Chapter 19 Flashcards
1
Q
The exocrine pancreas makes up _% of the organ
A
80-85
2
Q
What is the exocrine pancreas composed of
A
Acinar cells that secrete enzymes for digestion
3
Q
In the exocrine pancreas, __ are carried by ducts to duodenum for activation via proteolytic cleavage
A
Pronzymes
4
Q
What are acinar cellls
A
Pyramid shaped epithelial cells with membrane bound granules rich in proenzymes (zymogens ) like trypsinogen, chymotrypsinogen, procarboxypeptidase, proelastase, kallikreinogen, and phospholipase A and B
5
Q
What is the endocrine pancreas
A
Islet of langerhan
6
Q
What are inslets of langerhans
A
Cell clusters throughout the gland that secrete insulin, glucagon, and somatostatin
7
Q
What percentage of the pancreas is endocrine pancreas
A
1-2%
8
Q
In the embryo, what does the dorsal primordium become
A
Body, tail, and superior/anterior aspect of the head of the pancreas; accessory duct of santorini
9
Q
In the embryo, what does the ventral primordium become
A
Posterior/inferior part of the head of the pancreas; main pancreatic duct (the duct of wirsung)
10
Q
What is the most common congenital anomaly of the pancreas
A
Pancreas divisum
11
Q
Why get pancreas divisum
A
Failure of the ventral and dorsal fetal duct systems to fuse properly
12
Q
What does the main pancreatic duct of wirsung do
A
Drains only a small portion of the head of the gland through the papilla of vaster
13
Q
Where do the majority of pancreatic secretions drain
A
Small caliber, minor papilla rather than the papilla of vater
14
Q
What are people with pancreas divisum predisposed to
A
Chronic pancreatitis
15
Q
What is an annular pancreas
A
Band like ring of normal pancreatic tissue that encircles the second portion of the duodenum
16
Q
What can annular pancreas cause
A
Duodenal obstruction
17
Q
Ectopic pancreas symptoms
A
Usually symptomatic, but at aberrant sites may lead to pain from localized inflammation( or rarely mucosal bleeding)
18
Q
What are most common sites of ectopic pancreas
A
Stomach, duodenum, jejunum, meckel diverticula, ileum
19
Q
Genetics of pancreatic agenesis
A
Homozygous mutation of PDX1
20
Q
What does PDX1 code
A
Gene normally encodes homeobox transcription factor critical for pancreatic development
21
Q
How does the pancreas protect itself
A
Synthesis of proenzymes packaged in secretory granules-biochemically separate
Duodenal enteropeptidase
Trypsin inhibitors
22
Q
Duodenal enteropeptidase(enterokinase)
A
In the small bowel activates trypsin which activates other proenzymes-anatomically separate
-intrapancreatic activation of proenzymes is normally minimal
23
Q
Trypsin inhibitors
A
Secreted by acinar and ductal cells
-serine protease inhibitor Kazan type I (SPINK1) further limits intrapancreatic trypsin activity
24
Q
Failure of pancreatic protection mechanisms
A
Pancreatitis
25
Acute pancreatitis
Reversible pancreatic parenchymal injury associated with inflammation due to diverse etiologies
26
80% of acute pancreatitis is caused by what
Alcoholism and biliary tract disease
27
What is th the ratio of male to female with acute pancreatitis caused by alcoholism
6:1
28
What is the ratio of females to males that get acute pancreatitis from biliary disease (cholelithiasis)
3:1
29
Pathogenesis of acute pancreatitis: three initiating events that lead to autodigestions
Duct obstruction, primary acinar icell injury, and defective intracellluar transport of proenzymes within acinar cells
30
Pathogenesis of acute pancreatitis: what causes parenchymal autodigestion
Inappropriate release and activation of pancreatic enzymes (trypsinogen)
- degradation of fat cells (phospholipase), damage to elastic fibers of blood vessels (elastase)
- pre-kallikrein leads to kallikrein which activated the kinin system and clotting(factor XII) and complements systems
- produces inflammation and thrombosis which further damage acinar cells and amplify the intrapancreatic activation of digestive enzymes
31
Acute pancreatitis : duct obstruction
- raises intrapancreatic ductal pressure and leads to accumulation of enzymes rich fluid in the intertitium
- lipase (secreted in an active form) has potential for local fat necrosis
- death of pancreatic tide releases “danger signals’ locally that stimulate parenchymal release of proinflammatory cytokines
- interstitial edema through a leaky microvascularization
- inflammation and interstitial edema compromise vascular flow, increased ischemia to the ongoing parenchyma injury
- due to gallstones, periampullarry neoplasms, choledochoceles (congenital cystic dilation of the common bile duct), parasites (espicially ascaris lumbricoides and clonorchis sinesis) and possible pancreatic divisum
32
Acute pancreatitis: primary acinar cell injury
Leads to release of digestive enzymes->inflammation and autodigestion
33
What causes primary acinar cell injury
- oxidative stress: free radicals-> membrane lipid oxidation-?AP1 and NFKB==pro-inflammatory
- Low ca: trypsin cleaves and inactivated itself
- high Ca autoinhibition is abrogated and activation of trypsinogen by trypsin is favored
34
Acute pancreatitis: defective proenzyme transport
Exocrine enzymes are misdirected to lysosomes rather than to secretion
Lysosomal hydrolysis of the proenzyme leads to activation and release
35
What is the most likely etiology of acute pancreatitis
Alcohol consumption
36
How does alcohol cause acute pancreatitis
- direct toxic effect on acinar cells
| - alcohol induced oxidative stress->free radicals->lipid peroxidation->free radicals->AP1 and NFKB==pro-inflammatory
37
Alcohol consumption and acute pancreatic causes transiently increased contraction of what
Sphincter of oddi (muscle at papilla of vater)
38
Acute pancreatitis: chronic alcohol consumption causes secretion of what
Protein rich pancreatic fluid causing inspissated protein plugs that block small ducts
39
Does chronic alcohol consumption commonly cause acute pancreatitis
Most do not, those who do, do after many years of abuse
40
What are some other triggers of acute pancreatitis
Metabolic disorders:hyperTG, hyperCa, hyperPTH
Genetic lesions:40% increased risk f prostate cancer
Medications:furosemide, azathioprine, estrogens
Trauma or ischemia to acinar cells
Infection:mumps
Hereditary pancreatitis: characterized by recurrent attacks of severe acute pancreatitis and ultimately leading to chronic pancreatitis
41
Hereditary pancreatitis
Recurrent attacks of severe acute pancreatitis and ultimately leading to chronic pancreatitis
42
Shared feature of hereditary pancreatitis
Shared feature of most forms is a defect that increases or sustains the activity to trypsin
43
Genetic mutations of hereditary pancreatitis
PRSS1
PSINK1
CFTR
44
PRSS! Hereditary pancreatitis
Gain fo function mutation of trypsinogen making trypsin resistant to self inactivation or prone to activation
Most common
AD
45
SPINK1 hereditary pancreatitis
Loss of function preventing inhibition of trypsin
AR
46
CFTR hereditary pancreatitis
Decreased bicarbonate secretion leads to protein plugins, duct obstruction, and pancreatitis
47
Patients with hereditary pancreatisi have a 40% chance of developing __ __
Pancreatic cancer
48
Morphology acute pancreatitis
Microvascular leakage leads to edema
Fat necrosis by lipolysis enzymes, released fatty acids combine with Ca that give a granular blue look to fat cells (saponofication)
Proteolytic destruction of the pancreatic parenchyma
Vascular injury with subsequent interstitial hemorrhage that appears red black with foci of yellow white chalky fat necrosis
Peritoneal cavity: serous, slightly turbid, brown fluid with fat globules
49
Acute pancreatitis presentation
Constant abdominal pain, may refer to upper back or L shoulder
Anorexia, nausea, vomiting
50
Labs acute pancreatitis
Increased plasma levels of amylase (24 hours), lipase (72096 hours)
10% glycosuria
Hypocalcemia due to deposition of Ca soap formation in necrotic fat (saponification)
51
Full blown acute pancreatitis
Acute abdomen (intense pain)
Peripheral vascular collapse
Shock due to activation of systemic inflammatory response syndrome (SRS)
- leukocytosis, disseminated intravascular coagulation, edema, ARDS (shock and acute renal tubular necrosis may occur)
- LIFE THREATENING EMERGENCY
52
Treatment acute pancreatitis
Total restriction of oral intake to rest the pancreas
IV fluids and pain meds
Nutrition+volume support
Function returns to normal if resolved
53
Complications acute pancreatitis
5% will die int he first week of severe acute pancreatitis
ARDS and acute renal failure
Sterile pancreatic abscess
Pancreatic pseudocyst
Infection of necrotic debris by gram -ve pathogens from alimentary tract
54
Chronic pancreatitis
Prolonged inflammation of the pancreas due to irreversible destruction of exocrine parenchyma, fibrous and eventually, the endocrine parenchyma
55
Who gets chronic pancreatitis
Middle age males
56
Causes of chronic pancreatitis
Long term alcohol use
Longstanding obstruction by calculi or neoplasm
Autoimmune injury
25% of chronic pancreatitis has a genetic component
57
Chronic pancreatitis often follows repeated bouts of __ ___
Acute pancreatitis
58
Chronic pancreatitis leads to perilobular fibrosis, duct distortion and altered secretions that can lead to what
Loss of parenchyma
Fibrosis
59
In chronic pancreatitis there is production of fibrogenic inflammatory mediators TGFB and PDGF
Induces activation and proliferation of periacinar myofibroblasts (pancreatis stellate cells)->deposition of collagen and fibrosis
60
Morphology chronic pancreatitis
Fibrosis, atrophy and dropout of acini
Variable dilation of pancreatic ducts
Pancreas is hard with focal calcification
Relative sparing of islet of langerhans
Chronic pancreatitis caused by alcohol abuse is characterized by ductal dilation, intraluminal protein plugs and calcification
61
Symptoms chronic pancreatitis
Usually silent, but there may be recurrent attacks of pain and/or jaundice
62
What triggers chronic pancreatitis
ETOH, overeating (increased demand) or opiates that increase tone of sphincter of oddi
63
With chronic pancreatitis, ____ __ and ___ eventually develop due to destruction of exocrine and endocrine organ
Pancreatic insufficiency
DM
64
Prognosis chronic pancreatitis
Not usually life threatening
20-25 year=50% mortality
65
How diagnose chronic pancreatitis
Clinical suspicion
Amylase levels are not always elevated and fever not always present due to acinar cells
Visualization of calcification in the pancreas via CT or ultrasonography
Weight loss and edema due to hypoalbuminemia from malabsorption
66
Complications chronic pancreatitis
Malabsorption, DM, pseudocysts (10%)
67
Autoimmune pancreatitis
Pathogenically distinct form of chronic pancreatitis that is associated with the presence of IgG4 secreting plasma cells int he pancreas
IgG
68
Characterization autoimmune pancreatitis
Duct-centric mixed inflammatory cell infiltrate, venulitis, and increased numbers of IgG4 secreting plasma cells
69
Treatment autoimmune pancreatitis
Steroids
70
Congenital cysts cause
Due to anomalous development of the pancreatic ducts
71
Congenital cysts are unilocular and thin walled with _ _ lining
Cuboidal epithelial
72
Congenital cysts have a thin fibrous capsule with __ __ _
Clear serous fluid
73
Genetics congenital cysts
AD polycystic kidney disease
74
What is ongeital cysts
Cyst in liver, kidney, and pancreatic cysts
75
Congenital cysts VHL
Tumors in retina, cerebellum/brain stem+pancrea, liver, kidney
76
What are the most common pancreatic cysts
Pseudocysts
77
Pseudocysts can occur __ the pancreas
Outside
Also inside
78
Describe pseudocysts
Localized collections of necrotic and hemorrhagic material rich in pancreatic enzymes
79
Why are pseudocysts called pseudo
Lack an epithelial lining
80
Why get pseudocysts
When areas of intrapancreatic or peripancreatic hemorrhagic fat necrosis are walled off by fibrousand granulation tissue
81
Treat pseudocysts
Spontaneously resolve
82
Prognosis pseudocysts
Spontaneously resolve, can become infected or compress or penetrate adjacent structures
83
Morphology pseudocysts
Walled off areas of fat necrosis
Encircled by fibrosed granulation tissue
Occur after acute pancreatitis or trauma
84
Serous cystic neoplasms
Entirely benign and multicystic
85
Where are serous cystic neoplasms usually
Int he tail of the pancreas
86
Morphology serous cystic neoplasm
Small, lined by glycogen rich cuboidal cells, and contain clear, thin straw colored fluid
87
Serous cystic neoplasms account for _% of all cystic neoplasms of the pancreas
25
88
Serous cystic neoplasms male or female
Women 2:1
89
Age serous cystic neoplasm
60-70
90
Presentation serous cystic neoplasms
Presents with nonspecific abdominal pain, often an incidental finding on imaging
91
Treat serous cystic neoplasm
Surgery is curative
92
Genetic serous cystic neoplasm
VHL inactivation (a tumor suppressor)
93
Mutinous cystic neoplasms
Precancerous
94
Mutinous cystic neoplasm men or women
95% women
95
Where are mutinous cystic neoplasms
Tail of pancreas
96
Pain and growth with mucinous cystic neoplasm
Painless, slow growing
97
Morphology mucinous cystic neoplasm
Filled with thick, tenacious mucin and lined by a columnar mucin-producing epithelium associated with a dense stroma similar to ovarian stroma
98
Treat mucinous cystic neoplasm non invasive
Surgical resection is curative bc non invasive
99
There is 50% mortality associated with __ __ arising in a mucinous cystic neoplasm
Invasive carcinoma
EARLY DETECTION CRITICAL
100
Genetics mucinous cystic neoplasm
KRAS oncogene
TP53 and RNF43 tumor supressor genes
101
Intraductal papillary mucinous neoplasm
Precancerous mucin producing neoplasm involving the larger ducts of the pancreas
102
Male or female intraductal papillary mucinous neoplasms
Male
103
Where are intraductal papillary mucinous neoplasms
Head>>tail
104
What percentage of intraductal papillary mucinous neoplasms are multifocal
10-20%
105
Morphological differences with mucinous cystic neoplasm
No dense ovarian stroma
Involvement of a pancreatic duct
106
Genes intraductal papillary mucinous neoplasms
GNAS and KRAS oncogenes
TP53, SMAD4, RNF43 tumor suppressor genes
107
Treatment intraductal papillary mucinous neoplasm
Surgerical resection curative
108
Intraductal papillary mucinous neoplasm can progress to
Invasive cancer with a higher mortality rate
| -early detection and treatment is critical
109
Solid pseudopapillary neoplasm
Precancerous
Large, well-circumscribed malignant neoplasms with solid and cystic components filled with hemmorhagiv debris
110
Solid pseudopapillary neoplasms men or women, age
Young women
111
Presentation solid pseudopapillary neoplasm
Abdominal discomfort owing to their large size
112
Morphology solid pseudopapillary neoplasm
Grow in sold sheets or pseudopapillary projections, poorly cohesive
113
Genetics solid pseudopapillary neoplasm
CTNNB1 (B catenin) oncogene mutation leads to hyperactivation of WNT signaling
114
Treatment solid pseudopapillary neoplasm
Surgical resection usually curative, though some may be locally aggressive
115
Pancreatic intraepithelial neoplasia
Well defined non invasive precursor lesions in small ducts that may give rise to invasive pancreatic cancers
No neoplastic epithelium->pancreatic intraepithelial neoplasia->invasive carcinoma
116
Epithelial cells in pancreatic intraepithelial neoplasia show dramatic __ ___
Telomere shortening
117
Infiltrating ductal adenocarcinoma
Pancreatic carcinoma
118
Infiltrating ductal adenocarcinoma is the _th leading cause of cancer death in the USA
4th
119
What are the top causes of cancer death in USA
Lung, colon, breast, pancreatic
120
Pancreatic cancer is one of the most aggressive of the ___ __
Solid malignancies
121
Prognosis infiltrating ductal adenocarcinoma
5 year survival <5% (usually caught in advanced stage)
122
Ribs factors for infiltrating ductal adenocarcinoma
Cirgarette smoke 2x risk-leading preventable cause
High fat diet, chronic pancreatitis family history, diabetes mellitus
Chronic pancreatitis and diabetes mellitus are both risk factors and complications
Ashkenazi jews (BRCA2) and african Americans>caucasiona
123
Location infiltrating ductal adenocarcinoma
60% head of pancreas
15% body pancreas
5% tail
20% diffuse involvement
124
Head of pancreas infiltrating ductal adenocarcinoma
Obstruct distsal common bile duct leading to jaundice
(Extrahepatic biliary obstruction and an elevation in direct bilirubin and alkaline phosphatase and no inflammation)
PAINLESS JAUNDICE
125
Body pancreas infiltrating ductal adenocarcinoma
Body and tail do not impinge on structures and remain clinically silent
May be large and widely disseminated at discovery
126
Morphology infiltrating ductal adenocarcinoma
Hard, stellate, gray white, poorly defined masses
127
Morphology infiltrating ductal adenocarcinoma
Poorly differentiated
Glands lined with pleomorphic cuboidal columnar epithelium
Forms abortive tubular structures or cell clusters
128
Aggressive infiltrating ductal adenocarcinoma
Aggressive, deeply infiltrating growth pattern, elicits an intense desmoplastic response with dense stromal fibrosis
129
Infiltrating ductal adenocarcinoma often grow along __ or invade __ _ and the __
Nerves
Blood vessels
Retroperitoneum
130
Who gets pancreatic cancer infiltrating ductal adenocarcinoma
Older adults 80% 60-80
131
Presentation pancreatic carcinoma
Clinically silent until they invade into adjacent structures
| -most present with pain and advanced disease-palliative disease
132
With pancreatic carcinoma there is migratory thrombophlebitis (__ sign) in 10% due to elaboration of platelet activating factors and procoagulants from carcinoma or it necrotic products
Trousseau
133
Pancreatic carcinoma after diagnosis is
Buried and progressive
134
What percent of pancreatic carcinomas are respectable
<20
135
Screening tests for pancreatic carcinoma
No reliable
-serum levels of several antigens (CA19-9 antigen) are often elevated in them
Not specific or sensitive
136
What can we use CA19 antigen and carcinoembryonic antigen for if not screening for pancreatic carcinoma
Follow individuals patients response to treatment
137
How confirm pancreatic carcinoma diagnosis
Imaging (endoscopic ultrasonography andcomputed tomography) but not for screening
138
Genetics pancreatic carcinoma
KRAS oncogene
CDKN2A tumor suppressor
SMAD4 tumor suppressor
TP53 tumor suppressor
DNA methylation abnormalities
Germline BRCA2 mutation
139
Pancreatic cancer KRAS oncogene mutation
Chromosome 12p
Point mutations constitutively activate this GTP-binding protein which normally interacts with tyrosine kinase to augment cell growth and survival via MAPK and PI3K/AKT
140
What is the most frequently altered oncogene in pancreatic cancer
90-95% KRAS
141
CDKN2A tumor suppressor mutation pancreatic cancer
Chromosome 9p
| Encode p16/INK4a and ARF
142
P16/INK4a
Cyclin dependent kinase inhibitor that antagonizes cell cycle progression
143
ARF
Protein that augments the function of the p53 tumor suppressor protein
144
CDKN2A may be hypermethylated, implying what
Epigenetics
145
What are germline CDKN2A mutations associated with
Pancreatic cancer and are almost always observed in individuals from families with an increased incidence of melanoma, which also frequently harbors CDKN2A loss of function mutations
146
Most frequently inactivated tumor suppressor gene in pancreatic cancer
95%
| CDKN2A
147
SMAD4 tumor suppressor pancreatic cancer
Chromosome 18q
Encodes a protein important for TGFB signal transduction
Inactivated in 55% of pancreatic cancers, but rarely mutated in other cancers
148
TP53 tumor suppressor pancreatic cancer
Chromosome 17p
FunctionL induce cell cycle arrest in response to DNA damage , inducing apopotosis or cellular senescence
Inactivated in 70-75% of all pancreatic cancer
149
DNA methylation pancreatic carcinoma
Hypermethylation of promoter of several tumor suppressor genes (CDKN2A)==transcriptional silencing—>LOF
150
BRCA2 pancreatic cancer
1-% of pancreatic cancer in ashkenazi jews
151
Acinar cell carcinoma
Acinar cell carcinoma form zymogen granules and produce exocrine enzymes such as trypsin and lipase
152
Acinar cell carcinome: syndrome of metastatic fat necrosis
Caused by the release of lipase into the circulation develops in 15% of individuals
153
Pancreatoblastoma
Rare neoplasms that occur primarily in children age1-15 years old
154
Morphology pancreatoblastoma
Distinct microscopic appearance: squamous islands and mixed with acinar cells
155
Prognosis pancreatoblastoma
Malignant, but survival is better than it is for pancreatic ductal adenocarcinomas
156
What is Acute pancreatitis
Acute inflammation of the pancreas commonly caused by gallbladder disease or chronic alcohol intake
157
Symptoms of acute pancreatitis
Abdominal pain, nausea, vomiting, anorexia, abdominal guarding , rigidity, decreased or absent bowel sounds
158
Risk factor for acute pancreatitis
Smoking
159
Labs acute pancreatitis
```
Incred WBC(low grade fever
Jaundice
```
160
Most likely cause of acute pancreatitis
Heavy alcohol and gallstones
161
Skin signs with acute pancreatitis
Jaundice, grey turners, Cullen’s sign
162
Which hemodynamics parameters occur as a result of pancreatic hemorrhage associated with acute pancreatitis
Hypotension and tachycardia
| -could get life threatening shock
163
Complications acute pancreatitis
```
Infection
Pseudocysts
Hemorrhage
DIC
Hypocalcemia
SIRS
ARDS (acute respiratory discress syndrome)
```
164
ARDS presentation
Widespread systemic inflammation
Dyspnea in patients with acute pancreatitis
165
Pancreatic pseudocyst
Circumscribed collection of fluid rich in pancreatic enzymes, blood, and necrotizing tissue. It is lined wth granulation tissue
Can extravasation to digest adjoining tissue
166
Hemorrhage acute pancreatitis
From acute necrotic destruction parenchyma, fat, o local vessels
Or rupture of pseudocyst
167
Causes of acute pancreatitis GET SMASHED
```
Gallstones
Ethanol
Trauma
Steroids
Mumps
Autoimmune
Scorpion sting
Hypercalcemia
Hyertg
Ercp
Drugs-valproic acid , asathioprine
```
