Nichols + ??? 2 Flashcards
Acinar Cell: Protective Mechanisms
- Inactive proenzymes
- Membrane enclosed
- Separate pathways
- Trypsin inhibitor
Acinar Cell: Acute Pancreatitis, mechanisms of injury
- Blockage of Secretion
- Co-localization of ZG and lysosomes
- premature zymogen activation
- autodigestion from within acinar cell
Cytokines and Acute Pancreatitis
- Proteases activate complement
- C3a and C5a recruit PMNs and macrophages
- Inflammatory cells release cytokines (TNF-alpha, IL-1, PAF, NO)
- Vascular injury and inflammatory responses
Local Effets
- autodigestion of the pancreas
- pancreatic swelling (edema)
- fat necrosis and hemorrhage
pain, nausea, vomiting
Systemic Containment Response
- circulation alpha1-antitrypsin (inactivates circulating proteases)
- Circulating alpha-macroglobulin
- binds to circulating trypsin
- facilitates monocyte clearance of macroglobulin-tyrpsin complexes
Severe Pancreatitis: Inflammatory
Cause: TNF-alpha, IL-6
-fever, malaise, confusion
Severe Pancreatitis: Vascular
Cause: kallikrein - hypotension
thrombin activation - DIC, hemorrhage
elastase - hemorrhage
chymotrypsin - hemorrhage
Severe Pancreatitis: Respiratory
Cause: Phospholipase A2 - hypoxemia
Severe Pancreatitis: Metabolic
Cause: Fat Saponification - hypocalcemia
Acute Pancreatitis: Causes
gallstones & alcohol
Acute Pancreatitis: Symptoms
abdominal pain, nausea, vomiting
Acute Pancreatitis: Diagnosis
- elevated serum amylase and lipase
- inflamed pancreas on CT scan
Acute Pancreatitis: Management
IV fluids, pain meds, remove stone (if causative)
Acute Pancreatitis: Etiologies
-miscellaneous
-autoimmune, hyperlipidemia, hypercalcemia, drugs, infection, iatrogenic, trauma, shock, genetic, scorpion bite
40% alcohol
40% gallstones
Hereditary Pancreatitis
tyrpsinogen mutation (arg to his) where degradation of trypsin cleavage is
Acute Pancreatitis: Diagnostic Criteria
2 of the 3
- abdominal pain, nausea/vomiting
- elevated serum amylase & lipase more than 3x upper limit of normal
- CT imaging showing pancreatic inflammation
Factors suggesting Pancreatitis is from Gallstone
- age >50
- female
- amylase > 4000 IU/L
- AST > 100 U/L
- alk. phos. >300 IU/L
Acute Pancreatitis: Supportive Management
- close observation (hospital)
- NPO
- very aggressive IV fluid replacement
- relief of pain
- nutritional support (if prolonged)
- antibiotics (if biliary pancreatitis)
Acute Pancreatitis: Predictors of Poor Outcome
- admission hematocrit >44% with failure to decrease after 24hrs of IV fluids
- admission BUN>25mg/dl with an increase after 24 hrs of IV fluids
Acute Pancreatitis: Clinical Prognosis CT
- Interstitial Pancreatitis (85%)
- multi-organ failure rate < 10%
- infection rate <1%
- mortality ~3%
- Necrotizing Pancreatitis (15%)
- multi-organ failure rate 50%
- infection rate 15-20%
- mortality 17%
Complications of Acute Pancreatitis
- fluid collections
- pseudocysts
- fistulas (ascites, pleural effusions)
- splenic vein thrombosis
Chronic Pancreatitis: Pathophysiology
-recurrent injury with tissue destruction and fibrosis
Chronic Pancreatitis: Cause
chronic alcohol
Chronic Pancreatitis: Symptoms
chronic abdominal pain
diabetes
steatorrhea
Chronic Pancreatitis: Diagnosis
imaging studies
Chronic Pancreatitis: Management
pain medications
insulin
enzyme supplements
Chronic Pancreatitis: Etiologies
80% alcohol
miscellaneous: cystic fibrosis, hereditary, tropical, autoimmune
Chronic Pancreatitis: Pathophysiology
- chronic alcohol ingestion goes to recurrent bouts of pancreatitis and injury, and abnormal secretion (protein plugs and ductal obstruction - calcification)
- the injury: stellate cell activation, fibrosis, pain & cell death, malabsorption diabetes
Chronic Pancreatitis: Pathology
- little dark blue dots (lymphocytes), acini are gone, ducts still present (empty)
- residual necrotic debris
- early fibrosis
Chronic Pancreatitis: Clinical Presentation
- chronic abdominal pain ~80%
- malabsorption (steatorrhea) ~35%
- diabetes ~35%
Chronic Pancreatitis: Causes of Pain
- increased pressure
- biliary strictures
- acute focal pancreatitis
- Neural Inflammation
Chronic Pancreatitis: Pain Managemetn
narcotics
acute exacerbations - abstinence, enzymes
neural inflammation -nerve block, splanchniectomy
ductal hypertension - drainage (stent/surgery)
pseudocyst pressure - drainage (stent/surgery)
Chronic Pancreatitis: Steatorrhea
-fat malabsorption occurs before protein or carbohydrate
-due to lipase deficiency
-treatment: reduce dietary fat intake
oral enzyme supplementation
acid suppression therapy
Chronic Pancreatitis: Diabetes
- only seen in severe disease (>80% gland destroyed)
- loss of both insulin and glucagon, difficult to control (brittle)
- low insulin requirements
- ketoacidosis is rare
Cystic Fibrosis: Pathophysiology
- genetic disorder of defective chloride secretion
- defective chloride secretion, inspissated secretory product, obstruction of ducts and lumens, infection, inflammation, tissue destruction
Cystic Fibrosis: Presentation
pediatric
Cystic Fibrosis: Symptoms
lung infection
chronic pancreatitis
hypertonic sweat
Cystic Fibrosis: Diagnosis
sweat chloride test
Cystic Fibrosis: Treatment
antibiotics
pancreatic enzymes
Cystic Fibrosis
- autosomal recessive
- most common lethal genetic mutation in caucasians (~1:25)
- most CF is caused by a 3 base pair deletion (F508) that affects the folding, processing, and functioning of CF gene product, the cystic fibrosis transmembrane conductance regulator
- CFTR is a cAMP-activated chloride channel
Cystic Fibrosis: Clinical Manifestations
- obstructive/ inflammatory lung disease
- chronic pancreatitis
- hypertonic sweat
- hepatobiliary tract disease
- meconium ileus in infants
- infertility
Pancreas: Pathology
- minimal pink fibrous tissue
- minimal thin secretions in ducts
Cystic Fibrosis: Pathology
-numerous ducts severely distended with inspissated, dark pink secretions, atrophy of acini and mildly increased fibrous tissue
Cystic Fibrosis: Diagnosis
Clinical Symptoms: frequent pulmonary infections (pseudomonas) diarrhea, malabsorption, failure to thrive, frequent episodes of dehydration
Testing: sweat chloride test, pulmonary function tests, genetic testing
Cystic Fibrosis: Clinical Management
- daily pulmonary toilet/inhalers
- treatment of pulmonary infections
- high dose pancreatic enzymes
- gene transfer?
Cystic Diseases of Pancreas
- pancreatic cysts can be either benign or malignant
- most common benign cyst-like lesion in pancreas is pseudocyst
- serous ones have very little malignant potential whereas mucinous ones have malignant potential
Benign Pancreatic Cysts
- pseudocysts - very common (chronic pancreatitis)
- rare non-neoplastic cysts
Cystic Neoplasms
- serous cystic tumors (benign)
- mucinous cyst neoplasms
- intraductal papillary mucinous neoplasms
- solid pseudopapillary neoplasms
Cystic Diseases: Diagnostic Evaluation
- imaging to assess cyst size
- endoscopic ultrasound (structure, obtain fluid and tissue for analysis)
- serum tumor markers (CEA for mucinous cystic neoplasm)
- ERCP for intraductal papillary mucinous neoplasms
Pancreatic Cancer
- vast majority are adenocarcinomas of ductal origin
- abdominal pain & weight loss
- prognosis is poor unless caught VERY early
Pancreatic Cancer Histology
90% are ducal adenocarcinomas
10% miscellaneous (cystic neoplasms, acinar cell neoplasms, lymphomas & sarcomas, neuroendocrine tumors) gastrinoma, insulinoma, glucagonoma
Risk factors for pancreatic Cancer
- cigarette smoking
- alcohol in setting of chronic pancreatitis
- hereditary pancreatitis
- family history of pancreatic cancer
Diagnosis of Pancreatic Adenocarcinoma
Features: weight loss, abdominal pain, jaundice
Lab Tests: elevated serum CA19-9 (tumor marker)
Imaging: mass of CT or MRI,endoscopic ultrasound with FNA
Management Considerations of Pancreatic Cancer
-70% arise in the head of pancreas
-presentation: 40% metastatic (unresectable)
40% advanced local disease (unresctable)
20% organ confined (resectable), less than 1/2 can be cured
-Chemo & radiation therapy have limited effectiveness
Surgery for Pancreatic Cancer
Cure: for tail lesions (distal pancreatectomy) -for head (Whipple resection) Palliation: relieve biliary obstruction -relieve gastric outlet obstruction -splanchnietomy for pain control
Tumors of Small and Large Intestine
- small intestine: rare
- colon & rectum: more primary than any other organ
- colon cancer mortality: 2nd only to lung cancer
- 5% americans get CRC, 40% will die
- 70% of colorectal tumors are adenocarcinomas
Polyp
bump or nodule in the mucosa
- sessile
- pedunculated
- papilloma
Non-neoplastic Polyps: Hyperplastic
sawtooth (serrated) lumens, due to overgrowth of mature cells in crypt bases, from KRAS mutation without APC mutation
Non-neoplastic Polyps: Hamartoma
mass of mature, but disorganized tissue indigenous to site (Peutz-Jaghers syndrome)
Non-neoplastic Polyps: Juvenile
retention in adults
-chronic inflammation, ulceration, dilated glands
Adenomatous Colon Polyps
most common type
- glandular structure can be tubular, villous, or tubulo-villous
- has malignant potential
Hyperplastic Colon Polyps
- diminutive, dilated glands
- no malignant potential
Inflammatory Colon Polyps
- occur in long-standing IBD
- not neoplastic
Epidemiology of Colorectal Cancer
- most common GI malignancy
- Higher incidence in developed countries
- thought to be secondary to high fat, low fiber diet
- Ca and folate in diet may be protective
- Folate may have anti-cancer benefit early in adenoma sequence
Increased Risk of Colorectal Cancer
-lack of physical activity
-red meat
-obesity
-cigarette smoking
-alcohol use
(diet & geography, age, family history, chronic colitis, adenoma, previous colorectal neoplasia)
Decreased Risk of Colorectal Cancer
- multivitamin containing folic acid
- aspirin & other NSAIDS
- postmenopausal hormone use
- Ca supplementation
- Selenium
- Consumption of Vegetables, Fruits, and Fiber
Presentation: Impact of Location
Ascending: Occult bleeding, anemia
Descending: Obstructive symptoms, overt bleeding
Rectum: Tenesmus, Pain, Bleeding
Barium Enema in Diagnosis of CRC
show mass or constricting lesion
Colon Cancer and Colonoscopy
- locate lesion
- remove polyps
- biopsy of lesions
Treatment of Colon Cancer
- endoscopic polypectomy can be curative if cancer is localized to head of polyp
- pre-op CT to look for metastatic disease
- surgery is mainstay of treatment, involves removal of tumor and adjacent lymphatic
Prognosis of Colon Cancer
-worsens as extent of invasion increases Mucosa Submucosa Muscularis Serosa Lymph nodes Dukes
Chemo in CRC
- Adjuvant Treatment in patients with positive nodes
2. Decreases recurrences and improves survival
Colon Polyp Progression to CRC
- APC
- KRAS/BRAF
- p53, PIK3CA, loss of 18q
- P53
Endoscopic Polyectomy
-removal of a stalked polyp with colonoscopy using cautery and a snare
Tumor Suppressor Genes
- genes that function normally in inhibition of cell growth
- abnormalities in tumor suppressor genes may be inherited
Oncogenes
- activation results in uncontrolled cellular proliferation
- activation is usually from environmental stimuli
- oncogenes are generally not inherited
Colonic neoplasia
(polyps and cancer) results from the accumulation of mutations (inherited and/or sporadic) of cellular oncogenes, tumor suppressor genes, and DNA repair genes that cause dysregulation of normal cellular growth
Familial Adenomatous Polyposis (FAP)
-autosomal dominant
>100 adenomatous polyps starting in (2nd & 3rd decade)
-all develop CRC without colectomy
-may also have gastric fundic gland polyps, duodenal adenomas and cancer, periampullary adenomas and cancer, desmoid tumors, and retinal pigmented lesions
Genetic Etiology of FAP
- one allele of the APC gene inherited in a mutated form (germ line mutation)
- this mutation present in every cell of the colon
- polyp growth begins when the second allele is somatically mutated thus causing loss of gene function
Hereditary Non-Polyposis CRC (HNPCC)
- germline mutation
- accounts for 5% of CRC in US
- proximal colon lesions are common
- may also be associated with endometrial, ovarian, urinary, and gastric cancer
- more common than FAP
Diagnosis of HNPCC
1) one relative with CRC at age <50
2) CRC spans 2 generations
3) 3 relatives with HNPCC tumors - 2 must be first degree relatives of 3rd
Goals of Screening for CRC
1) decrease mortality from colon cancer
2) prevent colon cancer by removing adenomatous polyps
Colorectal Cancer Screening
- average risk: asymptmatic, age >50, US Task Force recommended to stpo screening at age 75
- High Risk: asymptomatic, personal history of adenomas or cancer, family history, hereditary cancer (FAP, HNPCC), IBD colitis
Fecal Occult Blod in the Diagnosis of CRC
Phenolilc Guaiac (colorless) - peroxidase - Pigmented Quinone (turns in blue)
Fecal Immunochemical Test (FIT)
- responds to only human hemoglobin
- does not detect UGI bleeding
- requires 1 or 2 stool samples
- may detect as little as 0.3gmHb/gm stool
- more expensive than Guiac
- more sensitive & specific than Guiac
Virtual Colonoscopy
- helical CT reconstructed into 3D images
- studies on sensitivity & specificity have been variable
- requires bowel prep
- exposure to radiation
- not widely available
- role in screening is unclear
- positive test requires colonoscopy
Barriers to Colon Screening
- Limited access to medical care or colonoscopy
- Patient preference-bowel prep, time off from work for colonoscopy
- Risk and expense of screening test
- best test for individual patient is test that gets done
- only 65% of patients currently get screening between 50-75
Colon Neoplasms: Benign Polyps
Adenomas: 2 Types
- Tubular: more pedunculated
- Villous: larger, more sessile, higher risk of malignancy
Colon Neoplasms: Malignant Neoplasms
Adenocarcinoma: 2 Forms
- Polypoid
- Annular
Malignant Small Bowel Tumors
-2% of all GI tract cancers
<0.4% of all cancers
-mean age diagnosis-65Y
-adenocarcinoma and carcinoid most common
Signs & Symptoms of Small Bowel Tumors
- vague, non-specific-delay in diagnosis of 8-12 months
- crampy abdominal pain
- weight loss
- nausea/vomiting
- GI bleeding/anemia
- Jaundice with ampullary lesions
- symptoms more likely with malignant lesions
