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Pathology of Acute Pancreatitis
The mild and presumably reversible form of acute pancreatitis, termed interstitial or edematous pancreatitis, has not been extensively studied because of its brief and benign clinical course.
An infiltrate of polymorphonuclear leukocytes and edema of the connective tissue between lobules of acinar cells constitute the initial lesion.
There is no necrosis of acinar cells, fat necrosis, or hemorrhage.
Acute hemorrhagic pancreatitis is a condition of middle age, with a peak incidence at 60 years.
It is often associated with chronic biliary disease and alcohol abuse and erupts abruptly, usually following a heavy meal or excessive alcohol intake.
It is more common in men than in women, especially when it is associated with the chronic abuse of alcohol.
Clinically, the patient presents with severe epigastric pain that is referred to the upper back and is accompanied by nausea and vomiting.
Within a matter of hours catastrophic peripheral vascular collapse and shock ensue.
When shock is sustained and profound, pancreatitis may be complicated within the first week of onset by the adult respiratory distress syndrome and acute renal failure, a situation that is fatal in 7% of cases.
Early in the disease, pancreatic digestive enzymes are released from injured acinar cells into the blood and the abdominal cavity.
Elevation of serum amylase and lipase levels as early as 24 to 72 hours is diagnostic, as are high enzyme levels in the abdominal ascitic fluid.
Initially, the pancreas is edematous and hyperemic.
Within a day, pale, gray foci appear, rapidly becoming friable and hemorrhagic.
As the disease progresses, these foci enlarge and become so numerous that most of the pancreas is converted into a large retroperitoneal hematoma, in which pancreatic tissue is barely recognizable.
Yellow-white areas of fat necrosis appear at the interface between necrotic foci and fat tissue in and around the pancreas, including the adjacent mesentery.
These nodules of necrotic fat have a pasty consistency, which becomes firmer and chalk-like as more calcium and magnesium soaps are produced.
Saponification reflects the interaction of cations with free fatty acids released by the action of activated lipase on triglycerides in fat cells.
As a result, the level of blood calcium may be depressed - sometimes to the point of causing neuromuscular irritability, such as facial tics.
Extrapancreatic fat necrosis, arising as a consequence of the release of lipase from the injured pancreas into the blood, has been reported in subcutaneous fat, skeletal muscle, and bone marrow.
The most prominent tissue alterations in acute pancreatitis are acinar cell necrosis, an intense acute inflammatory reaction, and foci of necrotic fat cells.
Late sequelae in patients who survive the shock and its systemic complications include the formation of pancreatic abscesses and pseudocysts.
In the latter structures, large spaces limited by connective tissue contain degraded blood, debris of necrotic pancreatic tissue, and fluid rich in pancreatic enzymes.
Pseudocysts may enlarge enough to compress and obstruct the duodenum.
They may become secondarily infected and form an abscess.
Rupture is a rare complication that leads to a chemical or septic peritonitis, or both.
Pathogenesis of Acute Pancreatitis:
Autopsy studies at the turn of the century established the association of chronic cholecystitis and cholelithiasis with acute hemorrhagic pancreatitis.
In some cases gallstones were found lodged near the orifice of the common duct beyond the point where it is joined by the pancreatic duct.
Since a stone impacted at this site obstructs both ducts, it would be expected to cause the reflux of bile into the pancreas.
Therefore, it was theorized that such obstruction was the etiologic factor in the development of acute hemorrhagic pancreatitis.
This notion was prevalent for many years and gained support from experimental studies in animals in which hemorrhagic pancreatitis was induced by retrograde infusion of a mixture of pancreatic juice and bile into the main pancreatic duct.
However, in recent years it has become increasingly apparent that although pancreatitis is often accompanied by conditions that serve to impair normal duct secretion, frank obstruction of the common duct or pancreatic duct is often not present.
Increasingly, studies suggest that failure of one or more of the complex systems of physiologic checks and balance that exist in the blood, the pancreas, and other tissues that serve to prevent the inappropriate activation of pancreatic enzymes and to protect the host from their deleterious effects may also contribute to the development of acute pancreatitis.
From the study of various types of pancreatitis, it is clear that a breakdown of intracellular compartmentation of digestive proenzymes synthesized by acinar cell and inappropriate and premature activation of this proenzymes are common to all variants of pancreatitis.
Differences in the severity and duration of membrane damage in part determine the type of pancreatitis that ultimately develops.
The pancreas is protected from the harmful effects of its lytic enzymes by a series of highly compartmented systems of intracellular membranes effectively isolate the pancreatic enzymes from their synthesis by the rough-surfaced endoplasmic reticulum to their release into the ductular lumen in response to stimulation by the gastrointestinal hormone cholecystokinin.
This process involves the extrusion of the nascent proenzyme proteins into the cisternae of the endoplasmic reticulum, from which they are moved progressively by a system of vesicles to the cis and trans elements of the Golgi complex, and from that site to condensing vacuoles, from which the zymogen granules are ultimately derived.
On secretion the membrane of the granules fuses with the plasma membrane before its extrusion by exocytosis.
At each step of their formation and secretion the enzymes are totally sequestrated in a membrane-bound space.
The various potent inhibitors of proteolytic enzymes present in many body fluids and tissues constitute a second line of protection, defending the organism against inappropriate activation of the digestive proenzymes of the pancreas.
Four potent protease inhibitors have been identified in human plasma : alfa1-antitrypsin ; alfa2-macroglobulin ; C1 esterase inhibitor, and pancreatic secretory trypsin inhibitor.
Although collectively these can inhibit two types of trypsin in addition to chymotrypsin and elastase, they are without effect on two other potent proteases, carboxypeptidases A and B.
These inhibitors bind strongly to the proteases and render them inactive.
Although alpha2-macroglobulin reduces the capacity of either of the trypsin molecules to digest protein, it does not completely prevent them from cleaving small synthetic peptides.
Thus, tryptic activity is demonstrable in plasma , even when trypsin is bound by the inhibitor.
Further, a trypsin inhibitor in human pancreatic juice is unable to inhibit the enzyme completely, even when the inhibitor is present in excess.
Apparently the inhibitor is digested by the trypsin to which it is bound, a reaction that requires calcium ions.
Thus despite the variety of inhibitors of trypsin in different body compartments, the protection they render is less than complete.
Since it turns out that activated trypsin is also able to activate other pancreatic proenzymes, such as chymotrypsinogen, proelastase, prophospholipase, and procarboxypeptidase, its incomplete inhibition in pancreatic juice and plasma poses a hazard.
Secretion by acinar cells delivers fluid rich in proenzymes to the ductules, where they are activated almost immediately.
Although most of the secretion is discharged into the duct system and enters the duodenum, a small amount diffuses back into the periductular extracellular fluid and eventually the plasma.
Any condition that tends to diminish the patency of pancreatic ducts or the easy outflow of exocrine secretion could be expected to exacerbate back-diffusion across the ducts, which can trigger a massive inappropriate activation of digestive proenzymes.
If the obstruction is sufficiently severe, this process could even involve the acinar cells.
Well-documented causes of pancreatic duct obstruction include gallstones, frequently in association with chronic cholecystitis, and chronic alcohol abuse.
Although ethanol is well recognized as a chemical toxin, a direct toxic effect on pancreatic acinar or duct cells has yet to be demonstrated.
However, ethanol can adversely affect the pancreas by causing spasm or acute edema of the sphincter of Oddi, especially following an alcohol binge, and by stimulating the secretion of secretin from the small intestine, which in turn triggers the exocrine pancreas to secrete pancreatic juice.
When these effects occur together (i.e., enhanced secretion into an obstructed duct), the results may be disastrous.
The transudation of pancreatic secretion into periductal pancreatic tissues and eventually peripancreatic tissue leads to chemical injury.
The activated enzymes digest proteins, lipids, and carbohydrates of cell membrane.
Phospholipase A causes lysis of cell membranes, and when mixed with bile converts lecithin to the potent cytotoxin lysolecithin.
Damage to the capillaries leads to hemorrhage and local anoxia, which further intensifies and extends tissue damage.
In addition to the above, other factors that cause pancreatic acinar cell injury and pancreatitis include viruses, endotoxemia, ischemia, drugs, trauma, hypertriglyceridemia, and hypercalcemia.
The mechanisms by which some of these induce injury are known, but those those for others - such as corticosteroids, estrogens, azathioprine, hypertriglyceridemia, and hypercalcemia - remain unclear.
In hypertriglyceridemia and hypercalcemia, it is thought that toxic fatty acids are formed by the action of pancreatic lipase on triglycerides and the activation of trypsinogen by high levels of serum calcium.
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