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Pathophysiology ofLocal
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Pancreatic Complications
NicholasJ.Zyromski
1 Introduction
About 20% of patients with acute pancreatitis
develop a severe course of the disease marked by
systemic inammation, organ failure, and variable necrosis of the pancreatic parenchyma and
peripancreatic soft tissue. Both of the widely
used contemporary classication systems, the
Revised Atlanta Criteria [1] and the Determinant
Based Classication [2], recognize local complications as an important factor dening moderately severe, severe, and critical acute
pancreatitis.
Fig. 1 Local pancreatic
complications dened
by the Revised Atlanta
Classication, based on
the content of the
collection, duration of
collection, and whether
it is infected. (Adapted
from [3])
Content
Fluid
Solid fluid
no defined wall)
No infection Infection
Acute
pancreatic
fluid
collection
Acute
necrotic
collection
Local complications are inexorably linked
with pancreatic necrosis. A clear denition of
local pancreatic complications has been an
important advance for diagnosis, management,
and research (Fig.1). The morphology and extent
of necrosis have clinical importance and are
related to the likelihood of certain local complications, which include both pancreatic and peripancreatic complications. In addition to
pancreatic complications, there are important
vascular, alimentary, and biliary complications
(Fig.2).
Acute
(<4 weeks,
Infected
APFC
Infected
ANC
No infection Infection
Pseudocyst
Walled off
necrosis
Chronic
(>4 weeks,
defined wall)
Infected
pseudocyst
Infected
WON
N. J. Zyromski (*)
Department of Surgery, Indiana University,
Indianapolis, IN, USA
e-mail: nzyromsk@iupui.edu
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024
J. A. Windsor et al. (eds.), Acute Pancreatitis, https://doi.org/10.1007/978-981-97-3132-9_4
61
62
Visceral arterial pseudoaneurysm
uption
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Alimentary
Biliary
Cholecystitis
Cholangitis
Biliary obstruction
Bile duct stricture
N. J. Zyromski
Infected Necrosis
Pancreas
Early pancreatic fluid
collection
Pancreatic duct disr
Disconnected tail (DPDS)
Fistula
Fistula
Stricture
Ischemia
Obstruction
Fig. 2 Sequelae to local complications of pancreatitis including vascular, alimentary, and biliary complications
Local complications can occur at any time
point along the typically months-long necrotiz-
Vascular
Venous thromboembolism (VTE)
1.1 Cellular Events andCalcium
Signaling
ing pancreatitis disease course. Specic complications, however, do have more typical times of
presentation. For example, infection of pancreatic necrosis typically occurs relatively later
(e.g., 4–6weeks into the disease course), while
ischemia of the colon and gallbladder usually
presents much earlier. Strictures of alimentary
tract organs or bile ducts are nearly always present later. Recent studies on the natural history of
pancreatic collections have revealed that pancreatic necrosis becomes largely or fully encapsulated in 43% of patients by 3weeks and 100% by
week 5 [4].
The goal of this chapter is to discuss the
pathophysiology of pancreatic and peripancreatic complications with an eye to relevant molecular and cellular mechanisms covered more fully
in Chap. 6.
Acinar cells, stellate cells, and ductal epithelial
cells all play important roles in the cellular pathogenesis of acute pancreatitis and related local
complications. The acinar cell is the most common pancreatic cell type and is functionally
important for its enzyme production. The secretory demand on the acinar cell, a task that is
accomplished by exocytosis, requires enormous
energy consumption. Exocytosis is modulated by
calcium signaling currents [5]. Cholinergic and
cholecystokinin receptors on the basolateral
acinar cell membrane trigger an intracellular calcium ux, mostly at the apical zymogen granule
region. Further intracellular calcium is released
from basolateral endoplasmic reticulum (ER) [6].
In pathologic conditions, complete emptying of
the ER calcium stores leads to intracellular
Pathophysiology ofLocal Pancreatic Complications
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63
calcium overload, necrosis, and cell death. Both
ethanol degradation to fatty acid ethyl esters and
bile salts lead to strong calcium release from
intracellular stores. Sustained increased intracellular calcium concentrations then lead to trypsin
activation and ultimately necrotic cell death.
Thus, calcium channels are attractive targets for
pharmacologic intervention.
An understanding of the role of stellate cells
in acute pancreatitis pathogenesis is emerging
[7]. Calcium signaling in stellate cells produces
inammatory factors. Interesting recent work has
shown that blockade of trypsin by deleting the
trypsinogen gene decreased pancreatic necrosis
but not the inammatory response in murine
experimental models of AP [5]. These data
suggest a possible role of stellate cells directly
modulating and promoting acute pancreatitis.
And stellate cells may have a role in regeneration
after acute pancreatitis [8].
Ductal epithelial cells may have a larger role
in acute pancreatitis pathogenesis than previously considered. The decreasing ow of
bicarbonate- rich uid secreted by ductal cells
potentially increases cellular exposure to activated enzymes within the pancreas, thereby
worsening local autodigestion and subsequent
necrosis [9].
Elucidation of these pathophysiologic mechanisms has identied potential therapeutic targets,
including calcium cell channels such as the
CRAC channel, which is the target in a current
clinical trial [10, 11].
1.2 Pancreatic Necrosis
andMechanism ofCell Death
Acinar cell necrosis underlies nearly every local
complication associated with severe acute pancreatitis. Although trypsin-mediated cell death
leads to pancreatic injury in the early stages of
pancreatitis, multiple parallel mechanisms,
including activation of inammatory cascades,
endoplasmic reticulum stress, autophagy, and
mitochondrial dysfunction in the acinar cells, are
now recognized to be important in driving the
profound systemic inammatory response and
extensive pancreatic injury seen in acute pancreatitis [5]. It is known that acinar cells in clinical
and experimental acute pancreatitis die apoptosis, nonregulated and programmed necrosis.
Apoptosis is programmed cell death biologically
necessary to eliminate senescent and unneeded
cells. The apoptotic process leads to cellular
shrinkage, nuclear fragmentation, and ultimately
apoptotic bodies, which are phagocytized. During
apoptosis, the cell membrane remains intact, and
no leakage of intracellular organelles occurs.
Therefore, this process of apoptosis does not lead
to inammation, which is the major difference
from necrosis. Not surprisingly, as necrosis
causes inammation, more severe acute pancreatitis is correlated with a higher percentage of
necrotic cell death. In fact, the necrosis-toapoptosis ratio is 10:1in mild acute pancreatitis
and greater than 1000:1in severe acute pancreatitis. These numbers are consistent in animal
experimental models of pancreatitis and analysis
of human acute pancreatitis patients [12].
The mechanisms mediating acinar cell necrosis in acute pancreatitis are less well understood.
Necrosis may occur from external factors, such
as mechanical pressure, chemical, or thermal
injury, or from internal factors, such as loss of
ATP, leading to the inability to maintain ion gradients through plasma and organelle membranes.
The intracellular calcium overload that is a pathological condition in acute pancreatitis leads to
mitochondrial overload and opening of the PTP
nonselective calcium channel in the mitochondrial membrane [6]. This situation ultimately
leads to loss of ATP production and cell necrosis.
Other factors are also involved in the pathogenesis of pancreatic necrosis, including Ischemia due
to splanchnic vasoconstriction secondary to
hypovolemia, microthrombosis in a procoagulant
milieu, and cytokine-mediated endothelial injury.
Importantly, necrosis leads to inammation
and is always pathological. Traditionally, cellular
necrosis was thought to occur in a nonregulated
fashion, but several avenues of programmed or
regulated necrosis have been highlighted. These
include necroptosis, pyroptosis, and ferroptosis
[13, 14]. These three programmed necrosis phenotypes all result in loss of plasma membrane
64
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N. J. Zyromski
integrity, with an associated cellular inammatory process. Necroptosis has been established to
play a role (although to a lesser extent than
unprogrammed necrosis) in acute pancreatitis.
Less is known about the other two pathways of
programmed necrosis in acute pancreatitis. The
mechanisms of each of these three pathways are
being unraveled, and each offers potential targets
for intervention [12]. These include RIP kinases
in necroptosis, caspases in pyroptosis, and peroxidases in ferroptosis.
Our current understanding is that unprogrammed necrosis regulated by PTP represents
the major type of cell death in necrotizing pancreatitis. Experimental approaches to reduce
necrosis include blocking the proteins mediating
PTP channel opening, normalizing cell and mitochondrial calcium signaling, and enhancing the
efciency of autophagy to eliminate damaged
mitochondria [15]. Some drugs targeting these
mechanisms are currently in clinical trials for
autoimmune diseases, psoriasis, Alzheimer’s
disease, and Covid-19.
1.3 Inuence ofFluid
Resuscitation
onDevelopment ofPancreatic
Necrosis
Fluid resuscitation is considered a cornerstone
treatment in acute pancreatitis, although there are
many unanswered questions [16]. Variables that
have been studied in acute pancreatitis are the
rate and volume of uid delivered as well as the
type of intravenous uid. Early clinical studies
recognized that hemoconcentration, which
reects decreased intravascular volume (dehydration), is associated with increased pancreatic
and peripancreatic necrosis.
The importance of adequate resuscitation to
restore intravascular volume has been studied in
both preclinical and clinical studies. Preclinical
models of acute pancreatitis using invivo microscopy and relative oxygen tension measurement
have documented decreased blood ow to areas
of the pancreas that correlate with increased
parenchymal ischemia and necrosis. Randomized
animal studies, both in small animal (mice) and
large animal (pig) models, have shown the ability
to decrease regional hypoperfusion with increasing uid volume administration [17, 18]. This
strategy was found to increase survival but, interestingly, did not routinely change the histologic
severity of necrosis. These types of studies in
general support the concept that uid resuscitation increases pancreatic perfusion and decreases
the extent of pancreatic necrosis.
Several well-controlled prospective clinical
studies have evaluated different resuscitation
strategies, but very few of these studies included
the development of necrosis as an endpoint. One
study of aggressive intravascular volume resuscitation has shown decreased systemic inammation, early organ failure, and length of
hospitalization but did not change the incidence
or volume of necrosis [19]. But aggressive uid
resuscitation, including rapid correction of hematocrit [20, 21], has been shown to increase newonset organ failure and in particular increased
rates of respiratory failure [22]. The recently
published Waterfall trial randomized 744 patients
from a multinational consortium to aggressive
versus non-aggressive goal-directed uid resuscitation in early acute pancreatitis. Interestingly,
the development of necrosis development was
lower (7.1%) in the moderate resuscitation group
compared to the aggressive resuscitation group
(13.9%). The trial was closed early as early
aggressive uid resuscitation led to a higher incidence of uid overload without change in clinical
outcome [23]. While uid resuscitation is a cornerstone treatment, delineating its effect on the
development of pancreatic necrosis requires further study, but the evidence appears clear that
aggressive uid resuscitation should be avoided.
1.4 Infection ofPancreatic
Necrosis
Infection of established pancreatic necrosis contributes directly to increased systemic inammation, organ dysfunction, and mortality in AP
patients [24]. Most infected necrosis occurs in
areas of established necrosis and later in the
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