Page 5 - Acute Pancreatitis (Viêm tụy cấp)

896 PART VII Pancreas

for infectious complications. Patients who are older and have continues and (b) disruption of the paracellular barrier of aci-
comorbid illnesses have a substantially higher mortality rate than nar cells and intralobular pancreatic duct (PD) cells. This bar-
younger healthier patients. In those who survive their illness, rier disruption facilitates the extravasation of pancreatic enzymes
severe pancreatic necrosis can result in chronic pancreatitis, with from acinar cells and from the duct lumen into interstitial spaces.
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all of its complications (see Chapter 59). This phenomenon may explain the rapid development of inter-
stitial edema and the increase in the concentration of pancreatic
PATHOGENESIS AND PATHOPHYSIOLOGY enzymes in the serum. 30
As discussed in Chapter 57, genetic mutations associated with
Most of the published data on the pathogenesis of AP comes hereditary pancreatitis also lend support to the hypothesis that
from work in animal models. Although gallstones and alcohol intrapancreatic activation of pancreatic zymogens is central to
may contribute to 60% of more of AP in humans, there is no the pathogenesis of AP. 30-32 The mutant trypsins in patients with
animal model of for these 2 predisposing causes. Cerulein and hereditary pancreatitis (usually a R122H or a N29I mutation)
taurocholate used to induce pancreatitis in animal models does cause trypsin to be resistant to degradation or causes premature
not cause human pancreatitis. Despite these limitations, the ana- trypsinogen activation (gain-of-function mutation), leading to
tomic and biochemical abnormalities in AP in animal models autodigestion of the pancreas and episodes of AP. Mutations
are similar to humans. Once the process of AP is initiated, the in the CFTR gene have also been implicated in pancreatitis (see
subsequent progression of events resulting in local and systemic Chapter 57). The CFTR anion channel allows for chloride and
complications are similar regardless of the inciting event. This is bicarbonate secretion into the PDs and thus allows flushing of
important because if any drug therapy becomes available to treat the liberated enzymes and proenzymes into the duodenum (see
this disease, it should be administered very early on and be able to Chapter 56). There are more than 1200 mutations that have
block the progression of events at that early stage. been described for the CFTR gene. Some of these are consid-
The initial step in the pathogenesis of AP is conversion of ered severe and some mild. Homozygous severe mutations
trypsinogen to trypsin within acinar cells in sufficient quantities produce a viscid, concentrated, acidic pancreatic juice, leading
to overwhelm normal mechanisms to remove active trypsin (see to ductal obstruction and pancreatic insufficiency in childhood.
Fig. 57.3). Trypsin, in turn, catalyzes conversion of proenzymes, Heterozygotes carrying minor or major mutations may have
including trypsinogen and inactive precursors of elastase, phos- acute recurrent or chronic pancreatitis by altering acinar or duc-
pholipase A 2 (PLA 2 ), and carboxypeptidase, to active enzymes tal cell function (e.g., alteration of bicarbonate conductance).
(see Chapter 56). Trypsin also may activate the complement and More recently, CFTR mutations associated with pancreas divi-
kinin systems. Active enzymes autodigest the pancreas and initi- sum have suggested a synergistic effect in the pathogenesis of
ate a vicious cycle of releasing more active enzymes. Normally, AP. Although most patients with pancreas divisum (7% to 10%
small amounts of trypsinogen are spontaneously activated within of the general population; see Chapter 55) never develop pan-
the pancreas, but protective intrapancreatic mechanisms quickly creatic disease, it may be that those persons who also harbor a
remove the trypsin. Pancreatic secretory trypsin inhibitor (now dysfunction of the CFTR transporter are at risk of developing
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called SPINK1) binds and inactivates about 20% of the trypsin pancreatitis when both are present. A third genetic abnormality
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activity. Other mechanisms for removing trypsin involve meso- associated with pancreatitis is a mutation of the SPINK1 gene.
trypsin, enzyme Y, and trypsin itself, which splits and inactivates As already noted, SPINK1 protects the pancreatic acinar cell by
other trypsin molecules. The pancreas also contains nonspe- inhibiting prematurely activated trypsin. Mutations of this gene
cific antiproteases such as α 1 -antitrypsin and α 2 -macroglobulin. presumably limit the activity of this protein, but the exact mecha-
Additional protective mechanisms are the sequestration of pan- nism is unclear.
creatic enzymes within intracellular compartments of the acinar The pathogenesis of gallstone-related pancreatitis is
cell during synthesis and transport and the separation of diges- unknown (see Chapter 65). Factors that may initiate gallstone
tive enzymes from lysosomal hydrolases as they pass through pancreatitis include reflux of bile into the PD 35,36 or obstruction
the Golgi apparatus, which is important because cathepsin B can of the PD at the ampulla from stone(s) or from edema result-
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activate trypsin from trypsinogen. Low intra-acinar cell calcium ing from the passage of a stone. Reflux of bile into the PD
concentrations also prevent further autoactivation of trypsin. could occur when the distal bile and PDs form a common chan-
In experimental pancreatitis, activation of trypsin occurs nel and a gallstone becomes impacted in the duodenal papilla.
within 10 minutes, and large amounts of trypsin and increased Alternatively, bile could reflux into the PD from the duodenum
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concentrations of trypsinogen activation peptide (TAP) accumu- through an incompetent sphincter of Oddi injured by recent
late within the pancreas. 23,24 TAP is produced when trypsinogen passage of a gallstone.
is activated to trypsin, and concentrations of TAP in plasma, Experimentally, reflux of bile into the PD, particularly if the
urine, and ascites correlate with the severity of the pancreatic bile is infected or mixed with pancreatic enzymes, causes pan-
inflammatory response, with the highest levels associated with creatic injury. Mixtures of bile and pancreatic enzymes increase
acinar cell necrosis and intrapancreatic hemorrhage. 25,26 the permeability of the main PD, which is associated with local
Co-localization of pancreatic enzymes in lysosomes, followed parenchymal inflammation. The common channel theory is
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by acinar cell injury, is an attractive hypothesis for the pathogen- somewhat problematic because PD pressure is invariably higher
esis of AP, but the relevance of such co-localization to the patho- than bile duct pressure, making bile reflux into the PD unlikely.
genesis of AP is unclear. Activation of trypsinogen occurs before Reflux of bile from the duodenum also is unlikely because pan-
biochemical or morphologic injury to acinar cells, in association creatitis does not occur in conditions with easily demonstrable
with co-localization of lysosomal enzymes, such as cathepsin B, reflux, such as after surgical sphincteroplasty or endoscopic
and digestive enzymes, including trypsinogen within unstable sphincterotomy.
vacuoles. 26,27 Complete inhibition of pancreatic cathepsin B A popular theory for the mechanism of gallstone pancreatitis
activity in vitro prevents trypsinogen activation induced by the is that an impacted gallstone in the distal bile duct obstructs the
CCK analog cerulein, supporting the co-localization hypoth- PD, increasing pancreatic pressure, thereby damaging ductal and
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esis. Thus, complete inhibition of cathepsin B may prevent or acinar cells. Experiments in the opossum supporting this theory
become a treatment for AP. However, enzyme co-localization are the observations that ligation of the PD causes severe necro-
may occur without inducing significant acinar cell injury. 29 tizing pancreatitis, and that decompression of the ductal sys-
36
Two other features of experimental AP are (a) early blockade tem within 3 days prevents progression to acinar cell necrosis and
of the secretion of pancreatic enzymes while enzyme synthesis severe inflammation. 37