Week 1 Flashcards

Question

Identify esophageal malignant tumor Morphology - Commonly form mucin and glands - Less common; diffusely infiltrative SIGNET-RING cells Location - usually in distal portion and involve the gastric cardia - malignant tumor with glandular differentiation Risk factors? Risk reducer? Ethnicity? Gender?

Answer 1

Esophageal ADENOCARCINOMA - most common in caucasians - males (70x) - has increase rapidly in US and western world - before it was just 5% of esophageal cancers now more than half of al esophageal cancer (50-70%) - most arise from Barrett (most important risk factor); remeber GERD - Barrett - Adenocarcinoma - Obesity and high BMI (strong risk factors, likely related to GERD) - Other risk factors include tobacco (moderate risk factor) - Risk reduced by diets rich in fresh fruit and vegetable - Some serotypes of H pylori associated with reduced risk (gastric atrophy, reduced acid production and decreasing reflux disease)

Answer 2

Esophageal Adenocarcinoma Clinical features A. Symptoms; • Difficulty swallowing • Weight loss • Hematemesis • Chest pain • Vomiting B. Occasionally discovered in evaluation of GERD C. Advanced stage at the time of diagnosis - Spread submucosal lymphatics (esophagus with extensive lymphatic network that allows horizontal and longitudinal spread even in superficial tumors) D. Recurrence common E. Overall 5 year survival less than 25% Treatment • Resection (may be preceded by neoadjuvant therapy) • Adjuvant chemoradiation is often given • (5 year survival for nonresectable tumors is rare)

Answer 3

SQUAMOUS CELL CARCINOMA • Worldwide most common esophageal malignancy • US strong male predominance • Risk factor include alcohol, tobacco, caustic esophageal injury, achalasia, tylosis (hyperkeratosis in palms and sole), Plummer-Vinson syndrome, consumption of very hot beverage, radiation • 6X more common on African American than Caucasians • Regions with highest incidence include Iran, central China, Hong Kong, Brazil, and South Africa

Answer 4

SQUAMOUS CELL CARCINOMA Morphology • Middle third of esophagus • Begins with dysplasia and in-situ carcinoma • Polypoid, ulcerated, diffusely infiltrative; lymph nodes involvement - upper third; cervical lymph nodes - middle third; mediastinal, paratracheal, tracheobronchial nodes - lower third; gastric and celiac nodes * *Usually in mid esophagus causing stricture * *Nests of malignant squamous cells

Answer 5

Flilarial Nematodes • Onchocerciasis • Loiasis • The Filariases (Bancroftian, Malayan, Timorian) Tissue • Dracunculiasis • Toxocariasis - *Schedule says toxoplasmosis but wrong toxo

Answer 6

ONCHOCERCIASIS • Onchocerca volvulus • Transmitted through repeated bites from Simulium black fly; Lives and breeds near fast-flowing streams and rivers • Can also cause severe skin disease A. Skin 1. Dermatitis • Most symptoms from dead or dying larvae • Secrete collagenase during migration loss of skin elasticity • Loss of melanin from basal cells, “leopard skin” • Atrophy of the dermis • Lichenified onchodermatitis (LOD), “sowda” 2. Nodules (onchocercomata) • Larvae travel to skin and form fibrous nodule, safe from human defense • Become detectable 1-2 yrs later • Males travel in between nodules, females release thousands of larvae to the surrounding tissues to be taken up by black fly B. Lymph Nodes • Can find enlarged nodes where lymphatics are draining areas of onchodermatitis C. Eye • Punctate Keratitis: initially observed, clears without scarring • Chorioretinitis: slow to progress over years leading to blindness

Answer 7

ONCHOCERCIASIS (River Blindness) Diagnosis - History, eosinophilia and skin snip; 3mm tent, incubate in NS for 24 hrs - dermatitis; tough, tough tough. Leopard skin - vitiligo? Leprosy> - Nodules; nodulectomy - Serum antibody testing, but can only tell filarial disease, not which one Treatment 1. Ivermectin • Kills microfilaria, not adults • Sterilize adults • Mass Drug Administrations give doses q6months 2. Doxycycline? • Targeting Wolbachia • Slow death of filaria 3. DEC • Used to be treatment, but causes rapid death and worsening of inflammation of eye leading to increased blindness ``` Prevention A. Avoid black flies • Long sleeves • DEET B. Onchocerciasis Elimination Program for the Americas (OEPA) ```

Answer 8

``` LOIASIS ; loa loa worm A. Repeated bites from Chrysops genus • deer fly, mango fly, mangrove fly, African red fly • Bite during the day, rainy season • Rain forest B. Endemic to central and west Africa • Also found in Malawi, Uganda, Zambia, Ethiopia • Higher rates in adults (M>F) ``` ``` Rare symptoms 1. Meningoencephalitis • High microfilaria burden • Mostly with treatment with DEC • Mild HA to coma or death 2. Renal • Hematuria and proteinuria • Immune complex glomerulonephritis or mechanical trauma 3. Endomyocardial Fibrosis 4. Pulmonary infiltrate or effusion ```

Answer 9

LOIASIS- loa, loa worm - calabar swelling (angioedema) - eye worm Diagnosis • Seek expert help! • Surgery of adult worms • Diethylcarbamazine (DEC); only from CDC - kills MF and adult - low MF load; calabar swellings, urticaria, fever - High MF load; meningoencephalitis, renal failure. *Need cytopheresis prior - Don’t use in conjunction with onchocerciasis d/t risk of severe skin/eye reaction • Albendazole - Long course if DEC ineffective

Answer 10

Lymphatic Filariasis • 3 species - Wucheria bancrofti - Brugia malayi - Brugia timori • Mosquito transmission; All mosquitos implicated • Typically in the tropics - subtropics Asia, Africa, west pacific, Caribbean, South America - endemic in Americas; Haiti, DR, Guyana, Brazil • Can persist for years in humans, especially since early disease can be asymptomatic • Live in lymphatic system of humans • Damage the lymphatics by inflammation or damage to the lymphatic valves

Answer 11

Lymphatic Filariasis Acute Clinical Features • Most are asymptomatic • Acute Filarial Lymphangitis - Acute inflammation along lymph vessel, death of adult worm - Pain, erythema, tenderness of lymph node prior to • Acute Dermatolymphangioadenitis - Bacterial infection - Severe pain, fever, chills - Often history of trauma to the skin prior (bite, cut, etc)

Answer 12

Lymphatic Filariasis - Chronic 1. Genital; 65% hydrocele • Epididymitis, orchitis, lymphedema of scrotum of vulva • Hydrocele most common, W. bancrofti • Adult worm causes lymphatic damage • Chylocele– rupture of intrascrotal 2. Lymphedema - 35% • Legs, scrotum, penis, breast and arms • Typically asymetric involvement • Bancroftian filariasis– may be entire limb • Brugian filariasis– typically distal extremity ****WHO Lymphedema grading system • Grade I: pitting edema reversible with elevation • Grade II: non-pititng edema not reversible with elevation • Grade III: non-pitting edema not reversible with elevation and thickening of skin/skin folds • Grade IV: non-pitting edema with papilomatous skin lesions with skin folds (elephantiasis) 3. Elephantiasis • Not reversible • Keeping wounds clean is essential • Wound care programs help prevent secondary infections 4. Chyluria • Rupture of dilated lympatic structures into renal pelvis • Loss of chyle= loss of dietary lipids, proteins, vitamins, weight loss, malnutrition 5. Tropical pulmonary eosinophilia • W. bancrofti or B. malayi, hypersensitivity as microfilariae travel through pulmonary blood vessels • Mostly men, 20-40 years old • Paroxysmal, non-productive cough (worse at night), wheezing, adenopathy, generalized malaise, weight loss • Eosinophilia, Elevated IgE, HIGH Ab titers • Typically no microfilaria in blood • CXR normal to small interstitial infiltrates • PFTs can show restriction • Can lead to chronic restrictive lung disease and fibrosis • DEC is treatment—patients show quick response Prevention and control 2. In 1997, WHO Global Program to Eliminate Lymphatic Filariasis (GPELF) • Stop trasnmission with mass drug administration (DEC or Ivermectin + albendzole) • Once yearly for 5 years reaching at least 65% of population • Reduce morbidity • Treatment of lymphedema and wound care

Answer 13

DRACUNCULIASIS “Guinea worm” - Dracunculus Medinensis ``` Treatment • Soak in water • Gentle traction on the worm • Wrap worm around guaze or stick • Extraction may take days to weeks • If the worm breaks, can cause abscess formation and worsening cellulitis ``` Eradication 1. Global eradication campaign started in 1980, 20 countries affected; Targeted Eradication Criteria • It is biologically and technically possible to eradicate this disease. • The benefits of eradication outweigh the costs. 2. Disability; avg process 8.5 weeks • What if this is during harvest? Or, planting season? • School attendance drops • Work attendance drops 3. Criteria (PPT) • GWD is now poised to be the first disease to be eradicated using core public health practices, such as surveillance, case containment, and simple interventions, without the use of vaccines or medicines

Answer 14

TOXOCARIASIS • 1996 30% dogs <6months shed eggs • 35% cats infected • Higher risk if left outside long periods of time • Higher risk if allowed to eat other animals • Prevalence in humans up to 40% in some places • Higher risk of humans contracting if dog owners • Higher risk if living in poverty • Higher risk if hot, humid climate--eggs viable longer in the soil

Answer 15

Tococariasis 1. Visceral larva migrans 2. Ocular larva migrans ``` Diagnosis • Good history • Consider if consistently elevated eosinophil count • Visceral larva migrans - ELISA for larval-stage Ag - Eosinophilia - Anemia & hypergammglobulinemia • Ocular larva migrans - Ab levels low in serum - Vitreous fluid - May not have eosinophilia • Stool sample– not helpful - Larvae don’t mature to excrete eggs ``` Treatment * ** SELF-LIMITING 1. Albendazole - available in US - preferred in ocular larva migrans 2. Mebendazole 3. Steroids - decrease systemic effects of inflammation 4. Surgery of eye - prevent retinal detachment Prevention • De-worm pets • Clean your pet’s living area at least once a week • Feces should be either buried or bagged and disposed of in the trash • Play areas with feces/sandboxes • Good hand hygiene • Don’t eat dirt

Answer 16

``` SCHISTOSOMIASIS • Schistosoma mansoni, S. haematobium, or S. japonicum. • “Bilharzia” • 200M people affected worldwide - Tropical climates - Highest prevalence 8-15years - Adults *may have acquired resistance • Negelcted Tropical Diseases • Live in freshwater snails • Cercaria (infectious form) emerge from snail into water • Affects areas with poor sanitation ``` 3 types 1. Schistosoma mansoni—intestinal and hepatic symptoms • distributed throughout Africa: lakes, rivers, also occurs in the Nile River valley in Sudan and Egypt • South America: including Brazil, Suriname, Venezuela • Caribbean (risk is low): Dominican Republic, Guadeloupe, Martinique, and Saint Lucia. 2. S. japonicum—intestinal and hepatic symptoms • found in Indonesia and parts of China and Southeast Asia 3. S. haematobium– Urinary symptoms • Throughout Africa, some areas of Middle East • found in areas of the Middle East

Answer 17

1. Schistosomiasis Mansoni 2. Schistosomiasis japonicum 3. Schistosomiasis haematobium ``` Diagnosis n treatment • History and exposure • Find eggs in stool!; O&P x3 • Other testing - Eosinophilia - Hematuria or hematochezia • Antibody testing– 6-8 weeks after exposure • Treatment with praziquantel; Steroids for swimmer’s itch and Katayama fever ```

Answer 18

TAENIA • Taenia saginata/solium • Beef or pork tapeworm • One of the most common parasitic infections • Ingestion of undercooked meat - Ingest cysticerci (infective cyst in muscle) - Typically mild symptoms to asymptomatic Disease • Ingest cysticerci in undercooked meat • Once ingested, attaches to intestinal wall • Matures into adult 10-12 weeks • Sheds proglottids, patient may see in stool • Symptoms - Epigastric pain, nausea, diarrhea, flatulence - Decreased appetite, weight loss • In rare cases, may lodge in bile or pancreatic ducts Diagnosis and treatment • Microscopic eggs in stool - Not available for 1st 3 months of infection • Collect 3 stool samples on 3 separate days to increase sensitivity • Praziquantel - Caution if patient has cysticercosis! - Collect stool samples for proglottids to identify species retention and control - FDA recommendation • Whole Cuts: cook to at least 145ºF in thickest part of meat, then allow to rest for 3 minutes prior to carving/consuming • Ground Meat: cook to at least 160ºF, do not require rest time • “rest time” amount of time the product remains at the final temperature, after it has been removed from grill, oven, or other heat source. During the three minutes after heat is removed from the heat source, its temperature remains constant or continues to rise, which destroys pathogens

Answer 19

CYSTICERCOSIS - TAENIA SOLIUM ***Neurocysticercosis (brain/spinal cord) • Infects brain, muscle, etc - Major cause of adult-onset seizure • Infection by eggs found in feces of infected person - Can be an autoinfection • NOT from undercooked pork! - …at least not directly - Intestinal tapeworm ***LEADING CAUSE OF SEIZURES IN DEVELOPING WORLD ``` A. Worldwide - free range pigs - poor hygiene B. Signs and symptoms - Caused by degenerating cysts - muscle; lumps under skin C. Eyes - blurry vision - swelling - retinal detachment D. Brain/spinal cord (Neurocysticercosis) u ```

Answer 20

Neurocysticercosis • Neurocysticercosis—symptoms correspond to where cysts are • Live cysticerci cause mass effect • Dying cysticerci cause inflammation and majority of symptoms • Parenchymal (within brain hemisphere or cerebellum) - 3-5 years after infection, but can be up to >30yrs - Seizures and HA • Extraparenchymal (intraventricular or subarachnoid) - HA, N/V - Altered vision, focal neurologic signs, AMS, meningitis

Answer 21

Cysticercosis; most common cause of seizures in developing nations Diagnosis • Clinical presentation - Seizure without focal neurologic findings or signs of meningitis - Late onset seizure with travel/exposure history • Imaging - CT /MRI - Enhancing lesions without midline shift • Serology nonspecific, stool exam insensitive d/t lack of active tapeworm ``` Treatment • Antiepileptic • Antiparasitic therapy (albendazole) for active lesion but run the risk of causing more degenerating cysts leading to increased inflammation • Corticosteroids • Test others in the home as well ``` Prevention • Wash your hands • Wash and peel all raw vegetables and fruits before eating • Drink only bottled or boiled (1 minute) water or carbonated drinks in cans or bottles • Filter unsafe water through an filter AND dissolve iodine tablets in the filtered water

Answer 22

Diphyllobothriasis * Diphyllobothrium latum * “Fish Tapeworm” * Ingestion of larval stage (plerocercoid) * Was reportable disease in US until 1982; Increased awareness and strict monitoring Prevention and control - Cooking; cook fish adequately (to an internal temperature of at least 145° F) Freezing • At -4°F or below for 7 days (total time), or • At -31°F or below until solid, and storing at -31°F or below for 15 hours, or • At -31°F or below until solid and storing at -4°F or below for 24 hours.

Answer 23

``` HYMENOLEPIASIS • Hymenolepis nana • “Dwarf tapeworm”; ~2inches • Utilizes insects as intermediate hosts (beetle, mealworm, flea) • Fecal-oral route ingesting eggs • Ingestion of infected arthropod • High prevalence in areas with poor hygiene and overcrowding • Common in children ```

Answer 24

Dipylidiasis ``` • Dipylidium caninum • Most common cestode of dogs - Can infect cats • Infect humans if ingest infected flea • Typically young children affected • Typically asymptomatic - Anal itching, loss of appetite, abdominal pain ```

Answer 25

Echinococcus; Echinococcus granulosus/multilocularis 2 types 1. Cystic caused by E. granulosus—can be asymptomatic for years 2. Alveolar caused by E. multilocularis– can be fatal • Sheep, cattle, goats and pigs are intermediate hosts - Ingest eggs from the ground • Dogs ingest cysts in the organs of above - Shed eggs from adult tapeworm • Fecal-oral route for humans • Prevalent where dogs are used to care for large flocks of sheep - In South America, endemic in Argentina, Bolivia, Chile, Brazil, Peru and Uruguay Cystic echinococcus*** • ”Hydatid disease” • Larval stage of E. granulosus ingested • Transported by blood stream to liver • Most infections asymptomatic • Slowly enlarging fluid-filled cysts in liver, lungs • Can contain liters of fluid

Answer 26

TREMATODES 1. Schistosomiasis - S. Mansoni, S. Japonicum, S. Haematobium, S. Mekongi, S. Intercalatum 2. Non-schistosomiasis A. Paragonimus - lung fluke B. Clonorchis/Opisthorchis - Chinese liver fluke C. Fasciola - Liver fluke/rot

Answer 27

PARAGONIMIASIS “LUNG FLUKE” ; Paragonimus Westermani A. Life cycle Man > Snail > Crab > Man ** • Human Stool/Saliva > Fresh water> Snail (Cercariae)> Crustacean (Metacercariae) > Human consumption. • Larvae (Metacercariae) burrow through intestinal wall and migrate to the lungs and develop into egg producing adults. • Eggs are coughed up or swallowed and the cycle repeats. EGGS identifying feature is OPERCULUM - LITTLE LID** **HIGHLY INFLAMMATORY B. Clinical presentation 1. Acute phase; diarrhea, abdominal pain, fever, cough (RUST COLORED SPUTUM), urticaria, HSM, eosinophilia 2. Chronic phase; COUGH**, SOB, CP, Hemoptysis, radiographic abnormalities

Answer 28

PARAGONIMIASIS “LUNG FLUKE” ; Paragonimus Westermani **Xray look like TB Dx: Often misdiagnosed as tuberculosis (thus must keep in DDx). Microscopic evaluation may reveal eggs in sputum or stool (i.e. O&P) though often difficult. Enzyme Immuno-Assay or Immunoblot may also be used (i.e. Serology). TX: Praziquantel

Answer 29

CLONORCHIASIS & OPISTHORCHIASIS aka “CHINESE LIVER FLUKE” Life cycle Man > Snail > Fish > Man • Human Feces (Bile)> Snail (Cercariae) > Freshwater Fish (Metacercariae) > Human Consumption. • Human consumption > Intestinal burrowing and migration to BILE DUCTS where they mature and produce eggs. • Mechanical injury from the suckers of the parasite contribute to inflammatory response. Mechanical obstruction of the biliary tract by the fluke is also a significant factor in pathogenesis. Eggs O. Viverrini, C. Sinensis eggs ; Prominent “Shoulders” i.e. Operculum Abopercular “Knob”

Answer 30

CLONORCHIASIS & OPISTHORCHIASIS aka “CHINESE LIVER FLUKE” Dx: Microscopic identification ( O&P) through stool examination. No serologic test exists. (*indistinguishable from one another on visual inspection.) TX: Praziquantel

Answer 31

FASCIOLIASIS - Fasciola Hepatica Life cycle Man > snail > fresh water plant > Man • Eggs in Cattle/Sheep Feces>Snail (Cercariae) > Freshwater plants (Metacercariae) > Human Consumption • Man is an accidental host. • Human consumption > Intestinal burrowing and migration to bile ducts/Liver where they mature and produce eggs.

Answer 32

FASCIOLIASIS - Fasciola Hepatica Dx: Microscopic Evaluation of stool (i.e. O&P); Serologic evaluation available via CDC. TX: Not Praziquantel – Unlike other trematodes, Praziquantel is not effective against Facioliasis. Triclabendazole is treatment of choice (WHO) though not readily available in US.

Answer 33

FASCIOLOPSIASIS - Fasciolopsis Buski Dx: Microscopic Evaluation of eggs in stool (i.e. O&P) or (rarely) adults in stool. Indistinguishable from F. Hepatica TX: Praziquantel

Answer 34

1. Amoeba 2. Flagellates 3. Ciliophora 4. Coccidial 5. Microsporidia infections

Answer 35

ENTAMOEBA HYSTOLYTICA Life cycle ; Fecal Oral transmission - Human consumption of mature cysts in fecally contaminated food, water, or hands > Excystation occurs in small intestine where Trophozoites are released> Trophozoites migrate from small to large intestine, multiply (Binary Fission), and form Cysts > Cysts and Trophozoites are passed in the feces. - Trophozoites may invade intestinal mucosa (Intestinal Sxn’s) or travel in blood stream to other locations (Extra- Intestinal Sxn’s). - Only cysts are able to survive external environment thus giving them their infectivity (Days to Weeks). - Cysts are resistant to chlorination and gastric acidity as well. - Trophozoites are able to invade tissue however cysts cannot.

Answer 36

ENTAMOEBA HYSTOLYTICA Intestinal Manifestations - Asymptomatic - Fever, Chills - Abdominal Pain –Severe Cramping - Tenesmus - Dysentery** - “Flask Shaped Ulcer” on histology ** Extra-intestinal manifestations - Fever, RUQ Pain - Elevated transaminases (AST/ALT, Alk. Phos). - Liver Abscess** - Pleuropulmonary (direct extension), Brain, Splenic Abscess (rare) - Often have no intestinal symptoms.

Answer 37

GIARDIASIS Giardia Lamblia: Cysts and Trophozoite (Latter typically described and “Pear Shaped or Tear Drop” and is flagellated with 2 nuclei- “Eyes”) . Lifecyles ; Fecal oral transmission - Human consumption of mature cysts in fecally contaminated food, water, or hands > Excystation occurs in small intestine where Trophozoites are released and colonize duodenum> Trophozoites multiply (Binary Fission) and form Cysts > Cysts and Trophozoites are passed in the feces. - Cysts may survive several weeks to months in cold water. - Animals are common reservoirs.

Answer 38

GIARDIA LAMBLIA - GIARDIASIS Diagnosis: - High Clinical Suspicion (Aka the right history). - Visualization of Cysts or Trophozoites on O&P*** - Serology (EIA) Treatment - Tinidazole or Metronidazole ** ** Historically board questions have associated BEAVERS and St. PETERSBURG, RUSSIA with Giardiasis. If you see either of these mentioned in the stem, have a high suspicion for GIARDIASIS.

Answer 39

TRICHOMONIASIS * Trichomonas Vaginalis – Flagellated; Most common pathogenic protozoan of humans in rich nations. Life cycle; sexually transmitted - Cannot live outside of humans . - Frequently asymptomatic. - Vaginitis with foul smelling, greenish vaginal discharge. - Vaginal itching and burning. - Dyspareunia and dysuria. - Males often asymptomatic; urethritis; epididymitis, prostatitis can occur. - Cervix classically is very friable (“Strawberry Cervix”)**

Answer 40

TRICHOMONIASIS -TROPHOZOITES Diagnosis; Motile trichomonads seen on microscopic examination of WET MOUNT** Treatment; Patient and Partner with Metronidazole or Tinidazole**

Answer 41

DIENTAMOEBA FRAGILIS Life cycle; Fecal Oral transmission - Life cycle has yet to be fully described. - Thought to be transmitted by fecal – oral route after ingestion of helminth eggs . Has no cyst stage. - Abdominal Pain, Diarrhea, Flatulence. - Eosinophilia possible - Diagnosis: Microscopic evaluation – O&P. - Treatment: Metronidazole, Iodoquinol or Paromycin.

Answer 42

BALANTIDIUM COLI **Trophozoite with “Bean shaped” nucleus Life cycle; Fecal -oral - Human consumption of cysts in fecally contaminated food or water. - Many are asymptomatic. - May experience anything from intermittent diarrhea to acute dystentary. - Diagnosis: Cysts and trophozoites seen on microscopic analysis of stool (O&P). - Treatment: Tetracycline, Iodoquinol, or Metronidazole.

Answer 43

CRYPTOSPORIDIOSIS - C. Parvum and C. Hominis account for vast majority of human infections. Life cycle; fecal oral - Consumption of OOCYTS in contaminated water or food sources > sporozoites are released and begin to reproduce and form oocysts which are excreted in stool. - Oocysts are infective upon excretion. - Size allows them to pass through water filters and are also chlorine-resistant** - Many outbreaks occur around water sources

Answer 44

CRYPTOSPORIDIOSIS Diagnosis: Oocysts in stool on microscopic evaluation with Acid-Fast Stain - OR - Antigen detection via EIA. Treatment: Prevention. - Usually Self-limited in immunocompetent though if symptoms worsen consider Nitazoxanide. ** *Of note: Nitazoxanide has not been shown to help in immunocompromised individuals.

Answer 45

``` ISOSPORA BELLI (CYSTOISOSPORIASIS) **Oocytes containing sporoblast ``` Life cycle; fecal oral - Consumption of sporozoite containing sporocysts > Invasion of intestinal epithelial cells> further replication produces immature oocysts which are excreted in feces > additional maturation results in sporocysts which produce sporozoites (infective) - Watery diarrhea most common symptom. - Eosinophilia may be present Diagnosis: Oocysts in stool on microscopic evaluation with Acid-Fast Stain. Treatment: Trimethoprim-sulfamethoxazole.

Answer 46

CYCLOSPORA CAYETANENSIS LIFE CYCLE; fecal oral - Ingestion of sporulated oocysts (infective) from contaminated food or water> Invasion of epithelium of GI tract and undergo reproduction and development into unsporulated oocysts > Sporulation occurs in environment. - Watery diarrhea most common symptom. - Stomach cramps, n/v, anorexia, muscle aches, low grade fever. - Untreated infections may lead to prolonged diarrhea (10-12 weeks). Diagnosis: Oocysts in stool on microscopic evaluation. May be enhanced by UV microscopy. Treatment: Trimethoprim-sulfamethoxazole. **C. Cayetanensis oocyst seen under UV microscopy. Historically board questions have associated raspberries and mesclun lettuce with Cyclospora. If you see either of these mentioned in the stem, have a high suspicion for Cyclospora.

Answer 47

SARCOCYSTOSIS Life cycle; undercooked meat - Humans consume undercooked meat (pork, beef) > bradyzoities invade intestinal epithelium> further maturation and development of oocysts> Oocysts shed in host feces. - Often asymptomatic. - Intestinal Infection: Mild fever, diarrhea, chills, vomiting. - Muscle Infection: Myalgia, Muscle Weakness, Edema. Dx; Oocysts in stool on microscopic evaluation. May be enhanced by acid fast stain or UV microscopy. Treatment: Trimethoprim- sulfamethoxazole.

Answer 48

MICROSPORIDIA Life cycle; spore inhalation or ingestion - Opportunistic – think severe AIDs. - Multiple clinical presentations depending on the subtype identified which range from diarrhea to ocular/respiratory/genitourinary infection. - Diagnosis: Transmission electron microscopy; IFA; PCR (Via CDC) - Treatment: Fumagillin or Albendazole.

Answer 49

PANCREAS - parts; head, neck, body and tail - systems; exocrine (digestive enzymes) and endocrine (secrete insulin, glucagon and somatostatin) 1. Main Pancreatic Duct - Most commonly drains the duodenum at the papilla of Vater 2. Accessory Pancreatic Duct-Drains into the duodenum through a separate minor papilla that is 2 cm proximal to the major papilla of Vater * *In most adults the main pancreatic duct joins the common bile duct proximal to the papilla of Vater, thus creating the ampulla of Vater

Answer 50

EXOCRINE PANCREAS - Acinar Cells

Answer 51

- Trypsinogen - Chymotrypsinogen - procarboxypeptidase - proelastase - kallikreinogen - phosphopholipase A and B * * Activation of proenzymes requires the conversion of inactive trypsinogen to active trypsin by duodenal enteropeptidase - Trypsin cleaves proenzymes to yield products such as chymotrypsin, elastases and phospholipases - Trypsin inhibitors including SERINE PROTEASE INHIBITOR KAZAL TYPE 1 are present within acinar and ductal secretions - Acinar cells are remarkable resistant to the action of trypsin, chymotrypsin and phospholipase A2.

Answer 52

Agenesis **Rarely is the pancreas totally absent

Answer 53

PANCREATIC DIVISUM - Failure of fusion of the fetal duct system of the dorsal and ventral pancreatic primordia **STENOSIS is caused by a bulk of secretions passing through the minor papillae - leads to CHRONIC PANCREATITIS

Answer 54

1. Annular Pancreas | 2. Ectopic pancreas

Answer 55

1. Inflammation A. Pancreatitis 2. Neoplasms A. Benign B. Malignant

Answer 56

PANCREATITIS ** Mild acute pancreatitis simply diagnosed with elevated amylase and lipase Acute; REVERSIBLE inflammatory process Chronic; IRREVERSIBLE loss of exocrine and endocrine function

Answer 57

PANCREATITIS Other causes - Obstruction - Medications - Infections - Metabolic disorders - Trauma - Genetic; mutations in the cationic trysinogen (PRSS1) and trypsin inhibitor (SPINK1) genes I GET SMASHED; Idiopathic, gallstones, ethanol, trauma, steroids, mumps, autoimmune disease, scorpion sting, hyperlipidemia, drugs

Answer 58

1. PANCREATITIS 2. HEREDITARY PANCREATITIS ; **recurrent attacks usually starting in childhood A. Cationic trypsinogen gene (PRSS1) - Trypsin becomes resistant to cleavage by another trypsin molecule and can lead to activation of other proenzymes and thus pancreatitis - Autosomal dominant B. Serine protease inhibitor Kazal type 1 (SPINK1) - Codes for pancreatic secretorytrypsin inhibitor that inhibits trypsin activity - Autosomal recessive

Answer 59

A. 1. Pancreatic duct obstruction - gallstones, chronic alcoholism 2. Acinar cell injury - alcohol, drugs, trauma, ischemia, viruses 3. Defective intracellular transport - alcohol B. Alcohol causes in several ways: - Chronic ingestion results in protein rich fluid which leads to protein plugs and obstruction of small ducts - Direct toxic effects, increase in exocrine secretion. C. Basic mechanism pancreatitis I. Due to action of pancreatic enzymes II. Trypsin is primary enzyme - It then activates other enzymes - Activated enzymes digest fat cells & damage blood cells - Trypsin activates kinin system, so get activation of clotting & complement cascades

Answer 60

ACUTE PANCREATITIS; most severe form, occurs in 5% of patients - a lot of fat necrosis and hemorrhage Pathologic lesions (2) 1. Fat necrosis - Results from the lipolytic enzymes, released fatty acids combine with calcium to form insoluble salts which precipitate * * can lead to low calcium (poor prognostic sign) - Hemorrhage; destruction of blood vessels causes this Results of enzyme activation - All result in acinar cell injury - Leads to activated enzymes - Endpoint is acute pancreatitis Clinical course - To predict severity of disease, have criteria which are based on patient age & lab values - Called Ranson’s criteria **PPT - Can’t be completed until 48 hours of hospitalization Clinical presentation - severe pancreatitis with necrosis is medical emergency - must differentiate from other causes of an acute abdomen Sequelae * *Get systemic inflammatory response - increased WBC - hemolysis - ARDS - can get shock and death from peripheral vascular collapse Differential - Ruptured acute appendicitis - Perforated peptic ulcer - Acute cholecystitis with rupture - Infarction of bowel from occlusion of mesenteric vessels Prognosis and therapy - Prognosis varies, worse in older patients - Adverse prognosis: old age, high WBC count, hyperglycemia - Supportive care

Answer 61

Definition - Is defined as an inflammatory injury associated with irreversible loss of exocrine and/or endocrine function - Development of pancreatitis in organ which is already damaged - Classically in middle aged male alcoholics Pathology; gross vs microscopic A. GROSS - Gland is hard with calcific concretions - Pseudocyst formation is common B. MICROSCOPIC - See FIBROSIS - Destruction of pancreatic acini, some obstruction of pancreatic ducts - Sparing of islets initially, can be destroyed with disease progression Clinical features - Often presents as repeated attacks of abdominal pain - Can present as jaundice and/or diabetes, malabsorption with steatorrhea - Need high index of suspicion to diagnose - CT & US show calcification,ductal dilatation and small cysts ``` Less common causes Long Standing Obstruction Tropical Pancreatitis Hereditary Pancreatitis CFTR Mutations—Cystic Fibrosis **40% of individuals with chronic pancreatitis have no recognizable factor ``` Pathogenesis * * Proposed that acute pancreatitis initiates a sequence of: - Perilobular fibrosis - Duct distortion - Altered Pancreatic Secretions ``` Clinical features **Diagnosis requires a high degree of suspicion Mild Fever Mild-moderate elevations in serum amylase Visualization of Ca by CT and US Weight Loss Hypoalbuminemic anemia ``` Prognosis and therapy - Chronic disabling condition - Pseudo cyst formation in 10% patients - Some increased risk of pancreatic ca - Supportive exocrine enzymes replacement andmanagementof Diabetes, steroid therapy some cases * *20 to 25 year mortality rate of 50%

Answer 62

1. CONGENITAL CYSTS 2. Pseudocyst formation - cystlike cavity - Localized collection of pancreatic secretions which develop after inflammation of the pancreas - Arise after acute or chronic pancreatitis - Account for 75% of cysts in the pancreas Pathology - Solitary - Occur within the pancreas or adjacent to it - Pseudocyst because no epithelial lining - Get drainage of secretions from damaged ducts into interstitium; **This becomes walled of by fibrous tissue forming cystic space - Can be 2 to 30 cm in size Radiologically; UNILOCULAR CYSTIC MASS Treatment - Supportive care - Surgical drainage - Excellent prognosis

Answer 63

1. Cystic neoplasms 2. Solid neoplasms * **Both can be benign and/or malignant

Answer 64

SEROUS CYSTADENOMA

Answer 65

MUCINOUS CYSTIC NEOPLASM

Answer 66

INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM IPMN | ***Most common in HEAD of pancreas***

Answer 67

SOLID PEUDOPAPILLARY NEOPLASM | **Very RARE**

Answer 68

PANCREATIC CARCINOMA - Adenocarcinoma, forming from the ductal epithelium - 4th most frequent cause of death from cancer

Answer 69

PANCREATIC CARCINOMA Pathogenesis and Genetics - Strongest environmental influence is smoking - Diets rich in fats has also been implicated - Occurs in patients with pancreatitis, but no causal relationship - Common mutations: KRAS&p53 - Familial clustering has been reported Inherited predisposition to pancreatic cancer - Hereditary breast and ovarian cancer (BRCA2) - Familial atypical multiple-mole melanoma syndrome (p16/CDKN2A) - Strong family history (3 or more relatives) - Hereditary pancreatitis (PRSS1 and SPINK1) - Peutz-Jeghers syndrome (LKB1) Precursors to pancreatic cancer - Progression from non-neoplastic to invasive lesion - Precursor lesions are called: Pancreatic intraepithelial neoplasia (PanINs)

Answer 70

PANCREATIC ADENOCARCINOMA - carcinomas are Normally hard, stellate, gray white, poorly defined masses Pathology - Architectural and cytological atypia of glands - Mitoses and necrosis - Solid sheets or single cells, squamous differentiation,mucin production, spindle cell component or endocrine differentiation Clinical course - Overall, itis often silent until cancer is more advanced - Obstructive jaundice, painless, draws attention to disease, but not soon enough - Weight loss - Trousseau’s sign Migratory thrombophlebitis Occurs in 10% of patients Tumor produces platelet aggregating factors - Less than20% of tumors are resectable at diagnosis - Prognosis is extremely poor ``` Treatment - Can perform Whipple procedure - Pancreaticoduodenal resection Palliative bypass procedures Radiation and chemotherapy 5yr survival:<5% ```

Answer 71

ACINAR CELL CARCINOMA

Answer 72

PACREATOBLASTOMA

Answer 73

1. Cardia - mucous cells secreting foveolar cells 2. Fundus; - parietal cells (acid) - chief cells (pepsin); digestive enzymes 3. Body 4. Antrum; - mucous cells secrete foveolar cells - G cells (gastrin); G (endocrine) cells release gastrin that stimulate acid secretion by parietal cells 5. Pylorus Histology 1. Mucosa 2. Submucosa 3. Muscularis externa

Answer 74

Congenital Hypertrophic PYLORIC STENOSIS • Hyperplasia of pyloric muscularis propria • 1/300-900 live births • Male>Female • Congenital - Increased risk in both mono and dizygotic twins - Turner syndrome and trisomy 18 - Third to sixth weeks of life (new onset of regurgitation) - Exposure to erythromycin or azithromycin (first two weeks of life) • Acquired - In antral gastritis, peptic ulcers, malignancy

Answer 75

Stomach; Gastropathy and Acute gastritis 1. Acute gastritis; neutrophils 2. Gastropathy; Gastric injury or dysfunction with rare or absent inflammatory cells • NSAIDS, alcohol, bile • Hypertrophic gastropathy: Menetrier disease and Zollinger-Ellison syndrome Pathogenesis 1. NSAIDs • Inhibit cyclooxygenase - (COX) dependent synthesis of prostaglandins E2 and I2 that stimulate defense mechanisms (mucus, bicarbonate, and phospholipid production) • Although COX-1 plays larger role than COX-2, both contribute to mucosal protection - (non-selective inhibitors aspirin, ibuprofen, naproxen) (selective inhibitor celecoxib) 2. Gastric Injury • Uremic patients and those infected with urease-secreting H pylori lead to inhibition of gastric bicarbonate transporters by ammonium ions 3. Reduced mucin and bicarbonate secretion • In older individuals- susceptibility to gastritis 4. Decreased oxygen delivery • Acute gastritis at high altitude 5. Direct injury by harsh chemicals (acids and bases) • Alcohol, radiation

Answer 76

* Protective mucin produced by foveolar cells (thin layer of mucus and phospholipids) * Bicarbonate ion secreted by surface epithelium * Continuous layer of epithelial cells * Rich vasculature delivers oxygen and nutrients

Answer 77

Stomach: Gastropathy and acute gastritis Clinical features • The presentation of gastropathy and acute gastritis varies according to etiology • Two cannot be distinguished on clinical grounds

Answer 78

Stress-related mucosal disease A. In patients with severe physiologic stress (trauma, burns, intracranial disease, major surgery, serious medical disease) B. More than 75% of severely ill patients develop gastric lesions • Stress ulcers: in shock, sepsis, or trauma • Curling ulcers: in severe burns and trauma, ulcers in proximal duodenum • Cushing ulcers: in intracranial disease, gastric, duodenal, and esophageal ulcers, high incidence of perforation

Answer 79

Stress-related mucosal disease Clinical features • Histologic evidence of gastric mucosal damage • Bleeding may require transfusion in 1-4% • Perforation may occur • Need to correct the underlying condition

Answer 80

NON-STRESS related gastric bleeding Other causes 1. Dieulafoy lesion • Improper branching (not branching enough) of submucosal artery (diameter up to 3 mm • Lesser curvature, near GE junction • Erosion of overlying epithelium can cause bleeding (usually NSAIDS) 2. GAVE (gastric antral vascular ectasia) • Watermelon stomach: stripes of edematous erythematous mucosa alternating with paler mucosa • Histology shows reactive gastropathy with dilated capillaries and fibrin thrombi • GAVE also associated with cirrhosis and systemic sclerosis ** GAVE; Dilated capillaries with fibrin thrombi

Answer 81

CHRONIC GASTRITIS ``` Main causes 1. Helicobacter pylori 2. Autoimmune gastritis 3. Less common causes • Radiation • Chronic bile reflux • Mechanical injury • Systemic disease; Crohn disease, amyloidosis ```

Answer 82

Helicobacter pylori gastritis • H. pylori present in 90% with chronic gastritis affecting antrum • Spiral shaped or curved bacilli present in gastric biopsy • Acute H. pylori infection does not produce symptoms • Epidemiology • Associated with poverty, crowding, limited education • Humans primary carriers, so transmission fecal-oral route • Typically acquired in childhood • Improved sanitation has cause marked reduction • Prevalence less in young individuals

Answer 83

Helicobacter pylori Morphology • Gastric biopsy (antrum) usually shows H. pylori in infected individual • Usually around the superficial epithelial cells • Distribution can be irregular • Special stain (Giemsa, Warthin-Starry silver stain, immunostain) • Endoscopically erythematous mucosa • May have neutrophils, plasma cells, or lymphocytes (Lymphoid aggregates) • Atrophy with intestinal metaplasia has an increased risk for adenocarcinoma Treatment • Combination of antibodies and proton pump inhibitors • Relapses due to incomplete treatment or reinfection ***WARTHIN_STARRY STAIN: abundant organisms in surface mucin

Answer 84

Autoimmune gastritis * Less than 10% of chronic gastritis * Typically spares antrum * Associated with hypergastrinemia Characterized by • Antibodies to parietal cells and intrinsic factor (detected in serum and gastric secretions) • Reduced serum pepsinogen I concentration • Endocrine cell hyperplasia • Vitamin B12 deficiency • Defective gastric acid secretion (achlorhydria)

Answer 85

Autoimmune gastritis Clinical features • Gastric atrophy occurs over 2-3 decades after antibodies to parietal cells and IF • Median age of diagnosis 60 • F>M • ****Pernicious anemia (Not enough RBC produced , VIT B12 DEFICIENCY*** due to lack of IF production) and autoimmune gastritis associated with other autoimmune diseases • Possible genetic predisposition Clinical presentation may be linked to symptoms of anemia • ATROPHIC GLOSSITIS (B12 deficiency) (smooth beefy red) • Epithelial megaloblastosis • Malabsorptive diarrhea • Peripheral neuropathy; parenthesis and numbness • Spinal cord lesions • Cerebral dysfunction • Neuropathic changes - Demyelination - Axonal degeneration - Neuronal death • Peripheral neuropathy (most common paresthesias and numbness) • Subacute combined degeneration of the cord: spinal cord lesion result from demyelination of the dorsal and lateral spinal tracts - Loss of vibration and position sense, sensory ataxia, positive Romberg sign • Cerebral manifestation include mild personality changes and memory loss to psychosis • Neurologic changes not reversed by Vit B12 replacement (anemia reversed)**

Answer 86

EOSINOPHILIC GASTRITIS ** Can be associated with peripheral eosinophilia and increased serum IgE

Answer 87

LYMPHOCYTIC GASTRITIS

Answer 88

Granulomatous gastritis Crohn - poor formed granuloma Sarcoidosis - well formed granuloma

Answer 89

1. Peptic ulcer disease 2. Mucosal atrophy and intestinal metaplasia 3. Dysplasia 4. Gastritis cystica

Answer 90

PEPTIC ULCER DISEASE Epidemiology • Incidence falling in developed world (reduced H. pylori prevalence) • 60+ may have increased due to NSAIDS - Low-dose aspirin in cardiovascular patients Pathogenesis - Imbalance between mucosal defense mechanisms and damaging factors

Answer 91

PUD - peptic ulcer disease * *Patient with free air under diaphragm, mucosal defect * *Necrotic ulcer with granulation tissue ``` Clinical features **PAIN • Epigastric burning or aching pain • 1-3 hours after meals • Worse at night (11pm-2 am) • Relieved by alkali or food • Pain referred to back, left upper quadrant, or chest in penetrating ulcer ``` TREATMENT • Eradicate H. pylori • Neutralize gastric acid (proton pump inhibitors) • Stop NSAIDS

Answer 92

Mucosal atrophy and intestinal metaplasia 1. Loss of parietal cells 2. Intestinal metaplasia; INCREASED RISK OF ADENOCARCINOMA • Greatest risk in autoimmune gastritis • Achlorhydria of gastric mucosal atrophy permits overgrowth of bacteria that produce carcinogenic nitrosamines

Answer 93

Dysplasia in chronic gastritis

Answer 94

Gastritis Cystica

Answer 95

Hypertrophic gastropathies 1. Menetrier disease 2. Zollinger-Ellison syndrome

Answer 96

``` Menetrier disease (Hypertrophic gastropathies) ** Foveolar hyperplasia with elongated and dilated glands ``` Morphology • Irregular enlargement of gastric rugae in body and fundus (antrum spared) • Hyperplastic foveolar mucous cells • Elongated and cystically dilated glands with corkscrew appearance • Inflammation (chronic) present • Diffuse and patchy atrophy Treatment • Supportive (IV albumin and parenteral nutritional supplement) • Gastrectomy in severe cases • Recently agents that block TGF-alpha receptor

Answer 97

Zollinger-Ellison Syndrome Stomach • Doubling of oxyntic cells • Hyperplasia or mucous cells • Proliferation of endocrine cells Treatment • Blockade of acid hypersecretion (proton pump inhibitors) • 60-90% of gastrinomas are malignant • Solitary and surgically removed • 75% sporadic, 25% MEN I (benefit from somatostatin analog)

Answer 98

* Inflammatory and hyperplastic polyps * Fundic gland polyps * Gastric adenoma * Gastric adenocarcinoma * Lymphoma * Carcinoid tumor * Gastrointestinal stromal tumor

Answer 99

Stomach: Inflammatory and hyperplastic polyp * Up to 75% gastric polyps are inflammatory or hyperplastic polyps * Associated with chronic gastritis (H. pylori infection) * 50-60 year olds * Inflammation lead to reactive hyperplasia and polyps * *Corkscrew-shaped foveolar glands * *Hyperplastic polyp with ulceration

Answer 100

Gastric polyp: Fundic gland polyp ``` Morphology • In body and fundus • Well circumscribed and smooth surface • Single or multiple • Cystically dilated irregular glands lined by flattened parietal and chief cells • No significant inflammation • Sporadic-no cancer risk • Familial (FAP)-dysplasia and cancer risk ``` ** Cystically dilated glands lined by flattened parietal and chief cells, no significant inflammation

Answer 101

GASTRIC ADENOMA • Polyp lined by dysplastic epithelial cells • 50-60 year olds • M>F • Background of chronic gastritis with atrophy and intestinal metaplasia • In FAP • Increased risk of carcinoma - Size (higher risk if more than 2 cm) - Carcinoma present in up to 30% of adenomas ** Dysplastic epithelial cells with architectural and nuclear atypia

Answer 102

Gastric adenocarcinoma • Incidence higher in Japan, Chile, Costa Rica and Eastern Europe - Mass endoscopic screening successful and cost effective • Metastatic disease common in low incidence areas - Common metastatic sites include supraclavicular node (Virchow node), periumbilical node (Sister Mary Joseph nodule), left axillary node (Irish node), ovary (Krukenberg tumor), or the pouch of Douglas (Blumer shelf) • More common in lower socioeconomic group • Gastric dysplasia and adenoma are precursor lesions • US rate dropped 85% in 20th century (most common cause of cancer death in 1930); now 2.5% of cancer deaths • Decrease rate closely linked to - Decrease in H pylori prevalence - Decrease consumption of dietary carcinogens (N-nitroso compounds and benzopyrene) • Cancer of gastric cardia is however on the rise due to Barrett esophagus

Answer 103

Gastric adenocarcinoma Morphology **Mainly involves the Antrum along the lesser curvature 1. Intestinal type • Bulky tumor with glandular structures • Exophytic mass or an ulcerated mass • Apical mucin 2. Diffuse type • Diffuse infiltrative growth, composed of signet ring cells • Discohesive cells (likely E-cadherin loss) • Large mucin vacuole pushing nucleus to the side- signet ring morphology • Linitis plastica: Leather bottle appearance, large area of infiltration with rugal flattening, rigid thick wall * *Intestinal type adenocarcinoma; - Elevated mass with raised border, center ulcer - Histology shows gland forming tumor * * Linitis plastica: Thickened wall and rugal fold loss * *Signet-ring cells; large cytoplasmic vacuole with margination of nuclei

Answer 104

GASTRIC ADENOCARCINOMA ``` Clinical features 1. Intestinal type • Predominates in high risk areas • Arises in precursor lesions • Mean age 55 • M:F=2:1 ``` 2. Diffuse type • Relatively uniform across regions • No precursor lesions • M:F=1:1 • Depth of invasion, nodal status, and distant metastasis most important prognostic features Treatment • Surgical resection (preferred treatment) • 5 year survival over 90% in resectable tumors • 5 year survival less than 20% in advanced tumors

Answer 105

GASTRIC LYMPHOMA • Extra-nodal lymphoma common in GI tract • Most common: Extra-nodal marginal zone B-cell lymphoma Pathogenesis • Sites of chronic inflammation (chronic gastritis) • Gastric MALToma (mucosa associated lymphoid tissue lymphoma) translocation • T(11;18) (q21;q21); t(1;14) (p22;q32), and t(14;18) (q32;q21) • Activation of NF-kappaB (transcription factor that promotes B-cell growth) • Can transform to more aggressive diffuse large B-cell lymphoma * * Gastric MALT lymphoma replacing gastric epithelium, lymphocytes infiltrating epithelium * * Serosal implants of lymphoid nodules Clinical Features • Dyspepsia and epigastric pain • Others include hematemesis, melena, weight loss

Answer 106

Carcinoid tumor • Known as well differentiated neuroendocrine tumor • Gastric carcinoid may be associated with endocrine cell hyperplasia, autoimmune atrophic gastritis, MEN-I, and Zollinger-Ellison syndrome

Answer 107

Stomach carcinoid • First pass effect: vasoactive substances released by intestine metabolized to inactive forms (so carcinoid syndrome associated with mets)

Answer 108

Prognostic factor for GI carcinoid tumors is its location 1. Foregut carcinoid tumors: Esophagus, stomach, duodenum proximal to ligament of Treitz • Rarely metastasize and cured by resection 2. Midgut carcinoid tumors: Jejunum and ileum • Multiple and more aggressive • Greater depth of invasion, necrosis and increase in mitotic figures 3. Hindgut carcinoids: Appendix and colorectal • Appendix and tip • Almost always benign • Rectal carcinoid can produce polypeptide hormones and present with abdominal pain and weight loss ** Submucosal nodule, golden tan Histology shows nests of tumor cells ** Bland cytology with “salt and pepper” chromatin *EM, cytoplasmic neurosecretory granules

Answer 109

Gastrointestinal stromal tumor (GIST) Epidemiology • Clinically silent • 60 Years • Carney triad (young females, gastric GIST, paraganglioma, pulmonary chondroma, extra-adrenal paraganglioma) - Nonhereditary syndrome of unknown etiology • Also increased incidence of GIST in neurofibromatosis type I (multiple benign tumors of nerves and skin)

Answer 110

Gastrointestinal stromal tumor (GIST) Morphology • Gastric GIST can be large (up to 30 cm) • Solitary well-circumscribed submucosal mass • Cut surface shows whorled appearance Histologic types • Spindle cell type • Epithelioid type • Mixed type **Immunohistochemical stain: KIT (CD117)

Answer 111

Gastrointestinal stromal tumor (GIST) Clinical features Symptoms related to mass effect • Mucosal ulceration can cause blood loss and anemia • Usually incidental finding Primary treatment • Complete resection • Unresectable, recurrent, or with metastasis, molecular phenotype is important - Tyrosine kinase inhibitors (imatinib) used for those with mutation Prognosis • Location, tumor size, mitotic rate • Gastric GIST less aggressive

Answer 112

1. D. HASHIMOTO THYROIDITIS 2. A. Interstitial cells of canal 3. C - hyperplastic polyps 4. D - Neuroendocrine cells

Answer 113

1. Duodenum - mucosa - submucosa with brunner’s gland - muscularis externa 2. Ileum - smooth muscle, lymph node, crypts, villi 3. Jejunum - epithelium, lamina propria, muscularis mucosa - smooth muscle fibers of muscularis mucosa, crypts (lamina propria), goblet cells

Answer 114

1. Atresia and stenosis 2. ECTOPIA 3. Diverticulum

Answer 115

A. Atresia B. Stenosis Complications obstruction, perforation, meconium peritonitis, brown bowel syndrome

Answer 116

ATRESIA 3 subtypes A. Fibrous diaphragm forms in the lumen of the bowel, creating a complete obstruction. B. Complete fibrosis of a segment of the bowel can leave the surrounding segments connected by a string-like cord. C. Complete separation between two sections of bowel wall and completely closes off each end.

Answer 117

ECTOPIA *Normal tissue in abnormal location 2 subtypes of HETEROTROPIC GASTRIC MUCOSA A. Lined by foveolar epithelium only (congenital or acquired) B. Lined by foveolar epithelium along with FUNDIC GLANDS (congenital only) Differential of Gastric Ectopia: Gastric metaplasia: Metaplasia→ transformation of one tissue into another - Involves only part of mucosal thickness, usually surface epithelium only, no parietal cells - Presence in duodenum - Associated with H. pylori infection - Probably not congenital - Typically no gross findings

Answer 118

Heterotopic gastric mucosa - multiple mucosal nodules - erosion **In duodenum, presenting as a polypoid mass Morphology A. Gastric foveolar epithelium; congenital or acquired B. Gastric foveolar epithelium and fundic glands ; congenital only

Answer 119

DIVERTICULUM 1. True diverticulum: blind outpouching of the alimentary tract that communicates with the lumen and includes all three layers of the bowel wall 2. Meckel diverticulum Most common true diverticulum - failed involution of the vitelline duct, which connects the lumen of the developing gut to the yolk sac

Answer 120

Meckel Diverticulum Characteristics of Meckel diverticula (Rule of 2s): - occur in approximately 2% of the population - generally present within 2 feet (60 cm) of the ileocecal valve - approximately 2 inches (5 cm) long - twice as common in males - most often symptomatic by age 2 (only ~4%) Complications - perforation, - enteroumbilical fistula, - peptic ulceration (usually in adjacent ileum and not in diverticulum), - hemorrhage (often massive in children), - intussusception, - obstruction, - carcinoid and other tumors

Answer 121

INTESTINAL OBSTRUCTION Causes - Hernias, intestinal adhesions, intussusception and volvulus (80%) - Tumors, infarction, other causes of strictures for example crohn disease (10-15%)

Answer 122

INTESTINAL OBSTRUCTION; HERNIA * Any weakness or defect in the abdominal wall may permit protrusion of a serosa-lined pouch of peritoneum called a hernia sac * Most frequently-associated with inguinal hernias * Obstruction usually because of visceral protrusion/entrapped -- >permanent entrapment (incarceration) ---- > compromised vascular supply (strangulation) -- > infarction

Answer 123

Intestinal obstruction; ADHESIONS • Peritoneal inflammation result in development of adhesions between bowel segments, the abdominal wall, or operative sites due to: - Surgicalprocedures - Infection - Other causes : Endometriosis etc

Answer 124

Intestinal Obstruction: VOLVULUS | • Most often in sigmoid colon> cecum> small bowel> stomach>transverse colon

Answer 125

Intestinal Obstruction: Intussusception • A segment of the intestine, constricted by a wave of peristalsis, telescopes into the immediately distal segment • Most common cause of intestinal obstruction in children <2 years of age: --- Idiopathic with no anatomic defect, viral infection and rotavirus vaccines • Rare in older children and adults: an intraluminal mass or tumor Management: - Contrast enemas: Diagnostically and therapeutically used for idiopathic intussusception - Surgical intervention when a mass

Answer 126

ISCHEMIC BOWEL DISEASE; Most of the intestinal injury in ischemic bowel disease is actually caused by Reperfusion Types 1. Chronic ischemia (progressive hypoperfusion); tolerate well, because of unique vascular supply - Celiac, superior mesenteric, and inferior mesenteric arteries --- > ramify into the mesenteric arcades - Interconnectionsbetweenarcades - Collateral supplies from the proximal celiac and distal pudendal and iliac circulations 2. Acute compromise of any major vessel ------ →infarction of several meters of intestine: - Mucosal - Mural (mucosa and submucosa) - Transmural (all three layers) 3. Lesions within the end arteries →small, focal ischemic lesions Severity of injury • Mucosal or mural infarctions: acute or chronic hypoperfusion • Transmural infarction : acute vascular obstruction

Answer 127

ISCHEMIC BOWEL DISEASE Predisposing causes 1. Acute arterial obstruction - atherosclerosis(oftenprominentattheorigin of mesenteric vessels), - aorticaneurysm, - hypercoagulablestates, - oral contraceptive use, - embolization of cardiac vegetations or aortic atheromas 2. Nonocclusive ischemia: - Hypoperfusion: cardiac failure, shock, dehydration, - Vasoconstrictive drugs (e.g., digitalis, vasopressin, propranolol) - Infections: CMV (immunosuppressive therapy) - Radiation Enterocolitis (endothelial injury) - Necrotizing enterocolitis (NEC) - Systemic vasculitides: polyarteritis nodosa, Henoch- Schönlein purpura, granulomatosis with polyangiitis (Wegener granulomatosis) 3. Mesenteric venous thrombosis (uncommon): - inheritedoracquiredhypercoagulablestates, - invasiveneoplasms, - cirrhosis, - trauma, - abdominal masses that compress the portal drainage

Answer 128

ISCHEMIC BOWEL DISEASE Gross findings • EARLY STAGE: intensely congested and dusky to purple-red with foci of subserosal and submucosal ecchymotic discoloration • SUBSEQUENTLY, the wall becomes edematous, thickened, rubbery, and hemorrhagic--- >lumen commonly contains sanguineous mucus or frank blood • ARTERIAL OCCLUSIONS the demarcation from normal bowel is usually sharply defined, but in VENOUS OCCLUSIONS the area of dusky cyanosis fades gradually into the adjacent normal bowel - Arterial occlusions : demarcation from normal bowel is usually sharply defined - Venous occlusions the area of dusky cyanosis fades gradually into the adjacent normal bowel. - Characteristic attenuated villous epithelium in this case of Acute mesenteric thrombosis. - Chronic colonic ischemia with atrophic surface epithelium and fibrotic lamina propria.

Answer 129

MALABSORPTION • Defective absorption of fats, fat- and water- soluble vitamins, proteins, carbohydrates, electrolytes and minerals, and water Mechanism; AT LEAST one of four phases of nutrient absorption process; 1) Intraluminal digestion; chronic pancreatitis, cystic fibrosis, primary bile acid malabsorption 2) Terminal digestion; celiac, environmental enteropathy, autoimmune enteropathy, disaccharides deficiency, IBD 3) Transepithelial transport; celiac, environmental enteropathy, primary bile acid malabsorption, carcinoid syndrome, autoimmune enteropathy, abetalipoproteinemia, IBD 4) Lymphatic transport of absorbed lipids; whipple disease * *IBD (inflammatory bowel disease) - 3 phases affected expect lymphatic transport Symptoms • General symptoms: Diarrhea, flatus, abdominal pain, and weight loss • Nutrient-specific symptoms: Anemia and mucositis, bleeding, osteopenia and tetany, peripheral neuropathy and a variety of endocrine and skin disturbances

Answer 130

Major site of absorption 1. Fat - proximal small intestine 2. Protein - mid small intestine 3. Iron - DUODENUM ** 4. Carbohydrate - Proximal and mid small intestine 5. Calcium - proximal small intestine 6. Folic acid - proximal and mid small intestine 7. Cobalamin (B12) - distal small intestine (ileum) 8. Water soluble vitamins - proximal and mid small intestine 9. Bile salts - distal small intestine (ileum) 10. H20 and electrolytes - small intestine and cecum

Answer 131

Malabsorption: Celiac Disease (Celiac Sprue /Gluten Sensitive Enteropathy) • Association between celiac disease and other immune diseases: - Type 1 diabetes - Thyroiditis - Primary biliary cirrhosis - IgA deficiency - Down syndrome - Turner syndrome - First degree relatives of individuals with celiac disease

Answer 132

Celiac Disease **Blistering disorders; Dermatitis herpetiformis Long term complications - Anemia, - Femaleinfertility - Osteoporosis - Cancer: Enteropathy-associated T-cell lymphoma and small intestinal adenocarcinoma

Answer 133

CELIAC DISEASE Histologic findings • Changes more in duodenum and upper jejunum • Increased intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy • Increased intraepithelial lymphocytes, particularly in the villus -> sensitive marker of celiac disease • Intraepithelial lymphocytosis and villous atrophy -> NOT SPECIFIC for celiac • Mucosal histology usually reverts to normal or near-normal following a period of gluten-free diet

Answer 134

Environmental enteropathy/Tropical enteropathy/Tropical sprue * Neither oral antibiotics nor nutritional supplementation, with calorie-dense foods, vitamins, or minerals, are able to correct these deficits * Recent data : IRREVERSIBLE LOSSES in physical development may accompanied by UNCORRECTABLE COGNITIVE DEFICITS * Global impact : > 150 million children worldwide; child death

Answer 135

Autoimmune Enteropathy • Common, autoantibodies to enterocytes and goblet cells; some patients may have antibodies to parietal or islet cells • Increased intraepithelial lymphocytes (less than celiac disease), neutrophils present. **Immunosuppressive drugs (CYCLOSPORINE)

Answer 136

A) Congenital lactase deficiency (AR): Rare - Gene mutation encoding lactase - Presents as explosive diarrhea with watery, frothy stools and abdominal distention upon milk ingestion B) Acquired lactase deficiency: Down-regulation of lactase gene expression - Common among Native American, African American, and Chinese populations - Can develop following enteric viral or bacterial infections and may resolve over time

Answer 137

Abetalipoproteinemia * Failure to properly export lipids from the small intestine mucosa to lymphatics ---→lipid accumulation in enterocytes ---- > reduces their capacity to absorb lipids from ingested food --→ lipid malabsorption syndrome * Presents in infancy; failure to thrive, diarrhea, and steatorrhea * Long-term inability to absorb lipids --- > deficiency of critical fatty acids or plasma membrane maintenance -- > Acanthocytes * * Acanthocytic red cells (burr cells) in peripheral blood smear * * Enterocytes with clear cytoplasm due to lipid accumulation

Answer 138

SMALL BOWEL NEOPLASM **NEUROENDOCRINE NEOPLASM (WHO) 1. Well differentiate Neuroendocrine TUMOR (either primary or metastasis) (previously called carcinoid): - -- Most common small bowel neoplasm 2. Poorly differentiated Neuroendocrine CARCINOMAS • Primary ADENOCARCINOMA: Rare - Duodenum: most common site • GI lymphoma: Rare

Answer 139

GI Neuroendocrine Tumor (NET) Peak incidence : sixth decade, but at any age ``` Symptoms: depends on hormones produced 1. Stomach: gastrin -- >ZOLLINGER-ELLISON SYNDROME 2. Ilealtumors----->CARCINOID SYNDROME;<10% • Cutaneous flushing, • sweating, • bronchospasm, • colicky abdominal pain, • diarrhea, and • right-sided cardiac valvular fibrosis ```

Answer 140

GI NET: Carcinoid Syndrome Most important prognostic factor : LOCATION • Foregut carcinoid tumors (stomach, duodenum proximal to the ligament of Treitz, and esophagus): - rarely metastasize - generally cured by resection • Midgut carcinoid tumors (jejunum and ileum) - Often multiple - Aggressive (greater depth of local invasion, increased size, and the presence of necrosis and mitoses) • Hindgut carcinoids (appendix and colorectum) - Typicallydiscoveredincidentally - Appendix: occur at any age, located at the tip - <2cmindiameter - Almostalwaysbenign - Rectalcarcinoidtumors:polypeptidehormones and, when symptomatic, present with abdominal pain and weight loss

Answer 141

GI Neuroendocrine Tumor (NET) Histology • Composed of islands, trabeculae, strands, glands, or sheets of uniform cells • Scant, pink granular cytoplasm and a round to oval stippled nucleus • minimal pleomorphism, but anaplasia, mitotic activity, and necrosis in rare cases • Immunohistochemical stains: - positive for endocrine granule markers (synaptophysin and chromogranin A) * *Microscopic; Microscopically the nodule is composed of tumor cells embedded in dense fibrous tissue. * *Carcinoid tumor of small bowel, showing a nesting (insular) pattern of growth * * In other areas, the tumor has spread extensively within mucosal lymphatic channels. * *EM; reveals cytoplasmic dense core neurosecretory granules

Answer 142

Gastrointestinal GI Lymphoma • Primary GI lymphoma is rare • Usually 2ndary of nodal lymphoma B cell lineage (~ 90% cases) - Diffuse large B cell lymphoma (DLBCL) - Mucosa-associated lymphoid tissue (MALT) - Follicular lymphoma - Mantle cell lymphoma - Burkitt lymphoma - Immunoproliferative small-intestinal disease(IPSID) T cell lineage lymphoma - EATL: Enteropathy-associated T-cell lymphoma - Peripheral T cell lymphoma (PTCL)

Answer 143

Gastrointestinal Lymphoma: (IPSID) ** Gross appearance of malignant lymphoma involving the ileum in a diffuse fashion and resulting in prominence of the transverse mucosal folds

Answer 144

Gastrointestinal Mesenchymal Tumors

Answer 145

Gastrointestinal stromal tumor (GIST) of small intestine A. Spindle cell tumor is seen B. KIT (CD117) is strongly positive

Answer 146

* Congenital: Hirschsprung Disease * Ischemic Colitis * Angiodysplasia * Sigmoid diverticular disease: Diverticulosis, diverticulitis * Appendicitis * Inflammatory Bowel Disease (IBD)

Answer 147

Hirschsprung Disease (Congenital aganglionic megacolon) • Occurs in ~1 of 5000 live births • 10% of all cases with Down syndrome and 5% with serious neurologic abnormalities • Lacks both the Meissner submucosal and the Auerbach myenteric plexus (aganglionosis) LEAD TO absent of coordinated peristaltic contractions LEAD TO obstruction LEAD TO dilation proximal to the affected segment (so massive called megacolon!) - wall thin to rupture ORGANS - always involves rectum, more proximal colon to varying extent Mechanics; UNKNOWN Genetics - nearly all cases (~4% of patients’ siblings; receptor tyrosine kinase RET gene)

Answer 148

ISCHEMIC COLITIS • Segments involved: Two watershed zones - Splenic flexure - Rectosigmoid colon • Surface epithelium particularly vulnerable to ischemic injury, relative to the crypts • Presentation: sudden onset of cramping, left lower abdominal pain, a desire to defecate, and passage of blood or bloody diarrhea **--- >may progress to shock and vascular collapse within hours in severe cases

Answer 149

Angiodysplasia Malformed submucosal and mucosal blood vessels bleed ( Chronic and intermittent or acute and massive) --- > TORTUOUS dilations of submucosal and mucosal blood vessels

Answer 150

SIGMOID DIVERTICULAR DISEASE **Sigmoid colon – caused by increased intraluminal pressure (more dilated area) and focal weakness in colonic wall • Most remain asymptomatic • ~ 20% of individuals with diverticuli develop manifestations of diverticular disease: - such as intermittent cramping, - continuous lower abdominal discomfort, - constipation, distention, or a sensation of never being able to completely empty the rectum. - alternating constipation and diarrhea that can mimic IBS. - minimal chronic or intermittent blood loss, and, rarely, massive hemorrhage. - Inflammation, abscess and perforation

Answer 151

ACUTE APPENDICITIS (in cecum) • Dx & Rx: CT, surgical resection • Complications: perforation, abscess, peritonitis • All age groups; most common indication for emergent abdominal surgery in children • Differential dx: diverticulitis, ectopic pregnancy * *Typical acute appendicitis with fibrinopurulent exudate on the surface * *Marked neutrophilic infiltration of appendices wall

Answer 152

IBD - INFLAMMATORY BOWEL DISEASE • Two types: 1) Ulcerative colitis, 2) Crohn disease • Distinction between ulcerative colitis and Crohn disease based, in large part, 1) Distribution of affected sites, and 2) Morphologic findings 1. ULCERATIVE COLITIS - Limited to the colon and rectum - Continuous ** - Extends only into the mucosa and submucosa **SUPERFICIAL** 2. CROHN DISEASE - Any area of the GI tract (oral cavity to anus) - Skip lesion** - Typically transmural (go through muscle) - Frequent ileal involvement (regional enteritis)

Answer 153

IBD - Inflammatory bowel disease Age on onset: - (15-40) years; frequently in teens and early 20s - Possible 2nd pick: (50-80) years Gender: Small differences - UC: female>male Genetic susceptibility: - 10-25% IBD: a first degree relative Racial and ethnicity: - European (Ashkenazi)Jews > whites> black and Hispanic - Israel: European and American-born> Jews from Asia and Africa Geographic distribution - Most common in North America, northern Europe, and Australia - Increasing world-wide and becoming more common in Africa, South America, and Asia where its prevalence was historically low

Answer 154

1. Crohn disease - Concordance rate for monozygotic twins ~50% - Phenotypic expression: twins affected by Crohn disease tend to present within a few years of each other and develop disease in similar regions of the GI tract **Genes involved in Crohn’s disease: NOD2, ATG16L1, and IRGM • NOD2 (nucleotide oligomerization binding domain 2): - Encodes an intracellular protein that binds to bacterial peptidoglycans ----- > activates signaling events, including the NF-

Answer 155

1. T helper cells; activated in Crohn disease and the response is polarized to the Th1 type cells 2. Th17 T cells; most likely contribute to disease pathogenesis - IL 23 receptor; involved in development and maintenance of Th17 T cells - Polymorphism of IL 23; reduce to risk develop IBD 3. Pro-inflammatory cytokines; TNF, interferon-y, IL 13 4. Immunoregulatory molecules; IL 10, TGF-beta

Answer 156

A. Crohn’s disease - Defects in intestinal epithelial tight junction barrier function in patients and a subset of their healthy first- degree relatives - Associated with NOD2 polymorphisms B. Ulcerative colitis: - Some polymorphisms, involving ECM1 (extracellular matrix protein 1), which inhibits matrix metalloproteinase 9 - Certain polymorphisms in the transcription factor HNFA

Answer 157

• NOD2, points to the involvement of microbes in the causation of Crohn disease • Antibodies against the bacterial protein flagellin: - Most common in Crohn disease patients associated NOD2 variants, stricture formation, perforation, and small-bowel involvement. - Uncommon in ulcerative colitis

Answer 158

CROHN DISEASE Complications • Iron-deficiency anemia (if colon involve) • Serum protein loss and hypoalbuminemia, generalized nutrient malabsorption, or malabsorption of vitamin B 12 and bile salts (Small bowel involvement) • Fibrosing strictures: commonly in terminal ileum and require surgical resection • Fistulae

Answer 159

ULCERATIVE COLITIS **Extraintestinal manifestations: overlap with Crohn disease and include - ~2.5% to 7.5% of individuals: primary sclerosis cholangitis • >50% patients have clinically mild disease • Up to 30% require colectomy within the first 3 years after presentation • Colectomy effectively cures intestinal disease in ulcerative colitis, but extraintestinal manifestations may persist

Answer 160

CROHN DISEASE (IBD) Location: any area of the GI tract - most common sites involved at presentation are the terminal ileum, ileocecal valve, and cecum. - small intestine alone ~40% of cases - small intestine and colon both in ~30% - Colon only ~30% • Multiple, separate, sharply delineated areas of ulcer • SKIP LESIONS** • Earliest lesion (APHTHOUS ULCER)**--- >multiple lesions often coalesce into elongated, serpentine ulcers along the axis of the bowel • COBBLESTONE appearance Pathology • Fissures -- > fistula -- > perforation • Strictures: common in Crohn disease (do not generally develop in ulcerative colitis) • Transmural: Extensive cases, creeping fat Microscopic findings - Acute inflammation -- > ulcer, crypt abscesses - Distortion of mucosal architecture: Branching of crypts - Paneth cell metaplasia of left colon - NONCASEATING GRANULOMAS: HALLMARK of crohn disease, present ~35% cases, absence of granulomas does not preclude CD

Answer 161

ULCERATIVE COLITIS Patho findings • Always involves the rectum and extends proximally in a continuous fashion - pancolitis - left-sided disease: extends till transverse colon - limited distal: ulcerative proctitis or ulcerative proctosigmoiditis • Small intestine: Normal; backwash ileitis • Slightly red and granular; extensive - >broad-based ulcers • Pseudopolyps ----- > mucosal bridges • Chronic disease - > mucosal atrophy (flat and smooth mucosal surface that lacks normal folds) ** Microscopic findings: - Similar like CD, but extensive and mucosal and submucosal involvement , negative for granulomas

Answer 162

COLITIS ASSOCIATED NEOPLASIA * *The risk of dysplasia is related to several factors (3) 1. Duration of the disease: - Risk increases sharply 8 to 10 years after disease onset 2. Extent of the disease: - Pancolitis are at greater risk than those with only left-sided disease 3. Nature of the inflammatory response: - Greater frequency and severity of active inflammation (characterized by the presence of neutrophils) confers increased risk

Answer 163

Importance of gut microbiota The fetus does not reside in a sterile intrauterine environment as it is constantly exposed to commensal bacteria from the maternal gut/blood stream that cross the placenta and enter the amniotic fluid. Colonizing intestinal bacteria are critical to the normal development of host defense. Disruption to this process may affect the development of the host immune system. The first 6 months of life, host defense is mainly from maternal sources of IgG, which is transported via FcRn from mother to fetus mainly during the last trimester of pregnancy. 6-36 months, gut microbiota fluctuates, coincides with the maturation of peyer’s patches, i.e., the immune system maturation. Species from the genus Bacteroides alone is about 30% of all bacteria in the gut, suggesting that this genus is especially important in the functioning of the host

Answer 164

Distribution * * ● 1000 different species in human gut. ● 100 trillion bacteria in our body (10 trillion in our gut). * * Composition of the human gut microbiota inferred from 16S rRNA sequences * * Human microbiota is composed by 5 phyla - Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia being * ***Bacteroidetes and Firmicutes around 90% of the total bacterial species. Most of the species are un- culturable. 1. Stomach ; 0-10^2 - lactobacillus - candida - streptococcus - helicobacter pylori - peptostreptococcus 2. Duodenum 10^2 - streptococcus - lactobacillus 3. Jejunum - streptococcus - lactobacillus 4. Proximal ileum - streptococcus - lactobacillus 5. Distal ileum - clostridium - streptococcus - bacteroides - actinomycinae - corynebacterium 6. Colon; 10^11 - 10^12 - bacteroides - clostridium groups IV and XIV - bifidobacterium - Enterobacter

Answer 165

Methods of alteration A. Introduction of pathogenic strains B. Administration of antibiotics C. Prebiotics (ie, dietary components that promote the growth of and metabolic activity of beneficial bacteria) D. Probiotics (ie, beneficial bacteria) E. Fecal transplant (Bacteriotherapy)

Answer 166

1. Probiotics beneficial microbes; list continues to grow - Strains of lactic acid-producing bacilli (Lactobacillus and Bifidobacterium) - Nonpathogenic strain of E. coli (eg E. coli Nissle 1917) - Clostridium buyricum - Streptococcus salivarius - Saccharomyces boulardii (nonpathogenic strain of yeast) 2. Mechanism of probiotic benefits - Suppression of growth or epithelial binding/invasion by pathogenic bacteria; - Improvement of intestinal barrier function; - Modulation of immune system; - Modulation of pain perceptions. 3. Infectious diarrhea; bloody vs watery (examples) A. Bloody; campylobacter, salmonella enterica, shigella, yersinia enterocolitica, EIEC, entamoeba histolytica, EHEC C. Watery; ETEC, cholera, C.diff, C.perfringens, giarrdia, crypto, rotavirus, norovirus ** Fecal WBC, RBCs usually indicate invasive infection Mucous, epithelial cells only seen in toxin-mediated disease Stool ova and parasite seen in protozoal infections

Answer 167

Campylobacter jejuni Diseases 1. Gastroenteritis-immunocompetent host 2. Diarrhea and septicemia-immunocompromised host (CD4 count of <200/ l) • Long-term complications: An association has been established between C. jejuni infection and the Guillain-Barre syndrome (GBS), an acute demyelinating neuropathy. • Serum antibodies against LPS cross-reacts with CNS gangliosides (autoimmune). • It is estimated that approximately one in every 1,000 reported Campylobacter illnesses leads to Guillain-Barré syndrome. As many as 30% of Guillain-Barré syndrome cases may be triggered by campylobacteriosis and 10% due to cytomegalovirus (CMV, HHV-

Answer 168

Helicobacter pylori General - Chronically infects about 50% of the world’s human population. • Colonizes gastric mucosa of humans. • WHO recently declared H. pylori a class I carcinogen. • 2/3 of patients diagnosed with gastric cancer die of this disease. ** Sliver stain of spiral-shaped bacteria adhering to the mucosal surface of gastric pit Disease associated with H.pylori 1. Chronic gastritis-inflammation of the lining of the stomach. 2. Peptic ulcer disease (PUD). 3. Mucosa-associated lymphoid tissue (MALT) lymphoma. 4. Maybe, stomach adenocarcinoma.

Answer 169

1. A healthy microbiome provides indispensable instruction to the developing immune system. - GALT - Antibody Production and CD8 cells - Th1, Th2 and Th17 cells 2. The human microbiome can confer susceptibility or resistance to pathogen colonization depending on its composition and harbors a diverse reservoir of antibiotic resistance genes. - Bacteroidetes and Firmicutes - Colonization resistance. 3. The human microbiota contributes to nutrition and human health. Dietary fiber is fermented to produce short-chain fatty acids (SCFA) volatile fatty acids (VFAs), ACETATE (C2), PROPIONATE (C3), and BUTYRATE (C4, ANTI- INFLAMMATORY EFFECT) *** Microbiota helps nutrient uptake and metabolism in gut epithelial cells; Priming the immune system early in life to recognize the flora as non foreign; Development of barrier to colonization by foreign bacteria.

Answer 170

* *Human microbiota is composed by 5 phyla Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia being * *Bacteroidetes and Firmicutes around 90% of the total bacterial species. Most of the species are un- culturable. 1. FIRMICUTES phylum, Gram-positive bacteria. 2. BACTEROIDETES phylum: Gram-negative. 3. FIRMICUTES TO BACTEROIDETES RATIO (F/B ratio): Related to obesity. Obese microbiota tend to have a higher level of Firmicutes, and also decrease the species diversity. 4. SHORT-CHAIN FATTY ACIDS (SCFA, R-COOH): Undigested diety fibers comes to colon where fermentation occurs: butyrate (C4), propionate (C3), lactate (C2) and acetate (C2) almost like the hormones produced by gut microbiota (endocrine organ) 5. BACTEROIDES FRAGILIS is the most commonly isolated bacteria species in human gut. **Segmented Filamentous bacteria (SFB); SEM of mouse

Answer 171

INVASIVE ENTERITIS (Campylobacter jejuni) Treatment • Campylobacter gastroenteritis is typically self-limiting (fluid replacement). - Erythromycin is the antibiotic of choice. - Tetracycline and quinolones are secondary antibiotics. - Systemic infections are treated with aminoglycosides.

Answer 172

Helicobacter pylori • HP present on the luminal surface of fovealar gastric mucosa, direct cause of chronic gastritis (CSG). • HP does not invade tissue. **Formation of gastric cancer; infection - inflammation - increase reactive oxygen and nitrogen molecules - epithelial cell damage - malignant transformation **Chronic inflammation of gastric mucosa Chronic gastritis: - lymphoplasmacytic infiltrate. - Shown here is lamina propria of the fundus and intraepithelial neutrophils. *ADENOCARCINOMA • Predominant form of gastric cancer, 95% of all cases. • Inflammatory infiltrate and toxic molecules causes damage to gastric epithelium resulting in genetic mutations which may lead to the formation of adenocarcinoma. * MALToma (MALT - lymphoma) - Mucosa-associated lymphoid tissue (MALT) - B-cell lymphoma. - HIGHLY associated with H. pylori infection TREATMENT * Triple therapy for 7-10 days - Proton pump inhibitor - Clarithromycin - Amoxicillin/Metronidazole * Testing often repeated to confirm eradication - Breath test, stool antigen, or biopsy * Treatment failures about 20% - Alternative regimens can be tried

Answer 173

1. Escherichia coli 2. Salmonella species 3. Shigella species 4. Campylobacter species 5. Yersinia enterocolitica 6. Vibrio cholera 7. Vibrio parahaemolyticus 8. Bacillus cereus 9. Clostridium perfrigens 10. Entamoeba histolytica 11. Giadia lamblia

Answer 174

Enterohemorrhagic E. coli (EHEC) • Consumption of hamburger “pink inside” • Does not produce LT or ST, but Shiga- like toxins (STL) (encoded on a phage). • Large intestine (Attaching-effacing) • Pediatric diarrhea, copious bloody discharge (hemorrhagic colitis), intense inflammation and hemolytic uremia syndrome (HUS)-antibiotic treatment controversial • About 50 serotypes, the most common- O157:H7, low inoculum size similar to Shigella, Infectious dose=10-100 HUS (Hemolytic uremia syndrome) • Simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury • Platelets are used to form microthrombi, resulting in hemolytic anemia with schistocytes. • Similar to thrombotic thrombocytopenic purpura (TTP). • Shiga toxin (verotoxin) damages endothelial cells in small vessels resulting in platelet microthrombi. • Use a similar mechanism by decreasing the activity of ADAMTS13 which cleaves vWF multimers. TTP patients produces an autoantibody. • TTP more common in CNS while HUS mainly occurs in kidney

Answer 175

1. Shigella * * similar to invasive E.coli Pathogenesis - Target the cells lining the colon - Invade the M cells in Peyer patches - Use the type III secretion system (IpaA-B-C-D) to induce membrane ruffling to engulf the bacteria - Lyse the phagocytic vacuole - Cell-to-cell spread through actin tail -Induce apoptosis Mechanism - S. dysenteriae can cause the hemolytic-uremic syndrome, mediated by Shiga toxin (Stx). - Bacteremia is uncommon with Shigella. - S. dysenteriae produce Shiga toxin, similar to the toxin made by EHEC. AB5. The host cell receptor is glycolic is GB3. A cleaves the 28S rRNA in the 60S ribosomal subunit Clinical diagnosis - Methylene blue stain of a fecal sample to determine the presence of PMN. If present, they could be an invasive organism such as Shigella, Salmonella, or Campylobacter ``` Treatment and prevention • Not normal GI flora • Fecal-oral transmission • Common in children • Diagnosis: Stool culture • Treatment - fluids/electrolytes - antibiotics improve symptoms, reducing shedding in stool; CAN LIMIT SPREAD - Cetriaxone or Ciprofloxacin ```

Answer 176

* * Colon section: an intense inflammatory response with the characteristic “plaque” (black arrow) overlying the intact mucosa (white arrow) * * Antibiotic-associated colitis: White plaques of fibrin, mucus, and inflammatory cells - Originally associated with use of clindamycin - Now associated with many other broad spectrum antibiotics - Massive watery diarrhea - Requires anti-anaerobic agent, metronidazole, or with oral vancomycin - Virulence factors, Enterotoxin (toxin A): produce chemotaxis for neutrophils, induce cytokine, hemorrhagic necrosis; Cytotoxin B (toxin B): induces depolymerization of actin. - Relapse of Clostridium difficile occurs in 10 to 25 percent of patients treated with metronidazole or vancomycin - Stool transplant

Answer 177

Fecal transplant (bacteriotherapy) is the transfer of stool from a healthy donor into the GI for the purpose of treating C. DIFFICILE COLITIS - the delivery of healthy donor stool to a patient by colonoscopy or NG tube - effective alternative to long term antibiotic use in treating this infectious disease * *Third invasive, less expensive option to treat C-diff; POOP IN A PILL (artificial poop)

Answer 178

- Shigella and EHEC produce shiga toxins - Both cause bloody diarrhea Shigella - Disease from bacterial invasion of mucosa - Toxin less important in disease than invasion - Only S. dysenteriae produces toxin. When toxin reaches systemic circulation, can lead to HUS EHEC - Do not invade cells - Disease from toxin (inflammation) - HUS

Answer 179

SALMONELLA spp • Genus only 2 species - S. bongori - S. enterica • Common in GI tract of animals, but not human flora. • S. enterica: 6 subspecies. Subsp. Enterica has more than 2500 serotypes. • S. enterica serotype choleraesuis - swine and human pathogen. Diseases caused by salmonella spp. 1. Gastroenteritis: the most common cause of food- borne infections, indicating it’s hard to develop immunity. 2. Typhoid (enteric) fever (S. typhi) 3. Bacteremia 4. Localized infections in other sites (osteomyelitis, meningitis)

Answer 180

Typhoid (Enteric) Fever • S. typhi and S. paratyphi, etiological agents • Typhoid fever is transmitted only by humans.

Answer 181

Enterocolitis (salmonella) Spread and multiplication • Fecal-oral route (all serotypes) • The diarrhea-causing Salmonella multiply in the lamina propria with uncertain mechanisms. • Asymptomatic carriers (S. typhi) • Typhoid bacilli are not killed and they steadily multiply within macrophages. Treatment and prevention A. Diagnosis: Culture (stool, blood). B. Treatment gastroenteritis - Fluids/Electrolytes - Few data showing antibiotics are helpful (may prolong illness) - Difficult to treat: Lots of AMR - Antibiotics used in severely ill patients only - Anti-peristalsis meds (Loperamide) contraindicated C. Typhoid fever: cetrixaxone; fluoroquinolones. D. Typhoid vaccine available - Inactive variant of bacteria given orally - Used for travelers to high risk areas

Answer 182

Shigella - No H2S - PMN - Cell to cell spread (Macropinocytosis) - Antibiotics - Nonmotile - Shiga toxin - Low infectious dose Salmonella - H2S (black on TSI - triple sugar Iron) - Monocytes - Hematogenous spread - No antibiotics - Motile (flagella)

Answer 183

YERSINIAE The genus has three main species, - Y. pestis, - Y. pseudotuberculosis, - Y. enterocolitica. • All three species carry plasmids with virulence genes. • Pigs, rodents, livestock and rabbits are the nature reservoir for Y. enterocolitica • Rodents, wild animals, and game birds are the natural reservoir for Y. pseudotuberculosis • Y. pestis is the etiological agent of bubonic and pneumonic plagues. • Y. pestis covered with protein capsule • Y. enterocolitica can grow at cold temp.

Answer 184

YERSINIAE ENTEROCOLITIS; pigs - CONTAMINATED PORK, rodent, livestock in cold area like canada - present like appendicitis * Y. enterocolitica and Y. pseudotuberculosis cause enterocolitis clinically indistinguishable from that caused by Salmonella or Shigella. * Y. enterocolitica and Y. pseudotuberculosis can both cause mesenteric adenitis, which clinically resembles acute appendicitis. * Y. enterocolitica infection is more common in the colder areas of North America, often transmitted through contaminated pork * Pathogens for rodents (Y. Pseudotuberculosis) and for cattle, deer, pigs and birds (Y. Enterocolitica) Treatment • Y. pseudotuberculosis: severe intestinal abscesses, ampicillin and tetracycline. • Y. enterocolitica: chronic intestinal abscesses, ampicillin, chloramphenicol, polymyxin. • Prevention: water purification and milk pasteurization. • No vaccines are available.

Answer 185

Clostridium difficile * *Antibiotic associated colitis; PSEUDOMEMBRANOUS LESIONS - Exposure to antibiotics causes overgrowth of C. difficile (endogenous infection) - Spores are found in hospital rooms (exogenous infection) ** Colon section: an intense inflammatory response with the characteristic “plaque” (black arrow) overlying the intact mucosa (white arrow)

Week 1 Flashcards

(209 cards)