of  patients  have  HIV  and  the  rest  have  some  other  type  of  immunosupp

Micro:  hyperparakeratosis  and  acanthosis  w/  balloon  cells  in  the  upper  spinous  layer  -­‐-­‐>  pic

CANNOT  be  scraped  off  like  thrush

Leukoplakia more  common  from  40  to  70  years  of  age  and  in  those  that  use  tobacco  

defined  as  a  white  patch  in  the  oral  cavity  which  cannot  be  scraped  off  and  cannot  be  diagnosed  as  another  disease  either  clinically  or  pathologically

Gross:  Solitary  or  multiple  white  patches  with  a  variety  of  appearances  form  smooth,  thin  and  well  demarcated  to  irregular,  thick  and  diffuse;  MC  locations  are  buccal  mucosa,  floor  of  mouth,  ventral  surface  of  tongue,  palate  and  gingiva;  Micro:  Varies  from  hyperkeratosis  and  acanthosis  to  marked  dysplasia  and  carcinoma  in  situ

" must  be  considered  premalignant  until  proved  otherwise  by  biopsy

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXErythroplakia less  common  but  much  more  

likely  to  have  malignant  transformation  than  leukoplakia;  red  plaque

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

"

Squamous  cell  carcinoma  (SCC)  of  the  oral  cavity

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

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

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

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

ESOPHAGUSesophageal  obstruction

1.  Functional  obstruction  due  to  esophageal  dysmotility

2.  Stenosis  –  may  be  congenital  but  often  due  to  scarring  from  chronic  GE  reflux,  irradiation  or  caustic  injury

3.  Mucosal  webs  –  ledge-­‐like  protrusions  of  mucosa  (less  than  5mm  protrusion  and  ~2-­‐4  mm  thick)  into  the  lumen;  MC  in  women  over  40;  associated  w/  chronic  GE  reflux,  chronic  graft-­‐versus-­‐host  disease  or  blistering  skin  disease;Plummer-­‐Vinson  syndrome  –  Web  with  Fe  deficiency,  glossitis,

4.  Schatzki  ring  –  Rings  are  circumferential  and  thicker  than  webs

Achalasia increased  tone  of  the  lower  esophageal  sphincter  (LES),  incomplete  LES  relaxation  and  aperistalsis  of  the  esophagus

Primary:  Idiopathic  failure  of  distal  esophageal  inhibitory  neurons,  thus  it  relaxes;  Secondary:  Chagas  disease  from  Trypanosoma  cruzi  infection  causes  destruction  of  myenteric  plexus  with  loss  of  peristalsis  and  esophageal  dilation;  Achalasia-­‐like  disease  w/  diabetic  neuropathy,  infiltrative  diseases  such  as  amyloidosis  or  sarcoidosis,  polio,  etc

Esophageal  Diverticuli

Pseudodiverticuli only  mucosa  protrudes  though  the  wall,  not  the  muscularis

Pulsion  diverticuli  Occurs  from  increased  stress  to  the  esophageal  wall  from  diffuse  esophageal  spasm  causing  increased  pressure  at  a  weak  spot  in  the  wall

Zenker  diverticulum  (pharyngoesophageal  diverticulum)  located  immediately  above  the  upper  esophageal  sphincter,  very  rare,  occurs  in  men  and  the  elderly;  Sx:  halitosis,  regurgitation,  dysphagia  (fills  up  with  food  causing  mass  effect);  complications  are  aspiration  and  pneumonia

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

Traction  diverticuli  due  to  pulling  forces  on  the  outside  of  esoph.  from  an  adjinflam  processDISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

Mallory-­‐Weiss  tears Longitudinal  tears  of  the  distal  esophagus  just  above  the  GE  junction  (may  involve  the  stomach  as  well)  associated  with  severe  retching  or  vomiting  classically  assoc  w/  acute  ethanol  intoxication;  Likely  occurs  due  to  sudden  rise  in  intraluminal  esophageal  pressure  due  to  failure  of  cricopharyngeus  muscle  to  relax  from  neuromuscular  dysfunction  in  prolonged  vomiting

look  at  linear  streak  -­‐-­‐>   generally  self  limited,  not  requiring  Rx;  Rarely,  a  distal  esophageal  rupture  may  occur  (Boerhaave  syndrome)  a  life  threatening  emergency

Esophagitis Esophageal  injury  due  to  alcohol,  acids  or  alkalis,  very  hot  fluids,  heavy  smoking,  pill-­‐induced;  Iatrogenic  -­‐  irradiation,  chemotherapy,  graft  versus  host  disease;  Infections:  immunosupp  w/  MC-­‐>  Herpes,  CMV  or  fungal

Esophagus  may  be  involved  with  desquamative  skin  disease  such  as  bullous  pemphigoid  or  epidermolysis  bullosaRarely,  Crohn’s  disease

Reflux  esophagitis  (Gastroesophageal  reflux  disease  (GERD))

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

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

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

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

Eosinophilic  esophagitis

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

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

large  numbers  of  eosinophils  in  the  squamous  epithelium,  particularly  superficially

avoid  food  allergens,  corticosteroids

Barrett  esophagus intestinal  metaplasia  of  the  esophageal  squamous  mucosa  and  confers  an  increased  risk  for  esophageal  adenocarcinoma  (However,  most  people  with  Barrett  do  not  develop  carcinoma)    

esophageal  mucosa  is  lined  by  non-­‐keratinzed  stratified  squamous  epithelium  -­‐-­‐>

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

Gross:  Red,  velvety  tongues  or  patches  of  mucosa  extending  upward  from  the  GE  junction  into  the  esophagus  w/intervening  pale  tan  squamous  mucosa;  Long  segment  (3  cm  or  more  of  esophagus  involved)  versus  short  segment  (less  than  3  cm  is  involved);  Micro:  Intestinal  metaplasia  as  defined  by  the  presence  of  goblet  cells  (mucous  vacuoles  imparting  the  shape  of  a  goblet  to  the  cell);  Foveolar  mucous  cells  are  NOT  goblet  cells

gastric  mucosa  is  lined  by  columnar  glandular  epithelium  -­‐>

can  only  be  diagnosed  by  endoscopic  evidence  of  abn  esophageal  mucosa  AND  histo  evidence  of  intestinal  metaplasia;  followed  by  regular  endoscopies  and  biopsies  to  look  for  the  dev  of  DYSPLASIA  (characterized  by  cytologic  and  architect.  abn)

see  big  goblet  cells,  which  do  not  normally  belong  in  esophagus

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXEsophageal  varices Dilated  congested  venous  

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

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

Morph:  On  venogram,  varices  appear  as  tortuous  dilated  veins  lying  in  the  submucosa  of  the  distal  esophagus  and  proximal  stomach  and  directly  beneath  the  esophageal  epi;  At  autopsy,  varices  may  not  be  obvious  since  they  collapse  with  no  blood  flow;  ucosal  ulceration  may  occur  w/hemorrhage  into  the  wall  of  the  esophagus;  W/  past  rupture,  venous  

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

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

esophageal  tumors POOR  prognosis!Adenocarcinoma Caucasian;  M7x>W;  freq  w/  

Barrett  esophagus  due  to  longstanding  GERD;  Other  risk  factors:  tobacco,  obesity  and  prior  radiation  therapy

May  discover  on  endoscopy  for  monitoring  of  Barrett  esophagus  or  in  the  initial  evaluation  of  GERD;  MC:  pain  or  diff  swallowing,  wt  loss,  hematemesis,  CP,  vomiting

Progression  of  Barrett  esophagus  is  due  to  a  stepwise  accum  of  genetic  and  epigenetic  defects  over  time

Gross:Location  is  distal  1/3  of  esophagus  and  may  involve  the  gastric  cardia;  Varies  from  flat  or  raised  patches  to  large  masses;may  have  ulcerations  and  diffuse  infiltration  and  invasion  w/o  large  masses;  Micro:  Glands,  mucin  formation  or  may  be  small  poorly  diff  cells;  may  have  diffuse  infilt.  of  signet  ring  cells;  Barrett  esophagus  may  be  adjacent  to  the  tumor

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

Squamous  cell  carcinoma

adults  >45,  M>F;  AA>C;  Risk  factors:  In  US,  alcohol  and  tobacco  are  major  risk  factors  and  felt  to  have  a  synergistic  effect;  nutritional  deficiencies,  nitrosamines  and  other  mutagenic  compounds,  fungus  contaminated  food,  HPV  is  some  high  risk  areas,  poverty,  caustic  esophageal  injury,  achalasia,  tylosis  (genetic  disorder  with  hyperkeratosis  of  palms  and  soles  and  oral  leukoplakia),  Plummer-­‐Vinson  syndrome,  frequent  consumption  of  very  hot  drinks

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

SMALL  INTESTINEIntestinal  obstruction

Adhesions bowel  gets  attached  to  another  part  of  itself,  but  doesn't  cut  off  blood  supply  

Volvulus Twisting  of  a  segment  of  bowel  on  its  mesenteric  base  of  attachment;  Leads  to  obstruction,  infarction,  gangrenous  bowel

Usual  locations:  Adults-­‐  cecum,  sigmoid  colon,  or  SI;  Children  -­‐  SI

Often  associated  with  congenital  intestinal  malrotation  of  gut  in  kids

TX:  surgical  exploration  to  untwist  and  resect  gangrenous  bowel  

Intussusception Telescoping  of  a  proximal  segment  of  bowel  into  the  distal  segment;  usually  idiopathic;  MC  occurs  at  terminal  ileum  -­‐>  ileocolic  intussusception

Leads  to  obstruction,  ischemia,  intestinal  mucosal  bleeding  term  “currant  jelly”  stool;  MC  in  infants  and  children

Contrast  enema  is  diagnostic  in  approx  95%  of  intussusception  cases  and  it  is  therapeutic  and  curative  in  most  cases  w/  less  than  24-­‐hour  duration

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXHirschsprung  Disease AKA  congenital  toxic  

megacolon;  by  congenital  absence  of  PNS  ganglion  cells  in  the  rectum  and  sigmoid  colon  resulting  in  obstruction80%  male;  usually  sporadic  :1  per  5,000  live  births

failure  to  pass  meconium,  obstructive  constipation;  may  have  occasional  passage  of  stool  or  diarrhea  if  only  a  short  segment  of  rectum  is  affected;  Prox  innerv  colon  may  b'c  massively  distended  (15  cm  in  diameter)  w/  mm  wall  hypertrophy  and  rupture/perforation,  may  have  superimposed  enterocolitis  and  electrolyte  abnormalities

the  part  w/  ganglion  cells  is  the  good  part;  lack  of  inhibitory  activity  but  increased  extrinsic  innerv.  Is  causing  uncoordinated  peristalsis  and  increased  tone

TX:  Surgical  resection

Ischemic  bowel  disease

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

Acute  transmural  infarction  –  sudden  onset  severe  abdl  pain,  w/  N&V,  bloody  D  or  melanotic  stools;  may  progress  to  shock  and  death  due  to  blood  loss  and/or  sepsis;  Mucosal  and  mural  infarctions  –  May  have  non-­‐specific  abd  complaints,  intermittent  bloody  stool,etc;  May  dev  collateral  circulation  in  chronic  ischemia  or  progress  to  more  extensive  infarction  if  underlying  cause  of  ischemia  not  corrected

Initial  hypoxic  injury  –  Epithelial  cell  lining  the  intestines  are  relatively  resistant  to  hypoxiaReperfusion  injury  –  greatest  damage  occurs  during  this  phase  with  infiltration  of  neutrophils  and  release  of  inflammatory  mediators  and  free  radical  productionMajor  variable  in  ischemic  bowel  disease:  the  severity  of  vascular  compromise;  the  vessels  affected;  the  time  frame

morph:  Mucosal  and  mural  infarction  (mural  involves  mucosa  and  submucosa)    usually  the  result  of  chronic  or  acute  hypoperfusion:    Continuous  lesions  or  segmental  and  patchy,  Dark  red  or  purple  mucosa  with  possible  hemorrhage  and  ulceration  and  thickened  edematous  bowel  wall  but  absent  serosal  involvement;  Transmural  infarction  usually  due  to  acute  arteria  obstruction  –substantial  portion  of  bowel  involved  with  sharp  demarcation  between  normal  and  infarcted  bowel    which  is  dusky  red  to  purple  and  edematous  with  serositis;  Perforation  may  occur

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

red  dusky  bowel

Dysentery Painful,  bloody  small-­‐volume  diarrhea

Diarrhea Increase  in  stool  mass,  frequency  or  stool  fluidity,  >  200  g/day;  Severe  cases  may  exceed  14  L  per  daySecretory  diarrhea loss  of  intestinal  fluid  that  is  isotonic  with  plasma  and  persists  during  fasting

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

osmotic  forces  exerted  by  unabsorbed  luminal  solutes;  the  diarrhea  fluid  is  over  50mOsm  more  concentrated  than  plasma  and  it  abates  with  fasting.

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

Exudative  diarrhea purulent  bloody  stool  (inflammation  of  the  mucosa  and/or  hemorrhage)  that  continue  during  fasting

Infections  causing  tissue  damage:  Shigella,  Salmonella,    Entamoeba  histolytica;  Infections  causing  both  tissue  damage  and  toxins:  clostridium  difficile;  with  antibiotic  therapy,  leading  to  pseudomembranous  colitisIdiopathic  IBS

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

Anemia:  iron,  folate  and  B12  def,  vit  K  def,  Osteopenia:  Ca  &  vit  D  def;  Amenorrhea,  impotence,  infertility;  Purpura:  vitamin  K  def;  Dermatitis:  vit  A  def;Peripheral  neuropathy:  folate  and  B12  def,  vit  A

nutrient  absorption:  1.  Intraluminal  digestion  –  proteins  and  fats  broken  down  into  forms  suitable  for  abs;  2.Terminal  digestion  –  hydrolysis  of  carbs  &  peptides  in  the  brush  border  of  SI;3.  Transepithelial  transport  -­‐transported  into  and  processed  by  epi;    4.Lymphatic  transport  of  absorbed  lipids

malabsorption  syndromes:  1.  Defective  intraluminal  digestion:  pancreatic  insuff,  defective  bile  secretion;  2.  Mucosal  abn:Disaccharide  def  (lactose  intolerance);  3.  Reduced  surface  area:  Gluten-­‐sensitive  enteropathy  (Celiac  disease)  ,  Surgical  resection;  4.  Infections:  Tropical  sprue?,  Whipple  disease

types  of  malabsorption  

diseases:  DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXCeliac  Disease AKA  celiac  sprue,  nontropical  

sprue  or  gluten-­‐sensitive  enteropathy;  An  immune  mediated  enteropathy  precipitated  by  gluten,  a  protein  in  wheat,  rye  barley  in  genetically  susceptible  people;  MC  in  European  ancestry;  prevalence  is  0.5-­‐  1%

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

Immune  reaction  to  gliadin,  an  amino  acid  produced  by  intestinal  digestion  of  glutenTwo  mechanisms  of  cellular  damage:  Gliadin  induces  epithelial  cells  to  express  IL-­‐15  ultimately  results  in  cytotoxic  T-­‐cells  killing  enterocytes;  Deamidated  gliadin  interacts  with  HLA-­‐DQ2  or  HLA-­‐DQ8  on  antigen-­‐presenting  cells  which  are  presented  to  CD4+  T  cells  which  then  produce  cytokines  causing  tissue  damage;  Other  immune  diseases  assoc  w/  celiac  disease  may  be  type1  diabetes,  thyroiditis  and  Sjogren  syndrome

Biopsy  from  duodenum  or  proximal  jejunum:  intraepithelial  lymphocytes,  villous  atrophy,  crypt  hyperplasia,  Increased  plasma  cell,  mast  cells  and  eosinophils  in  the  lamina  propria

Diagnosis  based  on  histology  in  combo  w/  serology;  most  sensitive  tests  are  IgA  antibodies  to  tissue  transglutaminase  or  IgA  or  IgG  antibodies  to  deamidated  gliadin;  Antiendomysial  antibodies  are  highly  specific  but  less  sensitive  than  above

Increased  risk  for  enteropathy-­‐associated  T-­‐cell  lymphoma  and  small  intestinal  adenocarcinoma

Treatment  is  gluten  free  dietpic  -­‐-­‐>  left  normal,  right  is  celiac

tropical  sprue Idiopathic  celiac-­‐like  disease  found  almost  exclusively  in  people  living  in  or  visiting  the  tropics

Micro:  loss  of  villi  similar  to  celiac  disease

broad  spectrum  antibiotics  is  effective  which  would  seem  to  indicate  an  infectious  etiology

Whipple  Disease Rare  disease  caused  by  Trophermyma  whipplei  (gram  positive  rod-­‐shaped  bacilli)May  involve  any  organ  but  typically  affects  intestine,  CNS,  and  joints;    MC  Caucasian  male  age  30-­‐50  yo

Presents  with  malabsorption,  diarrhea,  weight  loss

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

diff  from  mycobacterium  infection  -­‐-­‐>  this  will  stain  w/  acid  fast  stain,  and  whipple's  disease  will  not

Prompt  response  to  antibiotics

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

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

Infectious  Enterocolitis

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

Types:  ViralBacterial  Parasitic

Viral  Gastroenteritis Symptomatic  human  infection  is  caused  by  several  distinct  groups  of  viruses:  RotavirusCalciviruses  (Norwalk-­‐like  viruses,  Sapporo-­‐like  viruses),

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXRotavirus With  the  loss  of  absorptive  

function  and  excess  of  secretory  cells,  there  is  net  secretion  of  water  and  electrolytes,  compounded  by  an  osmotic  diarrhea  from  incompletely  absorbed  nutrients

 6-­‐24  months  of  age;  MC  cause  of  severe  childhood  diarrhea  and  diarrheal  mortality  worldwideFecal-­‐oral  mode  of  transmission  w/  estimated  minimal  infective  inoculum    of  10  viral  particles;  Selectively  infects  and  destroys  mature  enterocytes  in  the  small  intestine,  without  infecting  crypt  cells;  Surface  epithelium  of  the  villus  is  repopulated  by  immature  secretory  cells;  

Calicivirus Outbreaks  occur  following  exposure  of  multiple  individuals  to  a  common  source;  incubation  period  of  1  to  2  daysfollowed  by  12  to  60  hours  of  N/v/  watery  diarrhea,  and  abd  pain

 the  classic  Caliciviruses  (Sapporo-­‐like  viruses)  and  the  Norwalk-­‐like  viruses  (small  round  structured  viruses);  Sapporo-­‐like  viral  infection  is  rare

Norovirus    (previously  known  as  Norwalk-­‐like  viruses)  is  responsible  for  half  of  nonbacterial  food-­‐borne  epidemic  gastroenteritis  worldwide  and  a  common  cause  of  sporadic  gastoenteritis  in  developed  countries  (infections  spread  easily  in  schools,  hospitals,  nursing  

Self-­‐limited  disease

Enteric  Adenovirus cause  a  moderate  gastroenteritis  with  diarrhea  and  vomiting,  lasting  for  a  week  to  10  days  after  an  incubation  period  of  approximately  1  week

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

in  SI,  adenoviral  infection  causes  atrophy  of  the  villi  and  compensatory  hyperplasia  of  the  crypts  similar  to  rotavirus;  The  virus  can  also  cause  colitis  Identifying  nuclear  viral  inclusions  helps  in  making  the  diagnosis  

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

Self-­‐limited  disease

astrovirus Diarrhea,  anorexia,  headache,  and  fever

Named  after  its  starlike  appearance;  Primarily  affects  children  worldwide

Bacterial  Enterocolitis Symptomatic  human  infection  is  caused  by  numerous  bacteria;  AKA  food  poisoning

Rapid  onset  of  diarrhea,  abdominal  discomfort

mech:  Ingestion  of  preformed  toxin  (Present  in  contaminated  food,  Major  pathogens:  SA,  Clostridium  perfringens,  Vibrio  cholerae,  other  vibrio  spp.,  Bacillus  cereus  (yesterday’s  rice)),  Infection  by  toxigenic  orgs,  Infection  by  enteroinvasive  orgs

Cholera Incubation  period  -­‐  1  to  5  days;  Most  exposed  individuals  are  asymptomatic  or  develop  only  mild  diarrhea;    Abrupt  onset  of  voluminous  watery  diarrhea  (rice  water  stools);  1  liter  per  hour;  Dehydration,  shock  with  death  in  24  hours  for  severe  cases.

Endemic  in  Ganges  Valley  of  India  and  Bangladesh;  Contaminated  drinking  water  and  sporadic  cases  of  seafood-­‐associated  disease  in  North  America;  Vibrio  parahaemolyticus-­‐most  common  cause  of  seafood-­‐associated  gastroenteritis  in  N.  America;  

Comma  shaped  gram  negative  bacteria,  Non-­‐invasive  with  preformed  enterotoxin  causing  disease  (encoded  by  a  virulence  phage),  Flagellar  proteins  involved  in  motility  and  attachment  necessary  for  bacterial  colonization;Hemagglutinin  (metalloproteinase)  imp  for  bacterial  detach/shedding  in  stool  

Cholera  toxin  incorporated  into  the  cell  resulting  in  increased  cAMP  opening  the  cystic  fibrosis  transmembrane  conductance  regulator,  CFTR,  which  releases  chloride  ions  into  the  lumen  -­‐>causes  secretion  of  bicarbonate,  sodium  and  water  with  massive  diarrhea;  only  minimal  alterations  of  S.B  mucosa.

Mortality  50%  without  treatment  but  over  99%  survival    with  fluid  replacement.

IV  fluid  replacement  

E.  Coli Enterotoxigenic-­‐MC  cause  of  traveler’s  diarrhea,  secretory  diarrhea  with  production  of  heat-­‐labile  and  heat-­‐stable  toxin.  Enteroinvasive-­‐  invade  epithelial  cells,  bloody  diarrhea,  acute  self-­‐limited  colitis

Enterohemorrhagic-­‐O157:H7  serotype  seen  in  inadequately  cooked  ground  beef.  Shiga-­‐like  toxins.  Bloody  diarrhea  and  hemolytic  uremic  syndrome  (HUS)Enteroaggregative-­‐adhere  to  epithelial  cells,  traveler’s  diarrhea,  non-­‐bloody

 self-­‐limited,  no  need  for  Abx

Salmonella  (typhoid  and  non-­‐typhoid    Salmonella)  

Vomiting,  profuse  diarrhea  or  dysentery,  abdominal  pain

S.  enteriditis  causes  most  nontyphoid          Salmonella  infection  -­‐>    I  million  cases  a  year  in  US;  Contaminated  beef  and  chicken,  poultry,      eggs  and  milk

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

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXTyphoid  fever Invades  intestinal  epithelial  

cells  and  tissue  mps;  systemic  illness  caused  by  S.  typhi  or  S.  paratyphi  (Humans  are  the  sole  reservoir  of  both)

Week1:  fever,  chills,  septicemia  (90%  with  +  blood  cultures);  Week  2:  rash  (Rose  spots  on  chest  and  abd),  abd  pain  (may  mimic  appendicitis),  exhaustion;  Week  3:  ulceration  of  Peyer’s  patches  in  ileum,  intestinal  bleeding,  shock.          Perforation  may  occur;  -­‐  Typhoid  nodules,  macrophage  aggregates,may  develop  in  liver,  BM,  lymph  nodes  and  phagocyte  hyperplasia  in  spleen;  gallbladder  colonization  assox  w/gallstones  and  chronic  carrier  state

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

Invades  intestinal  epithelial  cells  but  do  not  go  beyond      lamina  propria  and  are  phagocytosed  by  mp  and  induce  apoptosis.  The  ensuing  inflamm  process  damages  surface  epithelium  and  allows  the  Shigella  to  have  access  to  the  colonocyte  basolateral  membrane  (left  colon  prominent  site  of  infection  but  ileum  may  be  involved)

Campylobacter  jejuni Flagellated,  gram-­‐negative,  comma-­‐shaped  organsimsMost  common  bacterial  enteric  infection  in  developed  countries  and  a  cause  of  traveler’s  diarrhea.

Colon  is  affected  GI  site;  Watery  or  bloody  diarrhea

Reservoir-­‐  Chickens,  sheep,  pigs,  cattle;  Transmission  –  poultry,  milk,  water

Complications-­‐  arthritis,  Guillain-­‐Barre  (rare)

Yersinia Yersinia  enterocolitica  and  pseudotuberculosis  cause  GI  disease;  Northern  and  central  Europe;  Affected  GI  sites-­‐  Ileum,  appendix,  right  colon.

Abd  pain/F/D    and  may  mimic  appendicitis;  extra-­‐intestinal  sx  of  pharyngitis,arthralgia,  and  erythema  nodosum  may  occur

Reservoir-­‐  pigs;  Transmission-­‐  pork,  milk,  water;  org  multiplies  extracellularly    in  lymphoid  tissue  with  hyperplasia  of    Peyers  patches  and  lymph  nodes

Complications-­‐  arthritis,  myocarditis,  thyroidits,  GN

parasites Entamoeba  histolytica:  oral-­‐fecal  transmission,  invasive,  amebic  colitis  and  amebic  liver  abscessesGiardia  lamblia:  oral-­‐fecal  spread,  contaminated  water  or  food  (cysts  are  not  killed  by  chlorination)  ,  noninvasive,  duodenum  and  jejunum,  diarrhea  and  malabsorptionCryptosporidium:  self-­‐limited  diarrhea  in  immunocomp  

left:  entamoeba  histolytica,  middle:  giardia,  right:  cryptosporidia  -­‐-­‐>  lots  of  mp

Pseudomembranous  Colitis

AKA  antibiotic  associated  colitis;  Acute  colitis  with  adherent  inflamm  exudate  (pseudomembrane)  overlying  sites  of  mucosal  injury,  usually  after  broad  spectrum  antibiotics  which  favor  the  overgrowth  of  Clostridium  difficile  over  other  gut  bacteria

diarrhea,  fever,  abdominal  pain Classically  assoc  w/  clindamycin  usage  but  also  seen  with  cephalosporins;  makes  a  toxin

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

TX:  oral  vancomycin  or  metronidazole

SI  tumors: Uncommon  site  for  benign  or  malignant  tumors

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

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

Peak  incidence  60s;  sx  depend  upon  the  hormone  secreted,  i.e.  gastrin  secreting  tumor  causes  Zollinger  Ellison  syndrome;  Carcinoid  syndrome  caused  by  vasoactive  compounds  rarely  occurs  in  GI  tract  carcinoids  due  to  first  pass  effect  thru  the  liver  unless  they  are  metastatic  

These  tumors  arise  in  the  GI  tract  from  endocrine  cells  which  secrete  hormones  which  coordinate  gut  function

Gross:  Intramural  or  submucosal  nodule,  Firm,  yellow-­‐tanMicro:Islands,  trabeculae,  glands  or  sheets  of  uniform  cells,  round  to  oval  nucleus  with  “salt  and  pepper”  nuclei  with  scant  ,pink  granular  cytoplasm;  Usually  minimal  pleomorphism

Prognosis  depends  on  location  with  those  in  the  jejunum  and  ileum  the  most  aggressive

Leiomyosarcoma  of  small  bowel

very  rare

Inflammatory  Bowel  disease

Chronic  bowel  disease  resulting  from  inapp  activation  of  mucosal  immune  response;  Due  to  reduced  frequency  of  enteric  infections,  the  immune  response  to  pathogens  is  poorly  regulated  resulting  in  an  overwhelming  immune  response  and  chronic  inflamm  disease  in  those  who  are  susceptible;  Acute  infectious  gastroenteritis  has  preceded  onset  of  IBD  in  some  individuals

More  common  in  femalesPresents  in  20’s  and  30’sMore  common  in  CaucasiansMost  common  in  N.  America,  northern  Europe  and  AustraliaHygiene  hypothesis  –  

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

Crohn’s  disease-­‐  may  involve  any  area  of  the  GI  tract  and  is  transmural

mild  D/F/abd  pain;  may  presents  w/  RLQ  pain,  bloody  D/F;  sx  free  periods  occur;  Attacks  can  be  precipitated  by  physical  or  emotional  distress,  specific  dietary  items;  Cigarette  smoking  assoc  w/  Crohn’s  and  disease  onset  has  occurred  w/  initiation  of  smoking  but  stopping  does  not  cause  remission

TRANSMURAL  INVOLVEMENT  Most  commonly  involved  sites  are  terminal  ileum,  ileocecal  valve,  and  cecum  but  may  involve  any  area  of  the  GI  tract  -­‐-­‐>  this  will  involve  entire  bowel  wall

morph:  Skip  lesions  –  areas  of  disease  interspersed  with  normal  areas;  Mucosa  has  cobblestone  appearance  (disease  tissue  is  depressed  below  the  normal  mucosa);  Mucosal  ulcers  may  coalesce  in  elongate  serpentine  ulcers  oriented  along  the  axis  of  the  bowel;  Mucosal  fissures  which  may  develop  b't  mucosal  folds  and  extend  thru  the  wall  become  fistula  tract  or  sites  of  perforation;  Strictures  are  common:  Wall  is  thickened  and  rubbery  due  to  transmural  edema,  inflamm,  submucosal  fibrosis  and  hypertrophy  of  the  muscularis  propria  which  contribute  to  stricture  formation;  Creeping  fat-­‐  Mesenteric  fat  may  extend  around  the  serosal  surface

micro:  Noncaseating  granulomas  –  a  hallmark  of  Crohn’s  seen  in  35%  in  active  or  uninvolved  regions  involving  any  layer  of  wall  and  may  occur  in  mesenteric  nodes;  cutaneous  granulomas  may  occur  (metastatic  Crohn’s);  Neutrophils  infiltrating  crypt  epi  and  may  form  crypt  abscesses  with  crypt  destruction;  Mucosal  ulcerations  with  intervening  normal  mucosaDistortion  of  mucosal  architecture  with  bizarre  branching  and  orientation  of  normally  straight  and  parallel  glands;  Metaplastic  change  -­‐  Pseudopyloric  metaplasia  and  Paneth  cell  metaplasia  in  left  colon

Complications:Malabsorption,  Fibrosing  strictures  req  surgical  resection;    freq  recurs  at  the  anastomotic  site;  Fistulae  formation  involving  adjacent  loops  of  bowel  or  strictures  such  as  bladder,  vagina  skin;  Colonic  disease  has  increased  risk  of  colonic  adenocarcinoma    w/long-­‐standing  colonic  disease;  Extraintestinalmanifestations  of  disease  include  uveitis,  migratory  polyarthritis,  sacroiliitis,  ankylosing  spondylitis,  erythema  nodosum,  clubbing;  Pericholangitis  and  sclerosing  cholangitis  may  occur  but  are  more  common  in  ulcerative  colitis

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXUlcerative  colitis disease  involves  the  mucosa  

and  submucosa  and  is  limited  to  colon  and  rectum  (unlike  crohn's);  relapsing  disorder    characterized  by  attacks  of  bloody  D  with  mucoid  material,  lower  abd  pain  and  cramps  temporarily  relieved  by  defecation;  

crypt  abscess  and  destruction  -­‐-­‐>  pic

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

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

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

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

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

Indeterminate  colitis Overlapping  signs  and  symptoms  of  Crohn’s  and  ulcerative  colitis

Overtime,  features  may  develop  that  help  establish  diagnosis  which  may  be  important  as  new  therapies  evolveMeckel  diverticulum A  blind  pouch  located  in  

distal  small  bowel  (ileum)  ;  MC  congenital  anomaly  of  SI;  results  from  failure  of  the  involution  of  the  omphalomesenteric  (vitelline)  duct;  ~1/2  contain  heterotopic  rests  of  gastric  mucosa  or  pancreatic  tissue;  The  rule  of  2’s:  2%  of  the  population,  2  inches  in  length,  2  feet  proximal  to  the  ileocecal  valve,  2  types  of  

most  asymp;  Overgrowth  of  bacteria  that  depletes  vit  B12  leading  to  anemia;  Ulcer  and  bleeding;  Obstruction

Most  cases  of  Meckel's  diverticulum  are  discovered  incidentally  during  surgical  procedures;  located  in  ileum

Acute  Appendicitis Acute  bacterial  infection  of  the  appendix  assoc  w/  obstruction  in  50-­‐80%  of  cases  usually  by  a  fecalith  and  less  commonly  by  a  gallstone,  tumor,  or  ball  of  worms  (enterobius  vermicularis)

periumbilical  pain  that  migrates  to  right  lower  quadrant,  nausea/vomiting,  anorexia,  tenderness  (direct  and  with  rebound)  at  McBurney’s  point,  leukocytosis

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

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

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXAngiodysplasia Characterized  by  malformed  

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

Mechanical  factors:  Norm  distension  and  contraction  of  colon  may  lead  to  intermittent  occlusion  of  submucosal  veins  causing  surface  vessels  to  b'c  congested  and  overdistended  w/  chronic  dilation  /tortuosity  developing  over  time;  degenerative  vascular  changes  related  to  aging;  Dev  component  -­‐  angiodysplasia  has  been  

morph:  Ectatic  nests  of  tortuous  veins,  venules,  and  capillaries,  Separation  of  the  vessels  from  the  bowel  lumen  may  be  only  the  blood  vessel  wall  and  a  layer  of  attenuated  epit  causing  increased  susceptibility  to  bleeding  by  only  minor  trauma

Diverticulosis Diverticulum:  blind  pouch  leading  off  alimentary  tract,  lined  by  mucosa  that  communicates  with  gut  lumen

Only  20%  develop  symptoms  –  due  to  infection  -­‐>  diverticulitis  (may  perforate)  or  cause  bleeding

Congenital:  have  all  3  layers  of  bowel  wall  (mucosa,  submucosa,  and  muscularis  propria)Acquired:    lack  or  have  attenuated  muscularis  propria  due  to  focal  weakness  in  wall  and  increased  intraluminal  P;  assoc  w/  Western  diets  (low  fiber  causes  prolonged  transit  time  and  increased  intraluminal  pressure  associated  with  low  volume  stools);  rare  in  Asia,  Africa,  South  America  where  high  residue  diet  is  common;Rare  before  age  30

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

Juvenile  polyps  (mostly  rectal,  present  with  bleeding);  Peutz-­‐Jeghers  syndrome  –  mostly  in  small  intestines  and  associated  with  mucocutaneous    hyperpigmentationCowden  syndrome  and  Bannayan-­‐Ruvalcaba-­‐Riley  syndrome    or  “PTEN  hamartoma  syndrome”;  Cronkite-­‐Canada  syndrome  –nonhereditary    but  unknown  cause  occurring  in  over  50  age  group  with  polyps  in  stomach,  SI  and  LI  with  cachexia,  weight  loss,  diarrhea,  with  50%  fatal

Peutz-­‐Jegher  polyps-­‐  MC  in  SI Arborizing  network  of  connective  tissue,  smooth  muscle,  lamina  propria  and  glands  which  may  have  a  complex  structure    lined  by  normal  appearing  epithelium

Increased  risk  fro  numerous  cancers  such  as  colon,  pancreas,  breast,  lung,  gonads,  etc.  BUT  the  polyps  themselves  are  NOT  preneoplastic  precursor  lesions

Familial  adenomatous  polyposis

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

FAP  variants:  1.  Gardner    syndrome  –  intestinal  polyps  and  osteomas  ofmandible  ,skull  and  long  bones,  dentla  abnormalities,  desmoid  tumors,  thyroid  tumors,  epidermal  cysts2.  Turcot  syndrome  –  intestinal  adenomas  and  tumors  of  the  CNS

Morphologically  indistinguishable  from  sporadic  adenomatous  polyp  except  FAP  may  also  have  flat  or  depressed  adenomas

these  are  precancerous;  Colorectal  CA  develops  in  100%  of  untreated  patients  before  age  30;  increase  risk  for  stomach  polyps  and  polyps  adjacent  to  the  ampulla  of  Vater

Standard  therapy  is  prophylactic  colectomy

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXHereditary  Non-­‐

polyposis  Colorectal  Cancer  (HNPCC)  

Occur  at  a  younger  age  than  sporadic  colon  cancers  and  often  located  in  right  colon;  

Caused  by  inherited  mutations  in  mismatch  repair  genes  encoding  proteins  responsible  for    the  detection,  excision  and  repair  of  errors  that  occur  during  DNA  replication;  Majority  of  HNPCC  involve  MSH2  and  MLH1  genes

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

Possibly  due  to  decreased  epithelial  cell  turnover  and  delayed  shedding  of  surface  epithelial  cell  which  then  “pile  up”;  imp  to  distinguish  from  sessile  serrated  adenomas  which  

Polyps  are  composed  of  mature  goblet  and  absorptive  cells  w/  crowding  that  creates  a  serrated  surface,  the  histo  hallmark  of  these  lesions  (on  the  surface  epithelium,  not  in  crypts

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

Classification  of  colonic  adenomas  based  on  architecture1)Tubular  adenomas  –  small  pedunculated  polyps  compose  of  small  rounded  or  tubular  glands2)Villous  –  larger  and  sessile  covered  by  slender  villi  and  contain  foci  of  of  invasion  more  frequently  than  tubular  adenomasRarely  secrete  large  amounts  of  protein  and  potassium  and  cause  hyp0proteinemic  hypokalemia3)Tubulovillous  –  mixture  of  tubular  and  villous  elements4)Sessile  serrated  adenomas-­‐  Serrated  architecture  like  hyperplastic  polyp;  however,  serration  also  involves  the  crypts  and  is  associated  with  lateral  growth  and  crypt  dilation.  Does  not  have  the  usual  app  of  dysplasia  but  are  considered  premalignant

morph:  Sessile  or  pedunculated  with  a  velvety  or  raspberry  surface;  Variable  size  with  those  less  than  1  cm  less  likely  to  harbor  a  malignancy;  however,  40%  of  lesions  large  than  4  cm  contain  foci  of  cancer;  epi  dysplasia  (usually  noted  at  surface  of  polyp  with  the  epithelium  on  the  stalk  being  benign)  with  nuclear  stratification,  enlarged,  elongated  hyperchromatic  nuclei

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

Colorectal  adenocarcinoma

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

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

Morphologic  and  molecular  changes  in  the  adenoma-­‐carcinoma  sequence  of  the  APC/B-­‐catenin  pathway  accounting  for  80%  of  sporadic  colon  tumors.  70%  of  FAP  has  a  mutation  in  APC  gene  

Morphologic  and  molecular  changes  in  the  mismatch  repair  pathway  of  colon  carcinogenesis.    These  molecular  alterations  are  common  in  sessile  serrated  adenomas.    Invasive  carcinomas  with  microstaellite  instability  often  have  prominent  mucinous  differentiation  and  lymphocytic  infiltrates  and  are  frequently  located  in  the  right  colon.  Important  to  identify  those  with  HNPCC  because  of  increased  of  malignancy  in  other  organs  as  well  as  increased  risk  for  a  second  colon  tumor.

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

 The  most  important  prognostic  factors  are  depth  of  invasion  and  presence  or  absence  of  lymph  node  metastases

metastatic  -­‐-­‐>  

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

Carcinomas  may  have  glandular  or  squamous  differentiation  or  basaloid  tumors  may  arise  from  the  basal  layer  of  transitional  epithelium;  These  different  tumor  types  may  occur  separately  or  be  mixed  together  as  wellSCC  of  the  anal  canal  is  frequently  STOMACH

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXPyloric  stenosis Due  to  hypertrophy  of  the  

muscularis  propria  of  the  pylorusCauses  gastric  outlet  obstruction

projectile  vomiting  beginning  in  2nd  week  of  life,  visible  waves  of  peristalsis,  epigastric    mass  (“olive”)

Associated  with  Turner  syndrome  and  Trisomy  18,  high  rate  of  concordance  in  monozygotic  twins

Congenital                                                                                      Diaphragmatic  Hernia  (CDH)

Defective  closure  of  diaphragm,  usually  left  sidedHernia  sac  usually  contains  all/part  of  stomach

Acute  gastritis Transient  mucosal  inflamm  process;  Factors  predisposing  to  gastritis:Excessive  alcohol  consumption,  non-­‐steroidal  anti-­‐inflammatory  drugs  (NSAIDS),  radiation    therapy,  chemotherapy,  decreased  oxygen,  uremia,  ingestion  of  acids  or  alkali

Asymptomatic  vs.  sympt  (epigastric  pain,  n/v    and  rarely  hematemesis)  

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

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

Acute  gastric  ulcerations

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

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

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

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

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

4  virulence  factors  in  H.  pylori:  Flagella  (motile  in  viscous  mucus)Urease  –  generates  ammonia  from  endogenous  urea,  elevating  gastric  pH;  Adhesin  –  enhance  bacterial  adhesion  to  epithelium;  Toxins  -­‐  cytotoxin-­‐associated  gene  A  (CagA)  which  may  increase  ulcer  or  cancer  risk

Gross:  occurs  MC  in  antrum  but  also  in  the  cardia  (uncommon  in  the  acid  producing  fundus  and  body)Infected  mucosa  may  be  red  with  coarse    or  nodular  appearance;    Micro:  (usually  antral  biopsy)  Spiral  or  curved  bacilli  within  surface  mucus  overlying  epithelial  cells;  Intraepithelial  neutrophils  and  subepithelial  plasma  cellsLong  standing  H.pylori  gastritis  may  involve  body  and  fundus  with  atrophic  mucosa  and  lymphoid  aggregates  with  potential  to  transform  into  a  MALT  lymphoma  (MALT  is  mucosa-­‐associated  lymphoid  tissue)

Histologic  ID,  Serology  for  H.  pylori  antibodiesUrea  breath  test  (based  on  generation  of  ammonia  by  bacterial  urease)  Rapid  urease  test  on  biopsiesDNA  detection  by  PCR

Abx  &  PPI

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXAutoimmune  gastritis Less  than  10%  of  chronic  

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

Median  age  at  diagnosis  is  60Women  slightly  more  than  menClinical  presentation-­‐  anemia,  possibly  atrophic  glossitis  other  manifestations  of  Vitamin  B12  deficiency,  especially  neurologicAssociated  with  other  autoimmune  disease  such  as  Hashimoto  thyroiditis,  insulin-­‐dependent  diabetes,  Graves  disease,  vitiligo,  myasthenia  gravis,  etc.Possible  complications-­‐  gastric  adenocarcinoma  and  carcinoid  tumors

Despite  presence  of  antibodies,  this  is  not  the  mechanism  for  injury  (transfer  of  antibodies  to  experimental  animals  does  NOT  produce  gastritis)CD4+  T  cells  are  directed  against  parietal  cell  components,  including  the  proton  pump  (transfer  of  CD4+  T  cells  against  the  proton  pump  into  experimental  animals  results  in  gastritis)Chief  cells  are  lost  also  in  the  gastric  gland  destruction,  even  though  there  is  no  autoimmune  response  against  them

Gross  :  Diffuse  atrophy  of  the  body  and  fundus  with  thinning  of  the  mucosa  and  loss  of  rugal  foldsWhen  atrophy  is  incomplete,  islands  of  oxyntic  (acid  producing)  cells  give  the  appearance  of  small  polyps;  Micro:Loss  of  parietal  and  chief  cells  with  lymphocyte,  macrophage  and  plasma  cell  infiltrate  (but  not  the  superficial  plasma  cells  of  H.Pylori)  and  lymphocyte  aggregates;Intestinal  metaplasiaAntral  endocrine  hyperplasia  (best  seen  on  special  stains)

Peptic  ulcer  disease  (PUD)

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

H.pylori-­‐induced  hyperchlorhydric  chronic  gastritis  is  associated  with  PUD  in  85  to  100%  of  duodenal  ulcers  and  65%  of  gastric  ulcers;  However,  only  20%  of  H.pylori  infected  people  develop  an  ulcer;  Location  of  MC  in  antrum  of  the  stomach  and1st  part  of  duodenum;May  also  occur  in  esophagus  and  a  Meckel’s  diverticulum

Gross:  Duodenal  ulcer  4  X  more  common  than  gastricDuodenal  ulcer-­‐1st  part  on  anterior  wall;  Gastric  ulcers  -­‐  lesser  curvature  near  antrum/body  interface;  Solitary  in  more  than  80%;Sharply  punched  out  defect  (heaped-­‐up  margins  are  more  characteristic  of  cancer  which  do  not  usually  develop  from  PU);  Micro:  Active  ulcers  have  fibrinoid  debris  with  underlying  neutrophilic  infiltrate  in  the  base;  w/  peptic  digestion  of  exudate,  base  of  ulcer  may  be  smooth  and  clean  w/  prominent  BV;  Granulation  tissue  beneath  base  w/  mononuclear  leukocytes  and  fibrous  tissue  or  scar  forms  

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

duodenal  ulcer  -­‐-­‐>  

Hypertrophic  gastropathy

May  mimic  infiltrative  carcinoma  or  lymphoma  of  stomach  on  endoscopic  and  radiographic  examination;  3  variants:  1.  menetrier  disease,  2.  Hypertrophic-­‐hypersecretory  gastropathy,  

Menetrier  Disease M:F~3:1;  Middle-­‐aged;Gastric  secretions  have  excess  mucus  and  decreased  acid  (diff  than  ulcer  disease

epigastric  discomfort,  diarrhea,  weight  loss

Gross:  enlarged  rugal  foldsMicro:  marked  foveolar  hyperplasia  with  replacement  of  parietal  and  chief  cells

Increased  risk  of  mucosal  metaplasia  and  gastric  cancer

Zollinger-­‐Ellison  syndrome

Gastrinoma  (typically  in  duodenum  or  pancreas)Increased  acid  secretionDuodenal,  gastric,  jejunal  ulcers

epigastric  discomfort/pain,  diarrhea

Associated  with  MEN1 Gross:  enlarged  rugal  foldsMicro:  gastric  gland  and  parietal  cell  hyperplasia

Gastric  polyps Inflammatory/hyperplastic  polyps  (75%  of  gastric  polypsFundic  gland  polypsGastric  adenoma

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXInflammatory/hyperplastic  polyp

Age  50  to  60  yearsPolyps  associated  with  chronic  gastritis

Injury  from  gastritis  stimulates  reactive  hyperplasia  leading  to  polyp  growth

Gross:  polyps  usually  smaller  than  1  cm,  frequently  multiple,  and  smooth,  oval  with  erosions;  Micro:  irregular,  cystically  dilated  foveolar  glands  with  edema,  inflammation  of  lamina  propria  and  possible  surface  ulceration

Risk  of  dysplasia  in  polyps  greater  than  1.5  cm

In  H.Pylori  gastritis,  polyps  may  regress  with  Rx

Fundic  gland  polyp  (PPI  association)

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

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

Gross:  Well  circumscribed,  smooth  and  may  be  multiple  or  singleMicro:  Cystically  dilated  glands  lined  by  flattened  parietal  and  chief  cells  with  

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

Adenomas  occur  in  a  background  of  chronic  gastritis  with  atrophy  and  intestinal  metaplasia

Gross:  Usually  solitary  in  the  antrumMicro:  Intestinal  type  of  columnar  epithelium  with  dysplasia,  high  or  low  grade  

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

gastric  tumorsGastric  adenocarcinoma

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

Early  Sx  -­‐  dysphagia,  dyspepsia  and  nauseaAdvanced  stage  –  weight  loss,  anorexia,  anemia,  hemorrhage

genetics:  Familial  gastric  cancer  –  Germline  mutations  in  CDH1  which  encodes  E-­‐cadherin  (adhesion  promoter)Loss  of  E-­‐cadherin  function  may  be  key  step  in  development  of  diffuse  gastric  CACDH1  mutations  also  common  in  lobular  CA  of  breast  with  loss  of  E-­‐cadherin  (remember  single  file  invasive  lobular  carcinoma)  BRCA  2  mutations  have  increased  gastric  CA  riskSporadic  cases  may  have  CDH1  mutations  and  multiple  other  genetic  abnormalites  

Gross:  Most  involve  the  antrum,  lesser  more  than  greater  curvatureExophytic  mass  or  an  ulcerated  tumor  form  with  intestinal  typeDiffuse  infiltrative  tumor  (linitis  plastica  or  a  “leather  bottle”  look)  with  thickened  stiff  wall  and  loss  of  rugae;  Micro:  (mucin  lakes  may  occur  in  both  types)

Most  important  prognostic  factors  are  depth  of  invasion  and  the  extent  of  nodal  and  distant  metastasis  at  the  time  of  diagnosisOver  5  year  survival  in  the  US  is  only  30%  since  most  cases  are  advanced  at  Dx.MetastasisLeft  supraclavicular  lymph  node  -­‐>  Virchow  nodeOne  or  both  ovaries  -­‐>  Krukenberg  tumorPeriumbilical  -­‐>  Sister  Mary  Joseph  nodule

intestinal  type Males>  females  2:1Risk  factors:  diet  (nitrites,  smoked  food),  chronic  gastritis  (H.  pylori),  antral  gastrectomy,  smoking,  

Occurs  in  setting  of  intestinal  metaplasia  and  mucosal  atrophy

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

diffuse  type Similar  frequency  in  males  and  femalesNo  well  defined  risk  factors  (no  known  relation  to  H.  pylori)

top  is  intestinal  type  composed  of  columnar,  gland-­‐forming  

infiltrating  thru  desmoplastic  stroma;  bottom  is  signet-­‐ring  cell  

in  diffuse  type

Signet  ring  cell  morph    in  desmoplastic  stroma;  Linitis  plastica  (“leather  bottle”  stomach)

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

gastric  MALToma

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

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

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

Gastrointestinal  stromal  tumor  (GIST)

Most  common  mesenchymal  tumor  of  the  abdomen  with  more  than  half  affecting  the  stomachSlightly  more  common  in  males  with  peak  age  at  diagnosis  ~60  years  oldSlightly  increase  incidence  in  neurofibromatosis  IMay  occur  in  children  as  part  of  Carney  triad  (NOT  to  be  confused  with  Carney  complex  of  atrial  myxomas)  which  is  seen  in  females  and  includes  GIST,  paraganglioma,  and  pulmonary  chondroma

Presenting  symptoms  may  be  related  to  mass  effect  or  anemia  due  to  chronic  blood  loss  from  mucosal  ulceration  or  an  incidental  finding

GIST  may  arise  from  or  share  a  common  stem  cell  with  the  interstitial  cells  of  Cajal  (cells  in  the  muscularis  propria  which  act  as  pacemaker  cells  for  gut  peristalsis);  Mut  of  the  c-­‐KIT  gene  or  PDGFRA  gene(platelet  derived  growth  factor  receptor  alpha)  w/  their  activity  promoting  tumor  cell  prolif  &  survival  which  is  usually  sporadic  w/  rare  germline  mutations

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

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

spindle  cell  tumor  -­‐-­‐>  

PERITONEUM The  peritoneal  cavity  contains  the  abdominal  vsiceral  organs  The  peritoneal  cavity  is  lined  by  a  single  layer  of  cuboidal  mesothelial  cells  covering  the  visceral  and  the  parietal  surfacesThe  peritoneum  is  formed  by  the  mesothelial  cells  overlying  a  thin  layer  of  connective  tissue  

Peritoneal  cavity  –  Inflammatory  diseases:  •  Peritonitis  due  to  a  variety  of  causes,  i.e.  bile  irritation  due  to  leakage  or  rupture  of  biliary  system,  pancreatitis,  foreign  material,  endometriosis,  perforation•  Bacterial  peritonitis  typically  occurs  with  perforation  of  GI  lumen  causing  release  of  bacteria  into  peritoneal  cavity  associated  with  disease  such  as  appendicitis,  peptic  ulcer,  cholecytitis,  diverticulitis,  intestinal  ischemia.

•  Additionally  ,  trauma,  peritoneal  dialysis,  acute  salpingitis  may  introduce  bacteria  into  peritoneum•  Spontaneous  bacterial  peritonitis  develops  without  obvious  source  and  associated  with  liver  cirrhosis  and  ascites  and  in  children  with  nephrotic  syndrome

acute  peritonitis Gross:  Tan  to  yellow  exudate  on  serosal  surfaces,  Purulent  fluid  may  collect;  Micro:  Neutrophils  and  fibrinous  material,  abscesses  may  form,  w/  resolution,  may  have  fibrous  adhesions

Sclerosing  Retroperitonitis

An  uncommon  cause  of  ureteral  obstruction  characterized  by  fibrous  proliferative  inflammatory  process  which  encases    retroperitoneal  structuresCauses  include  certain  drugs  (ergots,  beta-­‐blockers),  adjacent  inflammatory  conditions  such  as  diverticulitis  or  Crohn’s,  malignant  disease

70%  are  idiopathic  (Ormond  disease);  may  be  assoc  w/:    Riedel’s  fibrosing  thyroiditis,    other  fibrosing  diseases  such  as  Riedel’s  thyroiditis,  mediastinal  fibrosis  and  sclerosing  cholangitis  suggesting  that  the  disorder  is  systemic,  autoimmune  etiologyMicroscopic  exam  shows  fibrosis  with  a  prominent  infiltrate  of  lymphocytes,  plasma  cells  and  eosinophils

Primary  Tumors  of  peritoneum

Mesotheliomas  –  also  associated  with  asbestos  exposure  (swallowed  asbestos  fibers  may  penetrate  the  gut)Desmoplastic  small  round  cell  tumor  in  children  and  young  adults  (resembles  Ewing  sarcoma

Secondary  tumors  of  peritoneum

 direct  spread  or  metastatic  seeding  Pancreatic  and  ovarian  adenocarcinoma  are  the  most  commonly  tumors  to  produce  serosal  implants

Pseudomyxomatous  peritoneii  (extensive  mucinous  ascites,  cystic  epithelial  implants  on  peritoneal  surfaces,  adhesions)  seen  with  ovarian  mucinous  tumors  and  appendiceal  mucinous  carcinomas

LIVERDISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXHepatic  failure May  be  sudden  and  massive  

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

Failure  of  hepatocytes  to  perform  homeostatic  functions:  Jaundice,  Hypoalbuminemia,  coagulopathy  due  to  impaired  synthesis  of  clotting  factor;  Fetor  hepaticus  –  Musty  body  odor  due  to  formation  of  mercaptans  by  action  of  GI  bacteria  on  the  sulfur  containing  methinonine  and  subseq  portosystemic  shunting  of  blood;  Dec.  estrogen  metabolism  w/  elevated  estrogens  felt  to  resp  from  spider  angiomas,  palmar  erythema,    male  hypogonadism  and  gynecomastia

Hepatic  encephalopathy  –  CNS  dysfxn  due  to  inc.  ammonia  levels  (Alzheimer  type  II  astrocytes);Hepatorenal  syndrome  –  renal  failure  w/no  intrinsic  renal  defect  as  a  causative  factor  overall  due  to  dec.  renal  perfusion  P;  Hepatopulmonary  syndrome  -­‐chronic  liver  disease,  hypoxemia  and  intrapulm  vasc  dilations  causing  V/Q  mismatch;  enhanced  prod  of  NO  is  key  mediator;  Acute  liver  failure  defined  as  acute  liver  illness  assoc  w/  encephalopathy  w/in  6  mths  after  Dx  (fulminant  if  within  3  months)

Cirrhosis 12th  MC  cause  of  death  in  US  w/  main  causes  of  cirrhosis  being  alcohol  abuse,  viral  hepatitis  C,  and  non-­‐alcoholic  steatohepatitis  (NASH)

aympt  until  late  in  course  of  disease;  Non-­‐specific  sx  such  as  anorexia,  wt  loss,  weakness  and  hepatic  failure

Central  pathogenic  processes  are:1)  Death  of  hepatocytes2)  Extracellular  matrix  (ECM)  deposition:  fibrosis  due  to  prolif  and  activation  of  hepatic  stellate  cells  into  highly  fibrogenic  cells  along  with  portal  fibroblasts  and  other  cells;  3)  Vascular  reorg  w/  impairment  of  blood  supply  to  hepatocytes  and  impaired  ability  of  hepatocytes  to  secrete  substances  into  blood:  new  vascular  channels  in  fibrotic  septa  connect  vessels  in  portal  region  to  the  central  vein,  bypassing  the  parenchyma;  collagen  in  the  space  of  Disse  results  in  loss  of  sinusoidal  fenestration  impairing  the  exchange  of  solutes  b't  hepatocytes  and  blood

morph:  Bridging  fibrosis  linking  portal  tracts  to  each  other  and  portal  tracts  to  central  veins;  Parenchymal  nodules  –  hepatocytes  encricled  by  fiborsis  rangin  from  small  or  micronodular  (less  than  3  mm  )  to  large  (macronodular);  disruption  of  architecture  of  entire  liver  –  Parenchymal  injury  and  fibrosis  is  DIFFUSE,  not  just  a  focal  injury  -­‐-­‐>  affects  entire  liver

Trichrome  Stain  -­‐-­‐>  highlights  collagen  in  fibrosis

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

portal  HTN Increased  resistance  to  portal  blood  flow  due  predominantly  to  cirrhosis

Ascites  –clinically  detectable  clinically  at  500  cc  -­‐>Sinusoidal  HTN  and  hypoalbuminia  (dec.  oncotic  pressure)  drives  fluid  into  space  of  Disse,  then  removed  by  hepatic  lymphatics  -­‐>  lymph  exceeds  capacity  of  the  thoracic  duct  and  leaks  into  peritoneal  cavity;  splanchnic  vasodil  &  hyperdynamic  circ  lowers  systemic  P  triggering  activation  of  vasoconstrictors  and  ADH  -­‐>  increases  perfusion  P  of  interstitial  capillaries  and  causes  extravastion  of  fluid  into    abd

Increased  resistance  to  portal  flow  at  sinusoidal  level  due  to:Smooth  mm  contraction;  disrupted  blood  flow  from  scarring;  parenchymal  nodules;  Increase  in  portal  venous  blood  flow  due  to  increased  splanchnic  arterial  blood  flow  due  to  vasodilation  from  increased  NO  production  mostly  (also  prostacyclin  and  TNF);  the  theory  is  that  NO  prod  is  stim  by  red.  clearance  of  bacterial  DNA  absorbed  form  the  gut,  shunting  of  blood  from  portal  to  systemic  system  bypasses  Kupffer  cells  in  liver

clinical  cont….Portosystemic  shunts  –  venous  bypasses  around  the  liver  to  get  to  systemic  circ  thru  shared  capillary  beds:  1.  Esophagogastsirc  junction  –  esophageal  varices,    2.  hemorrhoids,  3.  retroperitoneal,  4.  Falciform  ligament    (involves  periumbilical  and  abd  wall  collaterals  appearing  as  caput  medusae,  dilated  SX  veins  extending  from  the  umbilicus);  Congestive  splenomegaly  –  may  have  thrombocytopenia  or  pancytopenia

Jaundice   aka  icterus;  describes  yellow  discoloration  of  the  skin,  mucous  membranes  and  eyes  (conjunctiva  over  the  sclera)  due  to  retention  of  bilirubin;  Bilirubin  is  the  end-­‐product  of  heme  degradation

Normal  source  of  bilirubin:  the  breakdown  of  senescent  red  blood  cells  in  the  spleen  releases  heme  that  changes  into  bilirubin  by  specific  enzymatic  reactions    

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

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

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

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

 accum  of  bile  pigment  in  the  hepatic  parenchyma;  elongated  bile  plugs  are  visible  in  dilated  bile  canaliculi;  Rupture  of  canaliculi  causes  extravastion  of  bile  with  ingestion  by  Kupffer  cells;  Bile  droplets  may  accum  w/in  hepatocytes  and  have  a  fine  foamy  app  (feathery  degeneration);  bile  duct  prolif  in  portal  triads  induced  by  bile  stasis  and  back-­‐pressure;  bile  lakes  may  occur  with  dissolution  of  hepatocytes;  unrelieved  obstruction  leads  to  fibrosis  and  ultimately  to  biliary  cirrhosis

GGT  (gamma-­‐glutamyl  transpeptidase)  and  serum  alkaline  phosphatase  are  characteristically  elevated  (plasma  membrane  enzymes  from  damage  to  bile  canaliculus)

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

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

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

Hepatitis Inflammation  of  LiverViral,  Alcohol,  immune,  Drugs  &  ToxinsAcute,  Chronic  &  Fulminant  -­‐  types

viral    Heterotropic  viruses  –  Hepatitis  A,  B,  C,  D,  ESystemic  -­‐    CMV,  EBV,  yellow  fever  from  a  Flavivirus  transmitted  by  mosquitos  in  the  tropics

Asymp;acute  infection  may  be  found  incidentally  by  elevated  serum  transaminases  HAV  and  HVB  may  be  asymptomatic    in  childhood  and  maybe  found  later  on  by  

acute  hepatitis 4  phases:  Incubation  period,  sympt  preicteric  phase,  sympt  icteric  phase,  convalescence

Hepatocyte  swelling  (balloon  cells)  and  apoptosis  (Councilman’s  bodies  -­‐>  see  arrows  in  pic  on  right);  inflammation  –  Mixed  inflamm  infiltrate  in  portal  tracts,  mp  aggregates  in  the  lobule;  

Hepatocyte  necrosis  –  isolated  cells  or  clusters:  Piecemeal  necrosis  or  interface  hepatitis  Inflmmation  siplees  over  from  the  protal  tract  to  the  adjacent  heaptocytes  (limiting  plate),  Bridging  necrosis;  Mild  fatty  change  –  HCV;  Cholestasis  –  canalicular  bile  plugs;  Regenerative  changes  –  hepatocyte  regeneration

Chronic  Hepatitis Lymphoid  aggregates,  mp,  occ.  plasma  cells  and  bile  duct  reactive  changes  in  portal  tracts;  Inflamm  form  portal  tracts  may  spill  into  adjacent  parenchyma  –  interface  hepatitis

Scattered  hepatocyte  apoptosis,  Fibrosis  –  Early  fibrous  expansion  of  portal  tract,  then  septal  fibrosis  advancing  to  bridging  fibrosis  and  ultimately  cirrhosis;  ground  glass  hepatocytes  (in  pic  on  right)  –  HBV;  mild  fatty  change  –  HCV

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

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

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

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXHepatitis  A  virus ssRNA  virus  (related  to  

picornavirus);  fecal-­‐oral  transmission(contaminated  water  and  food);  Incubation  period:  2-­‐6  weeks;  Virus  shedding:  2-­‐3  weeks  b/f  and  1  wk  after  app  of  jaundice;  50%  of  population  above  age  50  are  seropositive  in  USA,  no  carrier  state

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

No  increased  risk  for  chronic  hepatitis,  or  carcinoma

Effective  vaccine  available

Hepatitis  B  virus dsDNA  virus  (Hepadnavirus);  parenteral  transmission  (blood  products,  contam  needles  and  IV  drug  abuse),  sexual,  perinatal  transmission  during  childbirth  (vertical  transmission);  Incubation    4-­‐26  weeks

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

Effective  vaccine  available

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

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

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

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

Acute  coinfection  with  HBV;  Superinfection  when  a  chronic  HBV  carrier  contracts  HDV;  Helper-­‐indep  latent  infection  seen  in  liver  transplants    (HDV  is  in  nuclei  of  grafted  liver  hours  after  transplant  but  HBV  initially  suppressed  by  Hep  B  immunoglobulin  to  prevent  reinfection  but  eventually  HBV  escapes  neutralization  and  coinfects  the  cell)    

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

Epidemics  in  certain  populations;  Indian  subcontinent,  sub-­‐Saharan  Africa,  Mexico

Self-­‐limited  infection  (no  chronic  disease)  but  with  higher  mortality  of  approximately  20%  in  pregnant  females

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

Ingestion  of  food  (i.e.  sheep)contaminated  with  eggs  released  by  infected  dogs  (E.  granulosis)  or  foxes  (E.  multilocularis,  rare  but  most  virulent)  -­‐>Eggs  hatch  in  small  intestine  and  release  oncospheres  which  invade  liver,  lungs,  bones  and  rarely  brain  -­‐>Cysts  form  mostly  in  the  liver  with  5  to  15%  in  the  lungs  and  the  rest  in  bones,  brain  or  other  organs  -­‐>Cyst  DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

Autoimmune  hepatitis

Female  preponderance  (young  and  perimenopausal);  Classified  into  type  I  and  type  II  based  on  patterns  of  circulating  antibodiesType  I  more  common  in  US  and  associated  with  HLA-­‐DR3  serotype

Clinical  presentation  may  be  acute  (40%),  w/  a  fulminant  presentation  or  may  be  asymp  and  progress  to  cirrhosis  w/o  a  clinical  dx

 T  cell-­‐med  autoimmunity  due  to  genetic  factors  and  possibly  triggered  by  viral  infections  or  certain  drugs;  assoc  w/  other  autoimmune  diseases    such  as  SLE,  RA,  celiac  disease,  thyroiditis,  etc

histo:  autoimmune  hepatitis  is  clusters  of  plasma  cells  at  the  junction  of  the  portal  tract  and  adjacent    hepatocytes  (interphase  hepatitis);  May  progress  to  cirrhosis

Mortality  of  severe  untreated  autoimmune  hepatitis  is  ~40%  within  6  months  of  diagnosis  with  cirrhosis  developing  in  40%  of  survivors;  10    year  survival  in  liver  transplanted  pts  is  75%  but  disease  recurs  in  22  to  42%

immunosuppressive  drugs  and  transplant  in  end  stage  disease

Drug  and  toxin  induced  liver  disease

Drug  induced  liver  injury  is  the  MC  cause  of  fulminant  hepatitis;  Genetic  susceptibility;  Predictable  (intrinsic)  or  unpredictable  (idiosyncratic);  Predictable  rxns  occur  with  OD  of  acetaminophen,  Amanita  phalloides  toxin,  CCl4,  alcohol  but  genetics  does  play  a  role  in  individual  susceptibility;Idiosyncratic  reactions  may  be  assoc  w/  abx  ,allopurinol,  anti-­‐seizure  meds

Injury  results  from:1)  Direct  cellular  toxicity  to  hepatocytes  or  biliary  epithelial  cells2)  Hepatic  conversion  of  a  xenobiotic  to  an  active  toxin3)  Immune  mechs  (drug  or  metabolite)  acts  as  a  hapten  converting  a  cellular  protein  into  an  immunogen

Alcoholic  liver  disease Amount  of  alcohol  to  cause  liver  injury:  1.Short-­‐term  ingestion  of  80  g  (6  beers/8  ounces  of  80-­‐proof  liquor)  of  ethanol  over  one  to  several  days  leads  to  reversible  steatosis;  2.  Daily  intake  of  80  g  or  more  leads  to  significant  risk  of  severe  hepatic  injury;3.  Daily  ingestion  of  160  g  for  10-­‐20  years  consistently  leads  to  severe  injury

Other  factors  influencing  the  severity  and  risk  of  developing  alcoholic  liver  disease  are  gender  (F>M),  AA>C,  Genetic  factors;  Co-­‐morbid  conditions  such  as  HCV  or  HBV

Ethanol  causes  steatosis,  dysfunction  of  mitochondrial  and  cellular  membranes,  hypoxia  and  oxidative  stress:  1.  Acetaldehyde  (major  intermediate  metabolite  of  ethanol)  disrupts  cytoskeletal  and  membrane  function;  2.Cytochrome  P-­‐450  metab  prod  rxn  02  species;  3.Ethanol  induces  cytochrome  P-­‐450  enzymes  enhances  conversion  of  other  drugs  to  toxic  metabolites;4.    Steatosis  results  from  shunting  of  substrates  away  from  catabolism  and  toward  lipid  biosynthesis  due  to  excess  red  NADH+H  prod  as  a  result  of  alcohol  metabolism  by  alcohol  dehydrog  &  acetaldehyde  dehydrog;  5.  Impaired  assembly/secretion  of  lipotrotein  and  inc.  peripheral  catabolism  of  fat

Hepatic  steatosis  -­‐  reversible  Gross-­‐yellow,  greasy  liver  in  severe  steatosisMicro-­‐microvesicular  lipid  droplets  in  hepatocytes  becoming  macrovesicular  globules  w/chronic  intake  ;  Alcoholic  hepatitis:  Hepatocyte  swelling  (ballooning)  and  necrosis,  Mallory  bodies  (clumps  of  cytokeratin  complexed  with  other  proteins)  not  specific  for  alcoholic  hepatitis,  Neutrophilic  reaction,Fibrosis  (sinusoidal  and  perivenular;  occ.  periportal);Cirrhosis  ~10  to  15%    

mallory  bodies  -­‐-­‐>  

steatosis  is  reversible!!

Nonalcoholic  fatty  liver  disease  (NAFLD)

A  group  of  conditions  w/  hepatic  steatosis  in  person  who  do  not  drink  alcohol;  MC  cause  of  chronic  liver  disease  in  the  US;Diseases  include  simple  hepatic  steatosis,  steatosis  with  minor,  non-­‐specific  inflamm  and  non-­‐alcoholic  steatohepatitis  

1)  Hepatic  fat  accumulation  2)  Hepatic  oxidative  stress:  Oxid  stress  acts  on  the  hepatic  lipis,  resulting  in  lipid  peroxidation  and  release  of  lipid  peroxides  which  can  preduce  reactive  oxygen  species

morph:  Steatosis  -­‐  macrovesicular  and  microvesicular  steatosis,  predominantly  triglycerides;  NASH  has  steatosis  and  multifocal  parenchyma  inflamm(neutrophils),  Mallory  bodies,  hepatocyte  death  and  sinusoidal,  venular  and/or  portal  fibrosis;May  progress  to  cirrhosis

steatosis  -­‐-­‐>  

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

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

Primary  –  AR  disorder  caused  by  excessive  iron  absorption  (HFE  gene  on  chromosome  6);    Secondary  or  Acquired  -­‐>called  hemosiderosis  (example  would  be  excessive  blood  transfusions  causing  excess  iron)  

Micronodular  liver  cirrhosis,  skin  pigmentation  (bronzing)  ,  diabetes  mellitus(pancreatic  fibrosis)200X  increased  risk  for  hepatocellular  carcinoma;  Heart  involvement  leading  to  CHF  &  arrythmias,  hypogonadism

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

Wilson  Disease AR  disorder  characterized  by  accum  of  copper  in  liver,  brain,  eyes,  other  organs

neuropsychiatric  manifestations,  acute  and  chronic  liver  disease  and  Kayser-­‐Fleisher  rings  in  the  cornea  (green  to  brown  deposits  -­‐-­‐>  see  pic)  

The  mut  gene  (ATP7B)  is  located  on  chrom  13;  the  mutation  leads  to  failure  to  excrete  copper  into  bile,  ,  impairs  its  incorporation  into  ceruloplasmin  and  inhibits  ceruloplasmin  secretion  in  blood  

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

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

Alpha  1-­‐antitrypsin  deficiency

Fxn  of  alpha  1-­‐antitrypsin  is  to  inhibit  proteases;  def  leads  to  liver  disease  (due  to  accum  of  the  abn  alpha  1-­‐antitrypsin  protein  in  hepatocytes)  and  emphysema  due  to  uninhibited  proteases;Alpha  1-­‐antitrypsin  def-­‐>MC  dx  genetic  hepatic  disorder  in  infants  and  children

Round  to  oval  cytoplasmic  globular  eosinophlic    inclusions  in  hepatocytes  (PAS  positive,  diastase  resistant);  Most  of  the  globule  containing  hepatocytes  are  around  the  portal  tracts;  #  of  globules  are  not  correlated  with  severity  of  disease;  Liver  disease  is  variable  -­‐  neonatal  hepatitis  to  childhood  cirrhosis  to  chronic  inflam  hepatitis  

Primary  biliary  cirrhosis  (PBC)

likely  an  autoimmune  disease  causing  inflamm  destruction  of  med-­‐sized  intrahepatic  bile  ducts;  F>M,  ages  40-­‐  50;    Family  members  at  inc  risk

Insidious  onset  w/o  sx  for  yrs;  present  w/  fatigue  and  pruritis;HM,  eyelid  xanthelasmas;  Hyperpigmentation  due  to  melanin  deposition  and  inflamm  arthropathy;  +  anti-­‐mitochondrial  antibodies  in  95%  pts;  Elevated  alkaline  phosphatase,  gamma-­‐glutamyltransferase  and  chol;  Hyperbilirubinemia  is  a  late  dev  usually  signifying  incipient  hepatic  decomp;  

 unknown  with  likely  genetic  and  environmental  factors

Focal  and  variable  disease  -­‐  Pre-­‐cirrhosis  –  lymphocyte,  plasma  cell,  mp  infiltrates  in  the  portal  tracts  with  occ.  eosinophil;  Bile  ducts  infiltrated  by  lymphocytes  and  may  have  noncaseating  gran.  inflamm  w/  (see  pic  -­‐-­‐>  )  prog  destruction  and  obst.;  Portal  tracts  upstream  from  damage  bile  ducts  show  bile  ductular  prolif,  inflamm,  necrosis;Cholestasis,  liver  may  look  green;  fibrosis  and  cirrhosis  develops

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

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

Secondary  biliary  cirrhosis

due  to  prolonged  obs  of  the  extrahepatic  biliary  tree  w/  cholestasis,  then  secondary  inflamm  initiating  periportal  fibrosis  and  eventual  cirrhosis  Some  causes  include:Choledocholithaisis,  Malignancies,  Congenital  anomalies  (bilialry  atresis,  

May  develop  ascending  cholangitis  with  partial  obstruction

 Conjugated  hyperbilirubinemia,  inc:    alkaline  phosphatase,    bile  acids,    GGT&  chol

Primary  sclerosing  cholangitis  (PSC)

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

Asympt  w/  persistent  elevation  of  alk  phos;  Fatigue,  pruritis,  jaundice;  can  dev.  cholangiocarcinoma

Autoimmune  etiology  is  likely  as  evidenced  by:  Detection  of  T  cells  in  periductal  stroma  {T  cells  activated  in  gut  mucosa  (normally  reacting  to  gut  antigens  or  bacterial  antigens)  travel  to  liver  and  cross  react    with  bile  duct  antigens};  Numerous  circulating  autoantibodies  (Anti-­‐smooth  

Concentric  peri-­‐ductal  fibrosis  or    “onion-­‐skin  fibrosis”  -­‐>  replaced  by  a  solid,  cordlike  fibrous  scar;  Other  portions  of  Bile  ducts  b'c  ectatic  and  inflamed  from  downstream;  bstruction  due  to  bile  duct  fibrosis;  Cholestasis;  Eventual  biliary  cirrhosis

Inc.  incidence  of  chronic  pancreatitis  and  hepatocellular  carcioma

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

BENIGN  HEPATIC  MASSES:DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXNodular  hyperplasias Not  neoplastic,  Single  or  

multiple;  due  to  alteration  in  blood  supply  (increase  in  arterial  branches  unaccomp  by  portal  branches)

Two  main  types:  1.  Focal  nodular  hyperplasia,  assoc  w/  long-­‐term  use  of  anabolic  hormones  and  OC;  2.  Nodular  regenerative  hyperplasia

 Gross:  well  demarcated  but  poorly  encapsulated  nodule,  lighter  than  surrounding  liver  frequently  with  a  central  gray-­‐white  stellate  scar  Micro:  Central  scar  contains  large  vessels,  usually  arterial  showing  fibromuscular  hyperplasia  and  narrowing  or  the  lumen;  Radiating  fibrous  septa  have    lymphocytic  infiltrates  and  bile  duct  prolif;  Hepatocytes  between  the  septa  are  norm  but  lack  normal  sinusoidal  plate  architecture

Nodular  regenerative  hyperplasia

Nodular  regenerative  hyperplasia  occurs  in  conditions  affecting  intrahepatic  blood  flow  such  as  solid-­‐organ  transplantation  (particularly  renal  with  azothioprine  use)  vasculitis,    autoimmune  disorders,  hematologic  malignancies,  HIV  

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

Cavernous  Hemangioma

MC  benign  liver  tumors  and  are  soft  red-­‐blue  nodules,  usually  less  than  2  cm  and  frequently  located  directly  beneath  the  capsule;  Histology-­‐vascular  channels  in  fibrous  CT

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

Hormones  are  assoc  w/  their  dev  but  cause  is  unknown;  Mut  in  genes  encoding  TF  HNF1alpha  and  B-­‐catenin  have  been  found;  Multiple  hepatic  adenoma  syndromes  can  occur  in  maturity  onset  diabetes  of  the  young  with  HNF1  mutations

Gross:  Usually  solitary  (but  may  be  multiple)  nodule  which  is  pale,  yellow-­‐tan,  possibly  bile  stained,  well  demarcated  but  not  always  encapsulated  located  anywhere  in  the  liver  (often  beneath  capsule)  and  may  be  up  to  30  cm  in  sizeMicro:sheets  and  cords  of  hepatocytes  which  may  be  normal  or  have  variation  in  cell  and  nuclear  size  with  possible  steatosis  or  presence  of  glycogen;  Absent  portal  tracts  with  solitary  arteries  and  veins  in  tumor

May  be  mistaken  for  hepatocellular  CAMay  transform  into  hepatocellular  CA

MALIGNANT  TUMORS:Angiosarcomas rare  tumor  assoc  w/  vinyl  

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

Characteristic  feature  is  activation  of  WNT/B-­‐catenin  signaling  pathway;  assoc  w/FAP  syndrome  and  Beckwith-­‐Wiedmann  syndromeDISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

Hepatocellular  carcinoma(HCC)

Globally,  3rd  most  freq  cause  of  cancer  deaths  mostly  due  to  chronic  HBV  infection  in  dev  world;    Cirrhosis  is  absent  in  half  the  cases;  in  US,  HCC  usually  assoc  w/  cirrhosis  in  75  to  90%  of  cases  from  various  chronic  liver  diseases  including  HCV;  M>F;    Four  major  etiologic  factors:1.  Chronic  viral  infection  (HBV,HCV)2.  Chronic  alcoholism3.  Non-­‐alcoholic  steatohepatitis  (NASH)4.  Food  contaminants  (primarily  aflatoxins)

nonspecific  sx,  masked  by  the  underlying  liver  disease;  

Poor  5  year  survival  with  most  patients  dead  in  2  years

Exposure  to  aflatoxins    in  peanuts  and  grain  binds  with  DNA  causing  a  specific  mutation  in  p53;Repeated  cycles  of  cell  death  and  regen  such  as  seen  in  chronic  hepatitis  of  any  cause;  Continuous  cycles  of  cell  division  may  damage  DNA  repair  mechanisms  with  subsequent  accum  of  mut;  Global  gene  expression  studies  show  that  50%  of  HCC  are  assoc  w/  activation  of  WNT  or  AKT  pathways;  HBV    gene  integration  into  cell’s  DNA  may  activate  protooncogenes

gross:  Unifocal,  multifocal  or  diffusely  infiltrative  w/  possible  liver  enlargementi  n  all  3  patterns;  More  pale  than  surrounding  liver  or  may  appear  green  if  malignant  hepatocytes  are  secreting  bile;  Strong  propensity  to  invade  vasc  structures  w/metastases;  Invasion  of  portal  vein  may  cause  occlusion  of  portal  circ  or  IVC;  can  get  lung  and  lymph  mets  late  in  disease;  histo:Well-­‐diff    w/  malignant  hepatocytes  in  trabecular  or  pseudoglandular  architecture;  varying  from  large  giant  cells  to  small  cells  to  a  spindled  sarcomatous  appearance

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

Poor  5  year  survival  with  most  patients  dead  in  2  years

Fibrolamellar  carcinoma

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

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

Better  prognosis  than  conventional  HCC

Cholangiocarcinoma  (CCA)

Malignancy  of  intra-­‐  or  extrahepatic  bile  ducts;  Risk  factors:    primary  sclerosing  cholangitis,  congenital  fibropolycystic  disease  of  bile  tract,  HCV  infection,  Thorotrast  exposure,  chronic  infection  

Extrahepatic  (80  to  90%):Klatskin  tumors    (50  to  60%  of  all  CCAs)  occur  at  the  junction  of  the  R  and  L  hepatic  duct  forming  common  hepatic  duct;  Distal  bile  duct  tumors  (20  to  30%  of  CCAs)Intrahepatic  (~10%)  occur  in  non-­‐cirrhotic  liver

more  fibrous  look  than  other  liver  cancers;  pleomorphic  hyperchromatic  nuclei

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

PANCREATIC  NEOPLASMS:  Acinar  cell  carcinoma   prominent  acinar  cell  diff  

(may  have  metastatic  fat  necrosis  due  to  systemic  lipase  release)

Pancreatoblastoma   rare  malignant  neoplasms  which  occur  in  KIDS  w/  admixed  squamous  elements  and  acinar  cells

Cystic  neoplasms   fewer  than  5%

Serous  cystadenomas  benign.  W>M,  arise  in  7th  decade  are  benign  cystic  neoplasms  containing  serous  fluid  cured  by  surgery

Mucinous W>M,  arise  in  body  or  tail  with  one  third  containing  an  invasive  adenocarcinoma

Intraductal  papillary  mucinous  neoplasm

M>W,  head  of  pancreas,  may  be  benign  or  malignant

Solid-­‐pseudopapillary  young  women,  locally  aggressive  but  may  be  cured  with  surgical  excision.  B-­‐catenin/Adenomatous  polyposis  coli  genetic  pathway  is  altered

DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TX

Pancreatic  adenocarcinoma  (ductal)

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

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

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

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

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

Abdominal  pain  radiating  to  the  back,  N/V  -­‐>  MC  causes:    Alcoholism  ,  gallstones

reversible  lesions  characterized  by  inflammation  of  the  pancreas  ranging  in  severity  from  edema  and  fat  necrosis  to  parenchymal  necrosis  with  severe  hemorrhage

Gross:  Swollen,  edematous  or  hemorrhagic/necrotic,Yellow-­‐white,  chalky  areas  of  fat  necrosis,  Mesenteric    and  omental  fat  necrosis;  Micro:  Diffuse  interstitial  edema  due  to  microvascular  leakage,  Fat  necrosis  (fatty  acids  combine  with  calcium  to  form  insoluble  salts  causing  a  granular  appearance  to  fat  cells);  Severe  pancreatitis  will  have  necrosis  of  acinar,    ductal,  and    islet  cells  -­‐>Vascular  damage  and  hemorrhage,  neutrophils

Marked  elevation  of  serum  amylase  in  first  24  hours  followed  by  rising  serum  lipase;  Leukocytosis

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

Chronic  pancreatitis MC  cause:chronic  ethanol  abuse  -­‐>Repeated  attacks  of  pancreatic  inflamm  w/  irreversible  destruction  of  exocrine  pancreatic  parenchyma,  fibrosis  and  ultimately  destruction  of  endocrine  parenchyma;

Variable  pain,  sx  of  pancreatic  insufficiency  (malabsorption,  diabetes)

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

Complications:  diabetes  mellitus,  pseudocyst

GALLBLADDER:  DISEASE CAUSES CLINICAL  FEATURES PATHOGENESIS MORPH/HISTO LAB DX/PROG TXGallstones  (cholelithiasis)

Heterotropic  viruses  –  Hepatitis  A,  B,  C,  D,  ESystemic  -­‐    CMV,  EBV,  yellow  fever  from  a  Flavivirus  transmitted  by  mosquitos  in  the  tropics

freq  have  no  sx;  70-­‐80%  are  asymptomatic  throughout  their  lives;    RUQ  abdominal  pain

2  types:  chol  and  pigmented  stones  -­‐>  1.  chol:  Western  >  others,  Advancing  age,  female,  obese;Hyperlipidemia  and  bile  stasis;  2.  pigmented:  Asian  >  WesternHemolytic  anemiaBiliary  infection

comp:  cholecystitis,  Obstructive  cholestasis  or  pancreatitis,  cholangitis,  empyema,  perforaton,  fistulas;  Large  stone  may  erode  into  bowel  causing  obstruction  (gallstone  ileus  or  Bouveret’s  syndrome);  

Acute  cholecystitis Calculous:Due  to  chemical  irritation  and  inflamm  of  the  obstructed  gallbladder  precipitated  90%  of  the  time  by  obstructed  cystic  duct;  Primary  reason  for  emergency  cholecystectomy

Acalculous:No  stones  Occurs  in  severely  ill  patients,  severe  trauma,  burns,  diabetics  and  sepsis,  Likely  due  to  ischemia

Gross:  Enlarged,  tense  gallbladder  with  possible  subserosal  hemorrhage,  May  have  serositis  with  fibrinopurulent  exudateWall  is  edematous,  thickened  and  hyperemic;  may  have  gangrene  with  green-­‐black  necrosisMicro  -­‐    acute  inflammation  

Chronic  cholecystitis Gross:  variable  thickening  of  gallbladder  wall,  variable  adhesions  Micro:  Chronic  inflam  w/  Rokitansky-­‐Aschoff  sinuses  on  left  (reactive  prolif  of  the  mucosa  and  fusion  of  the  mucosal  folds  may  give  rise  to  buried  crypts  of  epithelium  within  the  wall);  fibrosis;  Dystrophic  calcification  

Gallbladder  Cancer MC  women,  ~72  yo;Rarely  discovered  at  a  resectable  stage  

Frequently  asymptomatic  until  advanced  stage;  RUQ  abdominal  pain,  anorexia,  N/v,    jaundice

Poor  prognosis,  5  yr.  survival  ~  5  to  12%Assoc  w/  gallstones  in  95%  of  cases