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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.
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An infiltrate of
polymorphonuclear leukocytes and edema of the connective tissue
between lobules of acinar cells constitute the initial lesion.
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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.
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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
alfa2-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.
Click on the image: The
pathogenesis of acute pancreatitis
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