Page 6 - Acute Pancreatitis (Viêm tụy cấp)

CHAPTER 58 Acute Pancreatitis 897

The pathophysiology of AP starts with acinar injury that, if glucagon), binding of calcium by free fatty acid–albumin com-
unchecked, leads to local inflammatory complications, a systemic plexes, intracellular translocation of calcium, and systemic expo- 58
inflammatory response, and even sepsis. Pathophysiologic mech- sure to endotoxin. 50
anisms include microcirculatory injury, leukocyte chemoattrac- Pancreatic infection (infected necrosis and infected pseudo-
tion, release of pro- and anti-inflammatory cytokines, oxidative cyst) can occur from the hematogenous route or from translo-
stress, leakage of pancreatic fluid into the region of the pancreas, cation of bacteria from the colon into the lymphatics. Under
and bacterial translocation to the pancreas and systemic circula- normal circumstances bacterial translocation does not occur,
tion. because there are complex immunologic and morphologic barri-
The release of pancreatic enzymes damages the vascular endo- ers to it. However, during AP, these barriers break down, which
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thelium, the interstitium, and acinar cells. 39-41 Acinar injury leads can result in local and systemic infection. Penetration of the gut
to expression of endothelial adhesion molecules (e.g., VCAM-1), barrier by enteric bacteria is likely due to gut ischemia secondary
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which further propagates the inflammatory response. Micro- to hypovolemia and pancreatitis-induced arteriovenous shunting
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circulatory changes, including vasoconstriction, capillary stasis, in the gut. In canine experimental pancreatitis, luminal Esch-
decreased local oxygen saturation, and progressive ischemia, erichia coli translocate to mesenteric lymph nodes and to distant
occur early in experimental AP. These abnormalities increase sites. In feline experimental pancreatitis, enclosing the colon
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vascular permeability and lead to edema of the gland (edema- in impermeable bags prevents translocation of bacteria from the
tous or interstitial pancreatitis). Vascular injury could lead to colon to the pancreas. 54
local microcirculatory failure and amplification of the pancreatic More recent studies present strong evidence that, although
injury. It is uncertain whether ischemia-reperfusion injury occurs trypsinogen activation to trypsin is likely a necessary first step
41
in the pancreas. Reperfusion of damaged pancreatic tissue could in the inflammatory cascade underlying pancreatitis, sustained
lead to the release of free radicals and inflammatory cytokines into pancreatic inflammation is dependent on damage-associated
the circulation, which could cause further injury. In early stages molecular pattern-mediated cytokine activation causing the
of animal and human pancreatitis, activation of complement and translocation of commensal (gut) organisms into the circulation
the subsequent release of C5a play significant roles in the recruit- and their induction of innate immune responses in acinar cells.
ment of macrophages and polymorphonuclear leukocytes. 43,44 Quite unexpectedly, these studies reveal that the innate responses
Active granulocytes and macrophages release proinflammatory involve activation of responses by nucleotide-binding oligomer-
cytokines in response to transcription factors such as NF-κB. ization domain 1 (NOD1), and that such NOD1 responses have
Proinflammatory cytokines include TNF, IL-1, IL-6, and IL-8, a critical role in the activation/production of NF-κB and type
and PAF. Proinflammatory cytokines frequently are followed by I interferon. Recent advances thus challenge the long-believed
production of anti-inflammatory cytokines (IL-2, IL-10, IL-11) trypsin-centered understanding of pancreatitis. It is becoming
that attempt to downregulate inflammation. Other mediators increasingly clear that activation of intense inflammatory signal-
45
of inflammation include arachidonic acid metabolites (prosta- ing mechanisms in acinar cells is crucial to the pathogenesis of
glandins, PAF, and leukotrienes), nitric oxide, proteolytic and pancreatitis, which may explain the strong systemic inflammatory
lipolytic enzymes, and reactive oxygen species that overwhelm response in pancreatitis. 58
scavenging by endogenous antioxidant systems. These substances Evidence has emerged indicating that smoking is an inde-
also interact with the pancreatic microcirculation to increase vas- pendent risk factor for AP. Using a stepwise approach, Barreto
cular permeability, which induces thrombosis and hemorrhage reviewed the effects of the various metabolites of cigarette smoke
and subsequently pancreatic necrosis. A recent study suggests on the constituents of the pancreas (exocrine, endocrine, sneu-
that gene polymorphisms that reduce acinar cell glutathione con- rohormonal, stellate cells, ductal system) and highlights their
centrations may lead to increased oxidant stress and more severe proven, and potential, mechanisms in triggering AP. 55
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pancreatitis. Meanwhile, ischemia and severe inflammation of In different animal models of AP, there is a central role
the gland can lead to disruption of the main and secondary PDs, for mitochondrial dysfunction, and for impaired autophagy
leading to local fluid accumulations within and surrounding the as its principal downstream effector, in development of AP.
pancreas that can eventuate into pseudocysts. 46,47 In particular, the pathway involving enhanced interaction of
Some patients with severe pancreatic damage develop systemic cyclophilin D with ATP synthase mediates L-arginine-induced
complications, including fever, acute respiratory distress syn- pancreatitis, a model of severe AP the pathogenesis of which
drome (ARDS), pleural effusions, renal failure, shock, myocar- has remained unknown. Strategies to restore mitochondrial
dial depression, and metabolic complications. SIRS is common in and/or autophagic function might be developed for the treat-
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patients with AP and is probably mediated by activated pancreatic ment of AP.
enzymes (phospholipase, elastase, trypsin) and cytokines (TNF,
PAF) released into the portal circulation from the inflamed pan- PREDISPOSING CONDITIONS
creas. Cytokines reaching the liver activate hepatic Kupffer
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cells, which, in turn, induces hepatic expression and secretion of A wide variety of causes of AP have been reported; however, it is
cytokines into the systemic circulation. These cause acute phase always difficult to be certain about the cause in a given patient.
protein synthesis (e.g., C-reactive protein [CRP], IL-6) and may For example, in a patient with alcohol history and gallstones,
cause SIRS and damage to the kidneys, lungs, and other organs either of the 2 factors or even a combination of both might be
leading to multiorgan dysfunction and failure. 49 responsible for the etiology of AP. If the serum ALT level is ele-
ARDS may be induced by active phospholipase A (lecithinase), vated in such a patient, then gallstones as the cause may be even
which digests lecithin, a major component of lung surfactant. a stronger consideration. However, an attempt must be made
Acute renal failure has been explained on the basis of hypovole- in every patient to ascertain a cause by a thorough history and
mia and hypotension. Myocardial depression and shock are likely physical examination, laboratory tests, and imaging. Before one
secondary to vasoactive peptides and release of a myocardial labels an episode as “idiopathic AP,” more specialized tests and
depressant factor. Metabolic complications include hypocalce- procedures like secretin-MRCP, EUS, and genetic testing should
mia, hyperlipidemia, hyperglycemia with or without ketoacidosis, be performed. Although the goal is to eventually reduce the pro-
and hypoglycemia. The pathogenesis of hypocalcemia is multi- portion of cases labeled as idiopathic, it may not be appropriate
factorial and includes hypoalbuminemia (the most important to list conditions as the cause for AP if those conditions are not
cause), hypomagnesemia, calcium-soap formation, hormonal convincingly proved to cause AP (sphincter of Oddi dysfunction,
imbalances (e.g., involving parathyroid hormone, calcitonin, and pancreas divisum, and others).