10. Acute pancreatitis. Pathophysiology and consequences

Explain the exocrine pancreas?

-More than 90% of the pancreas

Produces digestive enzymes

- They are secreted in proenzyme form inside granules -> not activated before they reach the duodenal lumen

Once they reach the lumen, they will be activated by brush border-bound enteropeptidase (aka enterokinase)

Most important pancreatic digestive enzymes?

- Trypsin

- Chymotrypsin

- Elastase

- Collagenase

- Lipase

- Phospholipase

- Amylase

Zymogen granules?

Enzymes are stored in their inactive form in intracellular granules

What happens if the zymogen granules are activated before they arrive the duodenal lumen?

If they are activated in e.g. the pancreas;

- They would start digestion of the organ itself

Is normally prevented with 3 mechanisms:

- The digestive enzymes are in proenzyme form

- Pressure inside the ducts is smaller than the pressure inside the parenchyma -> favoring the movement of secretion from the parenchyma toward the duct

- a1-antitrypsin in the parenchyma inactivates any enzymes that are activated

Acute pancreatitis?

There is an abnormal and premature activation of the digestive enzymes inside the pancreas

May occur due to:

• Zymogens and lysosomes fuse → causing proenzymes to be activated by lysosomal enzymes ⟹ The activated enzymes start to autodigest the pancreas

• Primary damage to the acinar cells that produce and secrete the zymogens

What will exacerbate the acute pancreatitis?

Inflammation of the pancreas recruits neutrophils that secrete proteolytic enzymes that may further activate the proenzymes -> worsening the problem

Severity of acute pancreatitis?

May be life-threatening, but in most cases it is not & patient will fully recover

Some cases may progress into chronic pancreatitis

Etiology of acute pancreatitis?

- Bile reflux into the pancreatic duct - often due to bile stone

- Alcohol abuse

- Idiopathic

- Large food intake, especially if consumed w/ alcohol or after starvation

- Trauma

- Drugs

- Infection (Coxsackie, mumps)

- Hypercalcemia - it enhances secretion

- Snake venom

- Steroids

- SLE (autoimmune)

- Vascular (Polyarteritis nodosa, shock, atheroembolism)

- ERCP, iatrogenic or preoperative injury

The most important (common) causes of acute pancreatitis?

Gallstone and alcohol abuse accounts for 80% of cases of acute pancreatitis (in the US)

Alcohol on the pancreas?

Alcohol causes the pancreatic secretions to be thicker, which slows down the secretions

- May cause congestion of the ducts

When secretions flow slower, there will be more opportunities for the zymogens to get into the parenchyma

How does alcohol damage the defense mechanisms of the pancreas?

• Decreases the a1-antitrypsin levels

• Increases the muscular tone of the Sphincter of Oddi

⟹ Alcohol is often a cofactor in acute pancreatitis

Alcohol-related acute pancreatitis?

Is strangely more common in non-alcoholics than in alcoholics

Large meals - acute pancreatitis?

Large meals ingested after a period of starvation or consumed w/ alcohol can lead to pancreatitis

= Simply because the amount of secretion is so large

Bile stones - acute pancreatitis?

Bile stones blocks the outflow of pancreatic juice

= The pressure inside the pancreatic ducts will increase -> forcing zymogens into the parenchyma

- Bile itself also active the proenzymes

Potential consequences of acute pancreatitis?

• Pancreatic adiponecrosis

• Fluid loss to the peritoneum → hypovolemic shock

• Phospholipase in the circulation → acute respiratory distress syndrome (ARDS)

• Ischemic pancreas produces MDF → depresses the myocardium

• Kallikrein-kinin system activation → increase permeability everywhere → extravasion of fluid

• Activation of coagulation → DIC

• Langerhans dysfunction → hyperglycemia

• Infections → sepsis

• Retroperitoneal bleeding → irritation of the peritoneum → paralytic ileus

What happens when the pancreas digests itself?

The pancreatic enzymes will be released into the organ and eventually into the systemic circulation

Released lipase:

- Break down peripancreatic triglycerides into fatty acids -> bind Ca2+ -> soap formation = adiponecrosis

The reduced serum Ca2+ may lead to symptoms of hypocalcemia -> TETANY

How can acute pancreatitis cause severe bleeding?

The self-digesting pancreas will digest some vessels = causing severe bleeding

= Bleeders into the retroperitoneum may induce paralytic ileus

Inflammation caused by acute pancreatitis?

The digestive enzymes triggers inflammation

- Potentially Systemic Inflammatory Response Syndrome (SIRS)

It is not uncommon that bacterial superinfection occurs -> may progress into sepsis

Kallikrein-kinin system?

• Cascade of metabolic events that interacts with the clotting system

• Plays important role in inflammation

• Kinins are potent vasodilators that regulate the inflammatory process; involved in pain sensation and cell growth

Kallikrein-kinin system in acute pancreatitis?

Released proteases activate the complement- and kallikrein-kinin systems in the vessels

• Bradykinin will be produced → causing vasodilation & increased vascular permeability

• Fluid extravasation will occur from the vessels, into the interstitium and body compartments (like peritoneum)

⟹ Hypovolemic shock

Both these systems that are activated contribute to formation of distributive shock

Phospholipase release in acute pancreatitis?

When phospholipase is released into the circulation, will it travel to the lungs

Phospholipase breaks down the surfactant -> causing ARDS

How can DIC occur in acute pancreatitis?

Digestive enzymes released into the circulation will damage the endothelium of tissues -> activation of coagulation cascade

= DIC

MDF in acute pancreatitis?

Ischemic pancreas will produce Myocardial Depressing Factor

- A protein that depresses the function of myocardium

= Contributes to cardiogenic shock

How to diagnose acute pancreatitis?

- Sudden, dull abdominal pain

- Serum lipase and amylase levels

Treatment acute pancreatitis?

Restricting oral feeding COMPLETELY

- As that would induce the production of more pancreatic secretions

Further:

- Supportive treatment like fluid replacement, parenteral nutrition if needed, antibiotics if needed and calcium supplement if needed

Surgical intervention may be necessary depending on the cause

Outdated information NB! What is true about oral feeding in acute pancreatitis?

The part about restricting oral feeding is outdated; nowadays we know that oral feeding as soon as possible improves the prognosis of acute pancreatitis. Unfortunately, pathophysiology has a tendency to teach outdated stuff.