How do low Ca2+ levels vs. high Ca2+ levels have an affect on trypsin?

- High Ca2+ --\> loss of autoinhibition = trypsin activation - Low Ca2+ --\> trypsin cleaves and inactivates itself = inactivation

Chapter 19: The Pancreas Flashcards by Maren Osterholt

What is the most common congenital anomaly of the pancreas?

What occurs embryologically?

Pancreas Divisum
Failure of fusion of fetal duct system of the dorsal and ventral pancreatic primordia

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In Pancreas Divisum the bulk of the pancreas (formed by dorsal primordium) drains through where?

Through the small-caliber minor papilla

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Annular pancreas is caused by what?

Can lead to what complication?

A band-like ring of normal pancreatic tissue completely encircles the 2nd portion of the duodenum
Can produce duodenal obstruction

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Very rarely the pancreas fails to develop (agenesis) and sometimes is due to germline mutation involving which gene?

PDX1

*‘P’ for pancreas!

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In Western countries which 2 factors account for the majority of acute pancreatitis?

Biliary tract disease
Alcoholism

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Pancreatic duct obstruction leading to acute pancreatitis is most commonly due to?

What are 4 other risk factors that cause obstruction?

Gallstones = most common
Periampullary neoplasms
Choledochoceles
Parasites —> Ascaris lumbricoides + Clonorchis sinensis
Possible pancreas divisum

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Local fat necrosis in acute pancreatitis is caused by what?

Lipase is produced in an active form –> local fat necrosis

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Which ion plays a key role in regulating trypsin activation?

Ca²⁺

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How do low Ca²⁺ levels vs. high Ca²⁺ levels have an affect on trypsin?

High Ca²⁺ –> loss of autoinhibition = trypsin activation
Low Ca²⁺ –> trypsin cleaves and inactivates itself = inactivation

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How does primary acinar cell injury play a role in the pathogenesis of acute pancreatitis?

i.e., role of oxidative stress, what’s activated and which TF’s expressed

Oxidative stress may generate free radicals –> membrane lipid oxidation + activation of TF’s such as AP1 and NF-kB
Increased Ca²⁺ flux leads to increased Trypsin

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Alcohol consumption causes a transient increase in the contraction of what?

Sphincter of Oddi

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Which 3 metabolic disorders are implicated in the development of acute pancreatitis?

Hypertriglyceridemia
Hypercalcemic states
Hyperparathyroidism –> increased Ca²⁺

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Which virus has been linked to pancreatitis?

Mumps - Paramyxovirus - ssRNA virus

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Hereditary pancreatitis due to a trypsinogen mutation has what type of inheritance pattern?

Which gene is mutated and is it a loss or gain of function?

Autosomal Dominant
Gain-of-function in PRSS1 (chromosome 7) –> Trypsinogen gene

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Hereditary pancreatitis can also be caused by a loss-of-function mutation in which gene?

Inheritance pattern of this mutation?

SPINK1 (chromosome 5) –> encodes a trypsin inhibitor
Autosomal recessive

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How do mutations in the CFTR gene lead to potential duct obstruction and the development of pancreatitis?

Decreased HCO3^- secretion by ductal cells –> promotes protein plugging + duct obstruction

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In the milder form, acute interstitial pancreatitis, what are the 3 histologic alterations seen?

Mild inflammation
Interstitial edema
Focal areas of fat necrosis (due to lipase)

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In the more severe form, acute necrotizing pancreatitis, what are some of the characteristic histological changes?

Which cells are necrosed?

Necrosis of acinar and ductal tissues + islets of Langerhans
Vascular injury –> hemorrhage into pancreatic parenchyma

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What is the cardinal clinical symptom of acute pancreatitis?

Where does this pain refer to and how is it characterized?

Abdominal pain
Constant + intense –> referred to upper back or left shoulder

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Elevated plasma levels of what support the diagnosis of acute pancreatitis?

Describe the timeline of these elevations (first 24 hours to 96 hours)?

Elevation of amylase during the first 24 hours
Rising lipase level by 72 to 96 hours

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Full-blown acute pancreatitis is a medical emergency and how does it typically manifest clinically?

What causes the serious systemic complications and what are these complications that may be seen?

Sudden disasterous onset of “acute abdomen”
Release of toxic enzymes, cytokines, and other mediators into circulation —> leukocytosis, DIC, edema, and acute respiratory distress syndrome
Shock and acute renal tubular necrosis may occur

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What is the key to management of someone who presents with acute pancreatitis?

“Resting” the pancreas by total restriction of oral intake and by supportive therapy w/ IV fluids + analgesia

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What are 2 ominous complications that can arise with acute pancreatitis?

Acute respiratory distress syndrome
Acute renal failure

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How does acute vs. chronic pancreatitis differ in the type of injury that occurs to the pancreatic parenchyma (ie., reversible or irreversible)

Acute is associated with reversible injury
Chronic is associated with irreversible injury

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Which patient population (age and sex) is most commonly affected by chronic pancreatitis? What is the most common cause?

- Middle-aged **males** - **Long-term alcohol abuse**

While many of the cytokines produced during acute and chronic pancreatitis are similar, which type tends to predominate in chronic pancreatitis? Leads to activation of?

- **Fibrogenic** --\> **TGF**-β and **PDGF** - Activation and proliferation of **periacinar myofibroblasts** (**pancreatic stellate cells**)

The activation of pancreatic stellate cells in chronic pancreatitis results in the deposition of?

**Collagen** and **fibrosis**

Autoimmune pancreatitis is a distinct form of chronic pancreatitis associated with the presence of which cells in the pancreas?

IgG4-secreting plasma cells

Why is it important to be able to differentiate Autoimmune Pancreatitis from a Pancreatic Carcinoma?

Autoimmune pancreatitis **RESPONDS** to **steroid therapy**

Which type of pancreatitis is characterized by fibrosis, atrophy and dropout of acini, and variable dilation of pancreatic ducts?

Chronic pancreatitis

Chronic pancreatitis caused by alcohol abuse is characterized by which histologic findings?

- **Ductal dilation** - Intraluminal protein plugs and **calcifications**

Chronic pancreatitis may present in many different ways, such as? May be precipitated by?

- Following repeat bouts of acute pancreatitis - Repeat attacks of mild-moderately severe abdominal pain **or** persistent abdominal pain - Attacks may be **precipated** by **alcohol abuse**, **overeating,** or the use of **opioids** + other drugs - Malabsorption sx's (steatorrhea) or DM

In some patients, chronic pancreatitis may be clinically silent until the development of what?

- Pancreatic insufficiency --\> **steatorrhea** - **Diabetes mellitus** (due to destruction of exocrine and endocrine pancrease)

Diagnosis of chronic pancreatitis requires a high degree of suspicion, but which finding on CT and ultrasound can be very helpful?

Calcifications with pancreas

Which type of pancreatitis is associated with a 40% lifetime risk of developing pancreatic cancer?

Hereditary pancreatitis

Pseudocysts of the pancreas are localized collections of what? They are rich in? Lack?

- Collections of **necrotic** and **hemorrhagic** material - Rich in **pancreatic enzymes** - Lack and **epithelial lining**

Pseudocysts of the pancreas typically arise following? May also arise as a result of?

**- Bout of acute pancreatitis**, particularly one **superimposed** on **chronic alcoholic pancreatitis** ## Footnote **- Trauma**

Pseudocysts may be situated within the pancreas but are **more commonly** found where?

- Lesser omental sac - Retroperitoneum btw **stomach** and **transverse colon** - Or btw **stomach** and **liver**

When areas of intrapancreatic or peripancreatic hemorrhage are walled off by fibrous tissue and granulation tissue, this forms what?

Pseudocysts

What is the 5-year survival rate for Pancreatic Carcinoma (aka infiltrating ductal adenocarcinoma)?

\<5%; **poor**

Invasive pancreatic cancers are believed to arise from which well-defined noninvasive precursor lesions in small ducts?

Pancreatic intraepithelial neoplasia (**PanIN**)

Which is the most frequently altered oncogene in pancreatic cancer? Which chromosome is it on?

***KRAS*** *-* Cr. **12p**

Mutations in KRAS signaling associated w/ pancreatic cancer most notably leads to activation of which 2 pathways?

**MAPK** and **PI3K/AKT-pathways**

What is the most frequently **inactivated** tumor suppressor gene in pancreatic cancers? Which chromosome is it on?

- ***CDKN2A/p16*** - Cr. **9p**

Which tumor suppressor gene is inactivated in 55% of pancreatic cancers and encodes a protein essential for TGF-β signaling?

***SMAD4*** on Cr. **18q**

Hypermethylation of the promoter of which tumor suppressor gene has been implicated in pancreatic cancer?

***CDKN2A***

What is the typical age range for the onset of pancreatic cancer? More commonly seen in which ethnicities?

- Age **60-80 yo** - **More common** in **blacks** and **Ashkenazi Jews** (***BRCA2****)*

What is the strongest enviornmental risk factor for the development of pancreatic cancer?

Cigarette smoking **doubles the risk** \*Consumption of diet rich in fats also been implicated

What are 2 risk factors for pancreatic cancer, which may also be complications of the development of cancer?

1. Chronic pancreatitis 2. Diabetes mellitus

New-onset DM in an older patient (60-80 yo) may be the first sign that they have?

Pancreatic cancer

Germline mutations in which gene is associated with **familial atypical multiple-mole melanoma syndrome** and almost always the development of **pancreatic cancer?**

***CDKN2A***

The majority of pancreatic cancers arise in which part of the pancreas?

Head (60%) \> Body (15%) \> Tail (5%)

The vast majority of pancreatic cancers take the form of?

Ductal adenocarinomas

What are 2 features characteristic of pancreatic cancer (i.e., behavior and reaction elicited)?

1. **Highly invasive** (even **"early"** invasive pancreatic cancers extensively invade peripancreatic tissue) 2. Elicits an **intense host reaction** in the form of **dense fibrosis** ("**desmoplastic response**")

Majority of the carcinomas of the head of the pancreas obstruct what? Leads to which clinical signs and symptoms?

- Distal common bile duct - Marked distention of biliary tree + **Obstructive** **Jaundice**

Why do pancreatic cancers of the body and tail often remain silent for some time?

Do not impinge on the biliary tract like those of the head

Pancreatic cancers often grow along whicn structures and can directly invade into which organs/structures?

- Often along **blood vessels** and **nerves** - Directly into: **spleen, adrenals, transverse colon,** and **stomach**

Which 2 sites are the primary sites for distant metastases by pancreatic cancer?

- Liver - Lungs

Which disorder is associated with the highest increased risk (**130-fold**) for the development of pancreatic cancer? What is the associated gene?

- **Peutz-Jegher syndrome** - ***STK11***

Which colorectal cancer is associated with an increased risk for pancreatic cancer? Associated genes?

- HNPCC - ***MLH1, MSH2***

Carcinomas of the pancreas typically remain silent until what occurs; producing what initial symptom? Symptoms of advanced disease?

- Until **invasion** occurs - **Pain** is usually the 1st symptom, but by this time the cancer is usually beyond cure - Weight loss, anorexia, and generalized malaise = **cachexia** = advanced disease

Which "sign" is seen in a small % of patients with pancreatic cancer?

**Migratory thrombophlebitis** or the ***Trousseau sign***

Which elevated serum markers associated with pancreatic cancer can be used to assess a pts response to treatment? Are they specific and sensitive?

- Carcinoembryonic antigen - CA19-9 antigen \*Non-specific and lack sensitivity needed to be used as tests to screen the wider population

Which rare pancreatic tumor occurs in children and what are its distinct microscopic findings?

- Pancreatoblastoma - **Squamous islands** admixed with **acinar cells** **\*Metastatic** but better prognosis than pancreatic ductal cell carcinomas

What is the hallmark of pancreatic cancer?

Intense **desmoplastc rxn** w/ dense **stromal fibrosis**