Management of Acute and Chronic Pancreatitis

Abstract

Pancreatitis is a major public health issue worldwide. There is geographical variation in the burden of acute and chronic pancreatitis (CP). Globally, the age-standardized prevalence rate increased from 1990 to 2017. Acute pancreatitis (AP) is now one of the most common reasons for hospitalization with a gastrointestinal condition. The essential requirements for the management of AP are accurate diagnosis, appropriate triage, high-quality supportive care, monitoring for and treatment of complications, and prevention of relapse. Clinicians should be aware of the time course and the best management of AP, identifying which patient will have a severe course allowing earlier triage to an intensive care unit and earlier initiation of effective therapy. CP is a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, and other risk factors who develop persistent pathologic responses to parenchymal injury or stress. Diagnosing the underlying pathologic process early in the disease course and managing the syndrome to change the natural course of disease and minimize adverse disease effects are the managing paradigm. In this review, we consider recent changes in the management of acute and CP, as well as common misunderstandings and areas of ongoing controversy.

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Chapter
Management of Acute and Chronic
Pancreatitis
Tommaso Stecca, Cristina Nistri, Bruno Pauletti,
Adriana Di Giacomo, Flavio Colaut, Mariangela Ruperto,
Ezio Caratozzolo, Luca Bonariol and Marco Massani
Abstract
Pancreatitis is a major public health issue worldwide. There is geographical
variation in the burden of acute and chronic pancreatitis (CP). Globally, the age-
standardized prevalence rate increased from 1990 to 2017. Acute pancreatitis (AP) is
now one of the most common reasons for hospitalization with a gastrointestinal
condition. The essential requirements for the management of AP are accurate diagno-
sis, appropriate triage, high-quality supportive care, monitoring for and treatment of
complications, and prevention of relapse. Clinicians should be aware of the time
course and the best management of AP, identifying which patient will have a severe
course allowing earlier triage to an intensive care unit and earlier initiation of effective
therapy. CP is a pathologic fibroinflammatory syndrome of the pancreas in individuals
with genetic, environmental, and other risk factors who develop persistent pathologic
responses to parenchymal injury or stress. Diagnosing the underlying pathologic pro-
cess early in the disease course and managing the syndrome to change the natural
course of disease and minimize adverse disease effects are the managing paradigm. In
this review, we consider recent changes in the management of acute and CP, as well as
common misunderstandings and areas of ongoing controversy.
Keywords: acute pancreatitis, chronic pancreatitis, management, clinical phases,
pathologic process
1. Introduction
Pancreatitis is a major public health issue worldwide. There is geographical
variation in the burden of acute and chronic pancreatitis (CP). Globally, the age-
standardized prevalence rate increased from 1990 to 2017. Acute pancreatitis (AP) is
now one of the most common reasons for hospitalization with a gastrointestinal
condition. The essential requirements for the management of AP are accurate diagno-
sis, appropriate triage, high-quality supportive care, monitoring for and treatment of
complications, and prevention of relapse. Clinicians should be aware of the time
course and the best management of AP, identifying which patient will have a severe
course allowing earlier triage to an intensive care unit and earlier initiation of effective
1

therapy. CP is a pathologic fibroinflammatory syndrome of the pancreas in individuals
with genetic, environmental, and other risk factors who develop persistent pathologic
responses to parenchymal injury or stress. Diagnosing the underlying pathologic pro-
cess early in the disease course and managing the syndrome to change the natural
course of disease and minimize adverse disease effects is the managing paradigm. In
this review, we consider recent changes in the management of acute and CP, as well as
common misunderstandings and areas of ongoing controversy.
Current concepts of the use of interventional methods in severe acute, necrotizing,
and CP (indications and timing of interventions, strategies for intervention, endo-
scopic and percutaneous treatment) are discussed in the other chapters of this mono-
graph on pancreatitis. We, therefore, consider it appropriate that they are illustrated
in detail in the respective chapters.
2. Acute pancreatitis
AP is an acute inflammatory condition of the pancreas with histological acinar cells
destruction. It has a wide spectrum of morphological and clinical manifestations and
can result in local injury, systemic inflammatory response syndrome (SIRS) and organ
failure [1, 2].
2.1 Epidemiology
AP is one of the most common gastrointestinal diseases requiring acute hospitali-
zation [3]. Its incidence is rising worldwide and ranges from 5 to 30 cases per 100,000
[1] and despite improvements in the diagnosis, management and treatment, the
overall mortality rate of AP remains around 2–5% [4, 5]. The average length of
hospital stay for AP is 8 days, with economic burden to patients and the health care
system all around the world [6].
2.2 Etiology
The most common causes of AP are gallstones (up to 40–70% of cases) and alcohol
abuse (25–35%).
Migrating gallstones cause transient obstruction of the pancreatic duct leading to
the blockage of pancreatic secretion and lysosomal dysfunction generating injury and
inflammatory response. Alcohol abuse exerts its effects in a complex way that include
direct toxicity and immunologic mechanisms: prolonged alcohol use (four to five
drinks in a day over a period of more than 5 years) is required and the type of alcohol
ingested does not affect the overall lifetime risk of alcohol-associated pancreatitis, that
range from 2% to 5% in heavy drinkers (“Heavy”alcohol consumption is generally
considered to be >50 g in a day).
In absence of gallstones or alcohol, other etiologies of AP (Table 1) must be
ruled out.
The agent or condition causing AP is not always clear and sometimes there is only
the evidence of factors known to be potential contributors of unexplained pancreati-
tis, such as smoke, obesity and diabetes. Accordingly, idiopathic AP has been defined
as a condition in which the etiological cause is not detectable after an accurate anam-
nesis excluding any substance abuse, infections, metabolic disorders, genetic muta-
tions and at least two second-level imaging techniques [endoscopic ultrasound and
2
Multidisciplinary Management of Pancreatitis

magnetic resonance imaging (MRI)] to exclude abnormality of pancreatic gland,
pancreatic or biliary and gallbladder lithiasis.
Any mass that obstructs the main pancreatic duct can cause AP: 5–14% of patients
with benign or malignant pancreatobiliary tumors present with this scenario and
pancreatic tumor should be suspected in any patient older than 40 years with idio-
pathic pancreatitis, especially those with prolonged or recurrent course [4–6].
2.3 Clinical signs and symptoms
Patients with AP usually present with epigastric or left upper quadrant pain,
usually described as persistent, severe and often radiating to the back, chest or flanks.
The intensity of pain is not correlated to the severity of the disease. Patients experi-
ence pain relief when sitting forward or worsening when lying flat. Nausea and
vomiting are also common, and sequestered fluid in the small bowel may lead to rapid
and severe dehydration. Diaphragmatic irritation may cause hiccoughs. The presenta-
tion can also be dominated by shock with tachycardia, tachypnea, hypotension, anuria
and mental status alteration. On the other hand, patients may be paucisymptomatic,
Cause Frequency Notes
Gallstones 40% Gallbladder stones or sludge
Alcohol 25–35% Usually an acute flares on underlying chronic pancreatitis
Drugs <5% Most strongly associated: azathioprine, 6-mercaptopurine,
dideoxyinosine, valproic acid, angiotensin-converting-
enzyme inhibitors, mesalamine
Hypertriglyceridemia 1–5% Triglyceride level >10 mmol/l (>1000 mg/dl)
Hypercalcemia Total serum calcium concentration >2.60 mmol/l
Autoimmune causes <1% Autoimmune pancreatitis (AIP), type 1 or type 2
Genetic causes Not
known
Mutations and polymorphisms in different genes encoding
cationic trypsinogen (PRSS1), serine protease inhibitor
Kazal type 1 (SPINK1), cystic fibrosis transmembrane
conductance regulator (CFTR), chymotrypsin C, calcium-
sensing receptor
Endoscopic Retrograde
CholangioPancreatography
(ERCP)
5–10%*
Trauma <1% Blunt or penetrating trauma
Infections <1% CMV, mumps, EBV
Tumors Malignant tumor of ampulla, distal choledocus or
pancreatic head**
Other causes of obstruction Rare Pancreas divisum, sphincter of Oddi dysfunction, any
benign or malignant mass that obstructs the main
pancreatic duct**
Other conditions, unknow Common Diabetes, obesity, smoking
*Among patients undergoing ERCP.**5–14% of patients with benign or malignant pancreatobiliary tumors present
with AP.
Table 1.
Causes of acute pancreatitis.
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with few physical signs. Abdominal examination reveals epigastric tenderness and
guarding; abdominal distension with paralytic ileus. Later signs may include mottled
skin or livedo reticularis and lace-like purplish discoloration of the skin. Abdominal
periumbilical ecchymosis (Cullen’s sign) and ecchymosis of the flank (Grey Turner’s
sign) result from the diffusion of fat necrosis and inflammation associated with
retroperitoneal or intra-abdominal bleeding [5].
2.4 Diagnosis
The diagnosis of AP is made following the Revised Atlanta Criteria, a global
consensus classification (generated in 1992 and revised in 2012) designed to stan-
dardize diagnosis, clinical assessment, evaluation, severity and complications of AP
and to help the communication between clinicians.
Diagnosis of AP requires two of the following three features:
•abdominal pain consistent with AP;
•serum lipase or amylase levels at least three times greater than the upper limit of
normal range;
•characteristic findings of AP on imaging [contrast-enhanced computed tomography
(CT) and less commonly MRI or transabdominal ultrasonography].
According to these criteria, it is important to underline that when the diagnosis of
AP is established by abdominal pain and by increased serum pancreatic enzyme
activities (clinical and laboratory criteria), the radiological findings (imaging criteria)
are not required for making the diagnosis [3, 7].
In the majority of patients, routine use of CT or MRI is unwarranted as the
diagnosis of AP is apparent and most have a mild, uncomplicated course. CT or MRI
imaging should be reserved for patients in whom the diagnosis is unclear or who fail to
improve clinically within the first 48–72 hours after hospital admission [6].
Contrarily, transabdominal ultrasound should be performed on admission in all
patients with AP, to define the underlying etiology and to identify the presence of
gallstones that are the most common cause of AP [3, 6].
Moreover, it is important to record the time interval between onset, first observa-
tion and hospital admission. In fact, the onset of AP is defined as the time of beginning
of abdominal pain and not the time of admission to the hospital [7].
In an episode of AP, the enzyme secreted by the pancreas (amylase, lipase, elastase
and trypsin) are released from acinar cells of the pancreas into the bloodstream at the
same time, due to increased permeability following inflammation.
Amylase is an enzyme synthesized mostly by pancreatic acinar cells and salivary
glands and in negligible levels by adipose tissue, gonads, fallopian tubes, intestinal
tract and skeletal muscle. Humans product one specific isoenzyme, α-amylase, with
two major isoforms specific to pancreas and to salivary glands that help to identify
different cases of hyperamylasemia. In case of AP, serum amylase rises rapidly within
a few hours after the onset, with peaks at 3–6 hours, half-life of 10–12 hours, persis-
tent elevation for 3–5 days and decrease to normal levels over the next three to 7 days.
Lipase is an enzyme that has a higher specificity because is mainly produced by
acinar cells of the pancreas; nevertheless, high serum level can be determined also in
patient with renal insufficiency, appendicitis, diabetic ketoacidosis, inflammatory
4
Multidisciplinary Management of Pancreatitis

bowel disease and intestinal obstruction. In AP, elevation of serum lipase arises within
three to 6 hours with peaks at 24 hours following the onset of symptoms and
persistent elevation up to 2 weeks, giving a larger diagnostic window in comparison to
amylase.
Therefore, serum lipase appears to be more specific and remains elevated for a
longer period than serum amylase after disease presentation. Moreover, lipase has a
better degree of sensitivity and specificity in diagnosing AP, during both early and late
phases of the disease (sensitivity of lipase and amylase tests ranges between 64–100%
and 45–87%, respectively).
According to these evidences, current guidelines recommend the preference use of
serum lipase for diagnosis of AP [2, 4, 6].
2.5 Classification
The most commonly used classification system for AP is the “2012 revision of the
Atlanta Classification and definitions”based on international consensus [8].
This classification identifies two types (Interstitial edematous pancreatitis and
necrotizing pancreatitis), three grades of severity (mild, moderately severe or severe)
and two phases (early and late) of AP.
2.5.1 Types of acute pancreatitis
Two different types of AP have been characterized: Interstitial edematous pancre-
atitis and necrotizing pancreatitis.
Interstitial edematous pancreatitis is an acute inflammation of pancreatic paren-
chyma and peri-pancreatic tissues, but without recognizable tissue necrosis. Devel-
oped by the majority of patients (80–85%), it is characterized by diffuse (or
occasionally localized) enlargement of the pancreas, due to inflammatory edema; the
clinical symptoms usually resolve within the first week.
Necrotizing pancreatitis is, instead, the presence of inflammation associated with
pancreatic parenchymal necrosis and/or peri-pancreatic necrosis. The natural history
of necrotizing pancreatitis is variable and this scenario evolves over several days
because necrosis can remain solid or liquefy, can remain sterile or become infected,
persist or disappear over time. This explains why an early CT made for assessment of
AP may underestimate the eventual extent of pancreatic and peri-pancreatic necrosis.
Moreover, most evidence suggest no correlation between the extent of necrosis and
the risk of infection and duration of symptoms and usually infected necrosis is rare
during the first week. Developed by 15–20% of patients with AP, this type of evolu-
tion of AP has increased morbidity and mortality compared to patients with intersti-
tial edematous pancreatitis [5, 7].
2.5.2 Severity of acute pancreatitis
A preliminary overview of complications of AP is mandatory, because the com-
prehension of these terminologies is central to definition and stratification of severity.
•Local complications: acute peri-pancreatic fluid collection, pancreatic
pseudocyst, acute necrotic collection (sterile or infected), walled of necrosis
(sterile or infected), gastric outlet dysfunction, splenic and portal vein
thrombosis, ischemic colitis, colonic necrosis, enteric fistulas, hemorrhages.
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•Systemic complications: exacerbation of preexisting comorbidities, such as
chronic obstructive pulmonary disease, coronary artery disease or chronic liver
disease.
•Organ failure is defined using the modified Marshall scoring system, that has the
advantage of being simple, universally applicable, objective and easily repeatable
daily. In AP three organ systems have to be assessed: respiratory, cardiovascular
and renal. Respiratory failure is defined with a PaO
2
/FiO
2
ratio <300,
cardiovascular failure with a systolic blood pressure <90 mmHg non responsive
to fluid administration and renal failure with a serum creatinine level ≥1.9 mg/dl
(Table 2) [7, 9]. If organ failure affects more than one organ system, it is termed
multiple organ failure (MOF).
•Transient organ failure is defined as organ failure existing for less than
48 hours, while persistent organ failure is organ failure persisting for more than
48 hours [7].
There are three degrees of severity of AP:
•Mild AP: absence of organ failure and absence of local or systemic complications
•Moderately severe AP: presence of transient organ failure (<48 hours) and/or
presence of local or systemic complications (in absence of persistent organ
failure)
•Severe AP: presence of persistent organ failure (>48 hours), that can involve
single or multiple organs [7].
Usually, mild AP account for 80–85% of cases, while severe AP is reported in
15–30% of patients [6].
2.5.3 Phases of acute pancreatitis
AP is a dynamic disease with variable scenarios of evolution, but it has two
overlapping phases that need to be considered separately to better understand the
progression and consequences of this disease.
Organ system Parameter Score
01 2 34
Respiratory PaO
2
/FiO
2
>400 301–400 201–300 101–200 ≤101
Cardiovascular Systolic blood
pressure (mmHg)
>90 <90, fluid
responsive
<90, fluid
unresponsive
<90, pH
<7.3
<90, pH
<7.2
Renal Serum Creatinine
(mg/dl)
<1.4 1.4–1.8 1.9–3.6 3.6–4.9 >4.9
Table 2.
Modified Marshall scoring system for definition of organ failure in acute pancreatitis. A score of two or more in
any system defines the presence of organ failure.
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Multidisciplinary Management of Pancreatitis

The early phase usually takes place in the first and second weeks of the disease. It
is characterized by the host response to local pancreatic injury and inflammation, with
activation of the cytokine cascades that can lead to SIRS (Table 3).
In this phase the scenario of AP is still evolving and local complications may be
recognized but they are mutable and inaccurate to determine the grade of severity.
Furthermore, the morphologic changes due to local complications are not correlated to
the extension of organ damage and the severity of organ failure [7].
Instead, the presence of SIRS and his persistence over time are known to be
correlated to an increased risk of developing organ failure, are associated to high
mortality and are established as early indicator of the likely severity of AP [2, 10, 11].
Persistent SIRS (>48 hours) is associated with a mortality rate of 25% compared with
8% of transient SIRS [3].
Consequently, the determinant of severity in the early phase of AP is the presence
and duration of organ failure, that is assessed thorough clinical criteria [7] (see Section
2.6.1 Initial Assessment, Table 4) and appears to be related to the development and
persistence of SIRS [6].
In this phase, death occurs as a result of the development, the persistence and the
progressive nature of organ dysfunction; the reversal of early organ failure has been
shown to be important in preventing morbidity and mortality in patient with AP.
Heart rate >90 beats/minute
Core temperature <36°C or >38°C
White blood cells count <4000 cells/mm or >12000 cells/mm³
Respiratory rate >20 breaths/minute
PaCO
2
<32 mmHg
Table 3.
SIRS diagnostic criteria. The presence of two or more criteria defines the presence of SIRS.
Patient characteristic Age >55 years
Obesity (BMI >30 kg/m
2
)
Altered mental status
Comorbid disease
Presence of SIRS (see Table 3)
Laboratory findings BUN >20 mg/dl or rising Signs of hypovolemia
HCT >44% or rising
Elevated creatinine
Radiology findings Pleural effusion
Pulmonary infiltrates
Multiple or extensive extra pancreatic collections
BMI, body mass index; BUN, blood urea nitrogen; HCT, hematocrit.
Table 4.
Intrinsic patient-related risk factors for the development of severe disease.
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Therefore, if SIRS is identified in this phase of the disease, patients must be treated
according to the treatment of a severe AP [6].
The late phase usually develops after the second week of the disease and can
extent from weeks to months; it is delineated by the persistence of systemic signs of
inflammation or by the presence of local complications. Consequently, this scenario
develops only in patients with moderately severe or severe AP.
In this phase the disease is still evolving and local complications need to be assessed
and characterized with radiological imaging because they may need a specific man-
agement. Therefore, although the main determinant of severity in this phase is the
persistence of organ failure, the need of radiological definition of local complications
requires both clinical and morphological criteria [7].
In the natural history of AP, half of all deaths occur in the first 2 weeks and are
mainly due to failure of multiple organ systems while the other half occur after
2 weeks and are mainly due to pancreatic and extrapancreatic infections [5].
2.5.4 Prediction of severity
The three severity degrees of AP have distinct characterizations that have direct
implications for clinical management and are associated with different outcome and
mortality:
•Mild AP: self-limited disease that occurs in approximately 80–85% of patients
[5]. By 48 hours after the admission, these patients typically would have
substantially improved [6]. Radiological imaging is routinely not mandatory and
discharge generally occurs during the early phase. Mortality is rare (<2%) [5, 7].
•Moderately severe AP: usually radiological imaging is required to assess the
presence and extent of local complications, that may resolve without the need of
intervention but that may request prolonged specialist support and care.
Mortality is low (<5%) [5, 7].
•Severe AP: specific and aggressive treatment and specialist support and
care are needed. Mortality is high, ranging from 36% to 50%, and reflects
the presence and persistence of SIRS and the development of single or
MOF [7, 11].
Persistent SIRS (more than 48 hours) is related to a mortality rate of 25.4% and
persistent MOF is associated with a mortality reported to be as great as 42% [10].
Infection of the pancreatic and peripancreatic necrosis occurs in about 20–40% of
patients and is associated with worsening organ dysfunctions [2].
Therefore, there are important reasons to define and stratify the severity of AP: the
correlation between grade of severity and outcome and mortality, the need to identify
patients with potentially severe AP that require aggressive early treatment, the need
to identify patients that need transfer from a secondary care center to a specialist one
or to intensive care unit, the need to stratify patients into subgroups based on the
presence of organ failure and local or system complications to enable patient-tailored
treatment that may require a variety of interventions.
Consistently with the definitions of the degrees of severity, the real severity of AP
cannot be assessed on admission to the hospital or on first observation because it is not
known whether the patient will have transient or persistent organ failure.
8
Multidisciplinary Management of Pancreatitis

Moreover, the evolutions and changes of morphological features of local and sys-
temic complications over time ensure that it is generally not necessary to perform
radiological imaging during the first week of admission. When necessary, a CT scan
performed 5–7 day after the admission is more reliable in establishing the presence
and extent of local complications.
For all these reasons, the dynamic and evolving scenario that characterizes AP
need to be reassessed on a daily bases in the early phase of the disease and convenient
time points to re-evaluate the patients are usually 24 hours, 48 hours and 7 days after
admission to the hospital [7].
Different predictors of severity of AP have been developed over time to improve
clinical judgment, including single serum markers and scoring systems incorporating
clinical, radiological and laboratory findings. The features of the best predictive
criteria are: simplicity, universal applicability across international centers, ability to
stratify disease severity easily and objectively, possibility for use at presentation and
daily repetition.
Serum lipase or amylase levels are central to diagnosis of AP, but their degree on
bloodstream and their decrease have no prognostic value [5, 7].
Many authors consider an acute-phase reactant, the C-reactive protein (CRP), as
the “gold standard”for disease severity assessment. An elevated CRP concentration of
greater than 150 mg/l indicates that AP will have a complicated course with a sensitivity
of 85% in the first 72 hours after the onset of symptoms. The major drawback of CRP is
that peak levels are reached only after 48–72 hours from the onset of symptoms and
therefore is a predictor of severity that takes 72 hours to become accurate. Furthermore,
CRP is not disease-specific and can be elevated in other inflammatory conditions [2, 12].
Procalcitonin (PCT) is another acute-phase protein considered as a valuable
marker for the detection of severe pancreatitis, with a cut-off value of 0.5 ng/ml. An
increased PCT concentration in AP should be observed since the onset of the disease
and therefore it is useful in the early prediction of severe AP; nevertheless, some
authors suggest that it is more beneficial to measure the PCT level within 24–36 hours
from the occurrence of symptoms [13, 14]. A PCT value of 3.8 ng/ml or higher within
96 hours after the onset of symptoms indicated a pancreatic necrosis with a sensitivity
and specificity of 93% and 79%. Moreover, an elevated PCT predicts infected necrosis
in patients with confirmed pancreatic necrosis and has the ability to indicate a status
of bacterial infection [2, 12–14].
Several scoring systems have been developed over time: Ranson score (1974) [15],
Glasgow-Imrie score (1978) [16], Acute Physiology and Chronic Health Evaluation II
(APACHE-II) (1983) [17], APACHE combined with scoring for obesity (APACHE-O),
Simplified Acute Physiology Score (SAPS II) (1984) [18], CT Severity Index (CTSI)
(1990) [19, 20], Bedside Index for Severity in Acute Pancreatitis (BISAP) (2008) [21],
Harmless Acute Pancreatitis Score (HAPS) (2009) [22], Sequential Organ Failure
Assessment (SOFA) (2013) [23], Japanese Severity Score (JPN) (2013 revision) [24].
Ranson score is moderately accurate in stratifying patients in terms of severity but
required full 48 hours to be completed, with eleven criteria to be valuated (in addi-
tions, some data are not routinely ordered during hospitalization) [15, 25]. APACHE-
II is very complex: it evaluates the chronic health score and 12 physiologic measure-
ment, is not designed for day to day evaluation and is not specific for AP [2, 17, 25].
CTSI is based on local complications showed on CT scan findings and has the draw-
back of not reflecting the systemic inflammatory response [19, 20, 25]. BISAP is one
of the most accurate, is very simple (only five criteria), applicable in every day clinical
practice and easily applied in the early phases [2, 21, 25].
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The International Association of Pancreatology (IAP) and the American Pancreatic
Association (APA) evidence-based guidelines for the management of AP, advised the
use of SIRS to predict severe acute pancreatitis (SAP) on admission and at 48 hours.
SIRS can be diagnosed on the basis of four routine clinical measurement (Table 3) and
persistent SIRS (>48 hours) is associated with MOF and mortality (25% compared
with 8% of transient SIRS). Arguments to recommend SIRS over the other predictive
scoring systems are widespread familiarity, simplicity and the possibility for repetitive
measurements; none of the other scoring systems are considered clearly superior or
inferior to (persistent) SIRS [3].
Evidence on the predictive performance of all these scoring systems is variable and
their sensitivity and specificity for predicting severe AP range between 55% and 90%,
depending on the cut-off value and the timing of scoring. Limitations of these scoring
systems have been either the inability to obtain a complete score until at least 48 hours
into the illness (missing a potentially valuable early therapeutic window) or the
complexity of the scoring system itself [2, 12].
For all these reasons, there are no “gold standard”prognostic scores for predicting
severe AP [2]. They are still useful to prove or exclude severe disease but they cannot
replace ongoing evaluation by an experienced clinician and a good clinical judgment.
2.6 Management
2.6.1 Initial assessment
Severity score systems are complex, cumbersome and typically require 48 hours to
become accurate.
In absence of any available test to determine severity, clinicians need to be aware
of clinical finding associated with a severe course. These includes patient’s age,
comorbid health problems, body mass index, presence of SIRS, signs of hypovolemia
(such as elevated blood urea nitrogen (BUN) or elevated hematocrit) and presence of
pleural effusion (Table 4). These intrinsic patient-related risk factors for the devel-
opment of severe disease should be used for initial risk assessment and to consequen-
tially provide adequate initial management to patients presenting with AP [6].
2.6.2 Initial management
An adequate initial management should be provided to all patients presenting with
AP and patients with organ failure and/or SIRS should be admitted to an intensive care
unit whenever possible.
Initial management includes fluid resuscitation with early aggressive hydration,
pain management and adequate nutrition. Routine use of prophylactic antibiotics in
patients with severe AP and/or sterile necrosis is not recommended.
Early aggressive fluid administration, defined as 250–500 ml/hour of isotonic
crystalloid solution, is an effective intervention that is most beneficial during the first
12–24 hours and should be provided to all patients (unless cardiovascular, renal or
other related comorbidities preclude it, as the main risk is fluid overload). It amounts
to a total infusion of 2500–4000 ml within the first 24 hours and it seems to be
sufficient to reach the resuscitation goals within these first hours [2, 3, 5, 6]. Fluid
requirement should be reassessed at frequent intervals within 6 hours of admission
and for the next 24–48 hours [6]. The response to fluid resuscitation should be based
on clinical monitoring of fluid status (heart rate <120 beats/minute, mean arterial
10
Multidisciplinary Management of Pancreatitis

pressure between 65 and 85 mmHg, urinary output >0.5–1 ml/kg/hour) [3, 5] and on
biochemical targets (such as decreasing BUN and hematocrit and maintaining normal
creatinine) [5, 6].
Pain is the cardinal symptom of AP and its relief is a clinical priority. All
patients must receive analgesia and there is no evidence about any restriction in pain
medications: the best recommendations is to adhere to the most current acute pain
management guidelines, in a multimodal approach including non-steroidal
anti-inflammation drugs (NSAID), opioids, epidural analgesia and patient-controlled
analgesia (PCA) [2].
In patients with mild AP there is no need for complete resolution of pain or
normalization of pancreatic enzyme levels before oral feeding is started. A low-fat
soft or solid diet is safe and can be started soon after admission in the absence of
nausea, vomiting, severe abdominal pain and ileus [5, 6]. Need for nutritional support
may be predicted in severe AP or over day 5 from admission if the symptoms continue
to be severe or there is inability to oral feedings [5]. When artificial feeding is
required, enteral nutrition should be the preferred treatment and it is recommended
to prevent infectious complications. Nasogastric or nasoduodenal feeding are
clinically equivalent. Total parenteral nutrition should be avoided and reserved for the
cases in which the enteral route is not available, not tolerated or nutritional goals are
not met [2, 6].
Infectious complications (both pancreatic and extrapancreatic) are a major cause
of morbidity and mortality in patients with AP. Furthermore, patients with infected
pancreatic necrosis have a higher mortality rate when compared with patients with
sterile necrosis.
Although it was previously believed that preventing the development of infected
necrosis was important, different trials have shown no benefit of prophylaxis with
antibiotic therapy [5]. Now is established that the role of antibiotics is to treat
confirmed infected necrosis instead of prevent infectious complications in patients
with sterile necrosis. Antibiotics known to penetrate pancreatic necrosis are
carbapenems (such as imipenem), quinolones, fluoroquinolones, clindamycin,
piperacillin and metronidazole and their administration may be useful in delaying or
avoiding intervention.
Consequently, routine use of prophylactic antibiotics in patients with any type of
AP is not recommended unless infection is suspected or confirmed. Furthermore,
routine use of antifungal agents, along with antibiotics, is not recommended.
Nevertheless, antibiotics should be given for extrapancreatic infections such as
cholangitis, catheter-acquired infections, bacteremia, urinary tract infections and
pneumonia [2, 3, 6, 26].
There is no current available pharmacologic therapy to mitigate AP and current
treatment is largely supportive. Considering that pancreatic injury is mediated by
autodigestive enzymes, anti-secretory agents such as glucagon and somatostatin have
been tested as potential therapies with limited results. Use of protease inhibitors
agents (such as gabexate mesilate) have been studied with the aim of blocking
intrapancreatic activation of digestive enzymes but several trials showed conflicting
results on clinical benefit. Also administration of indomethacin and steroid therapy
have been assessed in clinical trials but their role remains to be determined [27]. A
recent Cochrane review about pharmacological intervention for AP stated that there
was no evidence of difference in short-term mortality between the groups in any of
the comparisons. Despite this evidence, the authors underlined that interventions
with at least two clinical benefits were: octreotide (somatostatin analog), which was
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associated with fewer serious adverse events and a lower proportion of people with
organ failure; and gabexate mesilate, which was associated with fewer adverse events
and a lower proportion of people requiring an additional invasive intervention com-
pared to inactive intervention [28].
2.6.3 Patient-tailored management (of late phase of acute pancreatitis)
Whether AP progresses to the late phase of the disease, patients may require a
variety of interventions that go beyond the initial management. Patient-tailored
management may include ERCP, endoscopic ultrasonography (EUS), endoscopic
and/or radiological drainage or surgical intervention for treatment of local
complications and referral for cholecystectomy to prevent recurrent attacks and
potential biliary sepsis [6].
ERCP is indicated in patients with biliary pancreatitis with common bile duct
obstruction and/or cholangitis [3, 5].
Asymptomatic acute peripancreatic fluid collections and asymptomatic
pseudocysts do not require therapy. The development of infection in the necrotic
collection is the main indicator for therapy and treatment should be delayed prefera-
bly for more than 4 weeks [3, 5, 6]. Clinical and imaging signs are accurate and routine
percutaneous fine needle aspiration and culture is not required [3, 5].
The optimal intervention strategy is always a step-up approach: initial broad-
spectrum antibiotics administration, subsequent percutaneous radiological interven-
tions followed, if needed, by endoscopic transmural drainage or endoscopic debride-
ment and eventually by surgical approach [3, 5, 6]. Minimally invasive operative
methods of necrosectomy and minimally invasive surgical approaches are always
preferred to open necrosectomy [6]. The optimal strategy must be individualized for
every patient and should be discussed by a multidisciplinary group of experts.
To prevent recurrence of AP, cholecystectomy should be performed before
discharge in patient with mild gallstone AP. In this subgroup of patients, cholecystec-
tomy performed 25–30 days after discharge has a higher rate of complications as
compared with cholecystectomy performed during the initial hospitalization and a
delay of cholecystectomy for more than a few weeks is associated with a high risk of
relapse (up to 30%) of AP. Instead, in patient with necrotizing biliary AP, cholecys-
tectomy should be delayed until active inflammation and fluid collections resolve or
stabilize [3, 6]. In AP without biliary etiology, other protective measures to prevent
relapses are mandatory such as smoking cessation, abstinence of alcohol intake,
withdraw of implicated medications and tight control of hyperlipidemia.
2.7 Long-term consequences
Approximately 20–30% of patients develop pancreatic exocrine and endocrine
dysfunction after AP and 30–50% of those patients will evolve in CP. Risk factors
for these long-term consequences are the etiology, the severity and the degree of
pancreatic necrosis of the initial attack of AP [5].
3. Chronic pancreatitis
CP is a clinical entity resulting from progressive inflammation and irreversible
fibrosis of the pancreas due to cumulative damage to the pancreas over time.
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It is a disease with various manifestations that can severely affect quality
of life, while its long-term complications such as exocrine pancreatic
insufficiency (EPI), diabetes mellitus, and risk of pancreatic cancer can become
life-threatening. Diagnosis of CP can be challenging because, despite recent
advances in imaging technology, radiologic findings are not apparent until late
stages of the disease.
Only dynamic observation of patients with controlled follow-up allows us to
classify pancreatitis and better define the disease by assigning definitive labels
supported by biochemical and radiological sources that are well characterized by
the various classification systems available. The clinician should recognize
pancreatitis at an early stage but avoid making a "definitive" classification
immediately.
3.1 Definition
In the last decade, advances in clinical and translational sciences have redefined
our understanding of CP, thus changing the definition, the diagnosis and the
management of the disease.
The traditional clinopathologic-based definition described CP as a “a continuing
inflammatory disease of the pancreas, characterized by irreversible morphological change,
and typically causing pain and/or permanent loss of function”. Such a diagnostic
assessment resulted in a delay between symptom onset and diagnosis, failing to
identify the underlying etiology, without predicting the clinical course or guide
preventative treatments, being limited to symptomatic or supportive care and
replacement of lost gland function [29].
In 2016, a new Mechanistic Definition of CP was published and adopted
worldwide. This definition affirmed the characteristics of end-stage disease (Table 5)
and addressed the disease mechanism as “a pathologic fibroinflammatory syndrome of
the pancreas in individuals with genetic, environmental, and/or other risk factors who
develop persistent pathologic responses to parenchymal injury or stress”. The new paradigm
is to focus on diagnosing the mechanistic disorder underlying the pathogenic process
early in the disease course and managing the syndrome to change the natural course
and to minimize adverse disease effects. Within this framework it is important to
recognize the difference between pancreatic dysfunction, pancreatitis-related
disorders, and pancreatic disease [30, 31].
Pancreatic atrophy
Fibrosis
Pain syndromes
Duct distortion and strictures
Calcifications
Pancreatic exocrine dysfunction
Pancreatic endocrine dysfunction
Dysplasia
Table 5.
Characteristics of end-stage chronic pancreatitis.
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3.2 Epidemiology
The epidemiology of CP is poor compared with other illnesses. There are few
studies that look at the population distribution of CP, and it is important to note that
these data are not available from large parts of the world. This is likely related to the
difficulties in conducting such studies due to the low prevalence of the disease, the
establishment of an accurate diagnosis, and the focus of previous studies on describing
the clinical profile and natural history of the disease. Over the past two decades, there
has been an interest in documenting the distribution of pancreatic disease in the
population. Incidence of CP is currently estimated between 4.4 and 14 per 100,000
people, with a prevalence of 36.9–52.4 per 100,000 persons, and a male predominance
by a factor of 1.5–4.6 [32, 33]
In 2016, a systematic review by Xiao et al. [34], that included only high-quality
studies conducted on general populations, demonstrated a global pooled incidence of
CP of 10 cases per 100,000 general population per year.
A recent 25-year population-based Danish study by Olesen et al. evaluated the
incidence and the prevalence of CP between 1994 and 2018. The mean incidence rate
was 12.6 per 100,000 person years for the total population; 8.6 vs. 16.7 per 100,000
person years in women and men, respectively. The Authors demonstrated that over a
25-year observation period the prevalence of CP was increasing in the Danish popula-
tion (from 126.6 in 1996 to 153.9 in 2016), while the incidence remained stable; the
mean age at CP diagnosis increased by almost a decade (52.1–60.0 years) [35].
3.3 Etiology
3.3.1 Risk factors
The most common risk factor for CP is alcohol abuse [36, 37]. In 1995, a study from
Levy et al. demonstrated a logarithmic relationship between the relative risk of devel-
oping CP and the quantity of consumed alcohol, although the type of alcohol con-
sumed is irrelevant [38]. There is not a threshold value, but a minimum of 80 g alcohol
per day for a period of at least 6 years is considered to be a risk factor for the
development of CP. An average of 18 11 years elapses between the start of excessive
alcohol consumption and the development of pancreatitis [39, 40].
Smoking is an independent risk factor. It accelerates the progression of CP, even
with alcohol abstinence. It leads to pancreatic pain exacerbations and to calcifications.
All patients should be advised to quit smoking [41–43]. In 2009, Yadav et al.
published the results of the North American Pancreatitis Study 2 that prospectively
enrolled 540 patients with CP. A dose-dependent association between smoking and
CP was demonstrated; and patients without an history of alcohol but with 21–35 pack
years have an increased risk of CP with a 3.26 odds ratio [44].
Primary hyperparathyroidism (pHPT) can lead to CP, with or without calcifica-
tions. 1% of patients with CP suffers from pHPT, conversely 12% of patients with
pHPT also have pancreatitis, thus leading to a 28-fold increased risk of developing
pancreatitis in this cohort of patients [45, 46].
Whether the anatomic anomaly pancreas divisum (the most common congenital
malformation of the pancreas) is a risk factor for the development of CP is still a
matter of debate. The S3-consensus conference on CP have reached an agreement on
the following statement: “the presence of pancreas divisum without any further risk
factors tend not to lead to chronic pancreatitis”[47].
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Several genes have been associated with the diagnosis of CP. Genetic testing aim is
to provide early information about the etiology of disease-related disorders that are
contributing to the pathogenic process, to assist in decision making, and to help
prevent the development of irreversible CP [48].
The most important genetic risk factors are variants in cationic trypsinogen
(PRSS1), SPINK1 and carboxypeptidase A1 (CPA1). Further genetic susceptibility
genes are CFTR, chymotrypsinogen C (CTRC) and carboxyesterlipase (CEL) [49–54].
Trypsinogen is a key molecule in the pathogenesis of pancreatitis, up to 66% of
patients with hereditary pancreatitis have a mutation of the PRSS1 gene. Such muta-
tions lead to CP with a penetrance of up to 80% and an autosomal dominant inheri-
tance pattern [55–58].
Mutations of the SPINK1 gene predispose to idiopathic CP, occurring in as many as
30% of patients, however only in 1–2% of the general population. The N34S mutation
in the gene encoding SPINK1 bears an odds ratio of 11.0 in developing CP.
Cystic fibrosis is an autosomal recessive disease with an estimated incidence of
1:2500. The first description of an association between CFTR variants and CP was
published in 1998 [59]. The association between gene mutations and CP has an odds
ratio of around 3–5 [55, 60]. CP patients carrying CFTR variants harbor at least one
mild variant allele giving them residual CFTR function. Pancreas involvement may
vary from a complete loss of exocrine and endocrine function to almost normal
function. Molecular changes in the CFTR gene are associated to up to 30% of patients
with idiopathic pancreatitis.
Patients with a CTRC mutation have an increased risk of developing CP. The first
report dates back to 2008 [52]. Such mutations occur in 3.3% of patients with idio-
pathic pancreatitis.
In addition to those etiologic factors, autoimmune pancreatitis has been recently
characterized. First reported in 1961 by Sarles [61], Yoshida first postulated this
clinical entity in 1995 [62]. This is a systemic fibroinflammatory disease in which the
pancreas is one of the affected organs. Men are affected twice than women. Clinical
symptoms include abdominal pain, jaundice and recurrent episodes of pancreatitis.
Radiological findings include “sausage-shaped pancreas”and diffuse or segmental
Wirsung stenosis, often without prestenotic dilation. Serum levels of immunoglobulin
(Ig) G and IgG4 have been found increased in the Asian patients, but only in 50% of
European ones. Diagnosis is reached according to the HiSORT criteria (Table 6) [63]
which include histology, serology, other organ involvement and response to steroid
therapy [64–66].
3.3.2 Classification models
Distinct classification systems have been developed but, so far, no globally
accepted classification system has been established. Classification systems currently in
use are: Manchester classification; ABC classification; M-ANNHEIM; TIGAR-O; and
Rosemont classification. Only the Toxic/metabolic, Idiopathic, Genetic, Autoimmune,
Recurrent acute pancreatitis, and Obstructive (TIGAR-O) and the pancreatitis with
Multiple risk factors-Alcohol consumption, Nicotine consumption, Nutritional fac-
tors, Hereditary factors, Efferent duct factors, Immunological factors, Miscellaneous
and rare metabolic factors (M-ANNHEIM) classification systems take the etiology of
CP into account.
The M-ANNHEIM system is a multirisk factor classification system. It adds infor-
mation on disease activity and stage, evaluating the role of various risk factors on the
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course of CP [67]. Relying upon traditional clinicopathologic criteria, and resulting in
a score between 0–25, it provides diagnostic criteria for etiology, clinical and diagnos-
tic stage (Table 7).
The TIGAR-O classification system comprises six etiologic groups: toxic-
metabolic, idiopathic, genetic, autoimmune, recurrent AP, and obstructive groups. It
Category Criteria
Histology One of the following:
1. Periductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform
fibrosis (LPSP)
2. Lymphoplasmacytic infiltrate with storiform fibrosis showing abundant IgG4
positive cells (≥10 cells/HPF)
Imaging CT/MRI Typical: diffusely enlarged gland with diffuse rim enhancement, diffusely irregular
attenuated pancreatic duct
Other: focal pancreatic mass or enlargement; focal pancreatic duct stricture;
pancreatic duct stricture, pancreatic atrophy; pancreatic calcification or
pancreatitis
Serology Elevated serum IgG4 level (>135 mg/dl)
Other organ
involvement
Hilar/intrahepatic biliary strictures, persistent distal biliary strictures, parotid or
lacrimal gland involvement, mediastinal lymphadenopathy or retroperitoneal
fibrosis
Response to steroid
therapy
Resolution/marked improvement of pancreatic/extrapancreatic manifestation with
steroid therapy
LPSP, lymphoplasmacytic sclerosing pancreatitis; CT, computed tomography; MRI, magnetic resonance imaging; IgG4,
immunoglobulin G4; HPF, high powered field.
Table 6.
The Mayo clinic HiSORT criteria for the diagnosis of AIP.
Clinical feature Points
Patient report of pain
No pain without therapy
Recurrent acute pancreatitis (RAP)
No pain with therapy
Intermittent pain
Continuous pain
0
1
2
3
4
Pain control
No medication
Use of nonopioid drugs or use of mild opioids (WHO step 1 or 2)
Use of potent opioids (WHO step 3) or endoscopic intervention
0
1
2
Surgical intervention
Pancreatic surgical intervention for any reason 4
Exocrine insufficiency
Absence of exocrine insufficiency
Presence of mild, moderate, or unproven exocrine insufficiency not requiring enzyme
supplementation (including patient reports of intermittent diarrhea)
Presence of proven exocrine insufficiency (according to exocrine function tests) or presence of
marked exocrine insufficiency defined as steatorrhea (>7 g fat/24 hour), normalized or markedly
reduced by enzyme supplementation
0
1
2
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has been validated in multiple international studies, and in 2019 it was revised to
include new insights from the past 20 years. It is designed as a hierarchical checklist to
quickly document and track specific factors that may contribute to progressive pan-
creatic disease (Table 8) [68].
Clinical feature Points
Endocrine insufficiency
Absence of diabetes mellitus
Presence of diabetes mellitus
0
4
Morphologic status on pancreatic imaging (according to Cambridge classification)
Normal
Equivocal
Mild
Moderate
Marked
0
1
2
3
4
Severe organ complications
Absence of complications
Presence of possibly reversible complications
Presence of irreversible complications
0
2
4
Table 7.
The M-ANNHEIM scoring system for the grading of clinical features of chronic pancreatitis.
Toxic-metabolic
Alcohol-related (susceptibility and/or progression)
3–4 drinks/day
5 or more drinks/day
Smoking (if yes, record pack-years)
Non-smoker (<100 cigarettes in lifetime)
Past smoker
Current smoker
Other, NOS
Hypercalcemia (total calcium levels >12.0 mg/dl or 3 mmol/l)
Hypertriglyceridemia
Hypertriglyceridemic risk (fasting >300 mg/dl; non-fasting >500 mg/dl)
Hypertriglyceridemic acute pancreatitis, history of (>500 mg/dl in first 72 hours)
Medications (name)
Toxins, other
Chronic kidney disease (CKD)—(CKD Stage 5: end-stage renal disease, ESRD)
Other, NOS
Metabolic, other
Diabetes Mellitus (with the date of diagnosis if available)
Other, NOS
Idiopathic
Early onset (<35 years of age)
Late onset (>35 years of age)
Genetic
Suspected; no or limited genotyping available
Autosomal dominant (Mendelian inheritance—single gene syndrome)
PRSS1mutations (hereditary pancreatitis)
Autosomal recessive (Mendelian inheritance—single gene syndrome)
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3.4 Diagnosis
The diagnosis is made using a combination of modalities, including exposure
risk, underlying predisposition, cross-sectional imaging, and direct and/or
indirect pancreatic function tests. The first step to diagnose CP is to perform a
detailed history to attempt to elucidate underlying risk factors. Key elements that
must be investigated are hypertriglyceridemia, autoimmune diseases, diabetes
mellitus, and prior AP episodes [68, 69]. The most common clinical manifestations
of CP are abdominal pain and steatorrhea depending on the degree of pancreatic
dysfunction.
Pain is the dominant symptom of CP. It is usually recurrent and can be either episodic
(type A) or persistent (type B). Up to 80–90% of patients complain of pain during the
course of the disease. Painless pancreatitis occurs in 10–20%ofpatients[40,70–73].
The occurrence, the etiology and the sequalae of prior episodes of AP should be
determined. Family history is informative especially in patients with early-onset dis-
ease to determine if hereditary or genetic causes are responsible. The use of voluptu-
ous substances such as tobacco and alcohol should be investigated as these are the
main driving factors, for example using the AUDIT questionnaire.
CFTR, 2 severe variants in trans (cystic fibrosis)
CFTR, <2 severe variants in trans (CFTR-RD)
SPINK1,2 pathogenic variants in trans (SPINK1-associated familial pancreatitis)
Complex genetics (non-Mendelian, complex genotypes environment)
Modifier genes (list pathogenic genetic variants)
PRSS1-PRSS1 locus
CLDN2 locus
Others
Hypertriglyceridemia (list pathogenic genetic variants)
Other, NOS
AIP/steroid responsive pancreatitis
AIP Type 1—IgG4-related disease
AIP Type 2
RAP and SAP
Acute pancreatitis (single episode, including date of event if available)
AP etiology—extra-pancreatic (excluding alcoholic, HTG, hypercalcemia, genetic)
Biliary pancreatitis
Post-ERCP
Traumatic
Undetermined or NOS
RAP (number of episodes, frequency, and dates of events if available)
Obstructive
Pancreas divisum
Ampullary stenosis
Main duct pancreatic stones
Widespread pancreatic calcifications
Main pancreatic duct strictures
Localized mass causing duct obstruction
Table 8.
The TIGAR-O Version 2.0 risk/etiology classification, short form.
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Laboratory values should be tested: triglyceride-levels; Ca
++
-levels for ruling out
elevated pHPT; carbohydrate deficient transferrin (CDT)/phosphatidylethanol levels.
The sensitivity of pancreatic function testing to diagnose CP is low. To date, there
are no randomized clinical trials, systematic reviews or meta-analysis which specifi-
cally address the use of pancreatic function tests to diagnose CP. As such, pancreatic
function tests should only be used as ancillary test in making the diagnosis [74–76].
Pancreas has a large reserve and only a significant loss of function (usually >90%)
results in the clinically apparent symptoms of vitamin deficiency, steatorrhea and
azotorrhea [77]. EPI is the result of the imbalance within nutritional intake, pancreatic
digestive enzyme delivery to the small intestine, intestinal adaptation to disease and
nutritional needs. CP is an evolving process, and exocrine function is progressively
impaired from a reduced functional capacity to exocrine failure in the late phase. To
detect mild or moderate exocrine pancreatic impairment, invasive tests employing a
hormonal secretagogue (CCK or secretin stimulation tests) maximally stimulating
pancreatic secretion can be useful. Such tests are sensitive but poorly specific, they are
not diagnostic [78, 79]. Conversely, nonhormonal tests of pancreatic function can
detect severe exocrine insufficiency only. Indeed, fecal elastase and fecal chymotryp-
sin can be used in the follow-up of selected patients for identifying a progressive
impairment in pancreatic function by which the chronicity of the inflammatory
process can be confirmed [80–82].
It is critical to demonstrate typical morphological changes in the pancreas, as
imaging is a surrogate for histology. Diagnosis is established via high quality imaging
modalities, which allow identification of the following signs: increased density of the
parenchyma, atrophy of the gland, calcification, pseudocysts and irregularities of the
main pancreatic duct and its side branches. Diagnosis should be based on imaging
performed in symptomatic patients presenting with indicators suggestive of
pancreatic disease [29].
MR with MR cholangio-pancreatography and dynamic MRCP following secretin
administration and endoscopic ultrasound are the imaging techniques of choice to
diagnose early CP and to identify pancreatic malformations in patients with CP. In
early CP dynamic MRCP during secretin administration is useful in identifying initial
morphological changes of the pancreatic duct system and specifically of the side
branches [83].
CT is the technique of choice in diagnosing and localizing pancreatic stones inside
the lumen of the main pancreatic duct or side branches, and in patients with CP and
flare of the disease [84].
Transabdominal ultrasonography (US) is not able to identify early CP, but can
confirm the diagnosis of advanced CP, since it identifies the thinning of the pancreatic
parenchyma, the irregularity of the pancreatic margins, dilatation of the main pan-
creatic duct and of the side branches, and endoductal calcified stones [85].
When the diagnosis cannot be made by radiological or EUS morphologic criteria
and clinical and functional evidence of CP is strong, histological examination via EUS-
guided fine-needle biopsy is the gold-standard to diagnose CP [36].
Testing for germline mutations is not diagnostic of CP, but it rather identifies a
population at risk improving the accuracy of biomarkers and identifies the mechanism
underlying the pathogenic process. Therapies can target the mechanism, and knowing
the mechanism allow to select the most appropriate drug. Patients should be referred
to a genetic counselor for evaluation. At minimum patients with idiopathic CP should
be evaluated for PRSS1, SPINK1, CFTR, and CTRC gene mutation analysis.
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3.5 Management
3.5.1 Pain
Abdominal pain is the most common complication and prevailing symptom of CP.
It can manifest through a spectrum of intensity, form mild and intermittent to severe
unrelenting. Pain is experienced by 75% of patients at the time of presentation and up
to 97% during the clinical course. The pathophysiology is multifactorial and results
from pancreatic and extra-pancreatic causes. Pancreas-related causes include: paren-
chymal and nerve sheaths inflammatory infiltrates, augmented pressure by obstruc-
tion flow of pancreatic juice and increased pancreatic capsule tension due to raised
pancreatic parenchymal pressure. Extra-pancreatic causes include gastric or duodenal
ulcers and meteorism caused by bacterial overgrowth and maldigestion [47, 86].
The NAPS-2 Study categorized five distinct pain patterns according to severity and
pain control (Table 9) [87].
The only pain score explicitly validated for assessing pain in patients with CP has
been published in 1995 by Bloechle et al. [88]: the visual analogue scale. Pain manage-
ment should follow the WHO three-step analgesic ladder. However, WHO pain man-
agement has not been consistently used in the available literature, thus the question
about its effectiveness cannot be answered.
The natural course of pain in CP is characterized by a variable percentage of
patients (4780%) achieving spontaneous pain relief from 10 to 15 years from onset.
However, a part of patients will suffer of pain indefinitely. Waiting for a spontaneous
pain relief has been defined not reliable by the American Gastroenterological Associ-
ation (AGA) [36].
Endoscopic treatment (ET) is recommended as a first-choice therapy in patients
with an obstructive type of pancreatic pain and in patients with a pancreatic duct
dilatation. This could, also, be useful as a bridge to surgery. The aim of ET is decom-
pression of an obstructed main pancreatic duct, it decreases the numbers of hospital-
izations for pancreatic pain and reduces analgesics intake. Extracorporeal shock wave
lithotripsy (ESWL) therapy in painful CP is indicated if the stone size is >5 mm, the
stone is located in the head or pancreatic body, and there are no strictures of the main
pancreatic duct. It should be combined with ET in cases of large stones with pancre-
atic duct stricture [36, 47].
Surgical options for pain are classified into three categories: decompression
(focusing on ductal hypertension), resection (focusing on inflammatory masses in the
pancreatic head), and mixed techniques. Decompression is recommended in patients
with a main pancreatic duct >7–8 mm and no inflammatory mass. Pain relief is
achieved in 66–91% of patients, however, the long-term results show up to 50%
Pain pattern Description
A I have episodes of mild to moderate pain, usually controlled by medicines
B I have constant mild to moderate pain, usually controlled by medicines
C I am usually free of abdominal pain, but I have episodes of severe pain
D I have constant mild pain that is controlled, plus episodes of severe pain
E I have constant severe pain that does not change
Table 9.
Description of pain patterns used in the NAPS2 study.
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recurrences. Resection in patients with an inflammatory mass or an obstructive CP of
the body or tail. Pancreaticoduodenectomy is effective in 75% of patients but with a
significant morbidity (20%), as such most authors favor the more conservative mixed
techniques. Mixed techniques achieve a short-term pain relief in up to 70–100% of
patients and a long-term pain relief in 82–100%. Mixed techniques are based on the
resection of the inflammatory mass in the pancreatic head and drainage of the
obstructed main pancreatic duct (body and tail). The most widely used techniques are
the duodenal preservation (Berger) or the Frey method which consists in a longitudi-
nal pancreaticojejunostomy and in the coring out of the pancreatic head [47, 89].
A pain management strategy must be well structured and conducted with a logical
approach to minimize long term complication and sequelae. Is recommended to early
involve a pain management specialist during the clinical course, as delays lead to
poorer health and pain control [90].
3.5.2 Lifestyle
Complete cessation of alcohol and tobacco use is of utmost importance. Patients
must be aware that ongoing use will sustain the cycle of pain and lead to further
progression of the disease. Cognitive and mindfulness-based therapies should be
offered to all patients, especially for those who need assistance with abuse disorder.
3.5.3 Enzyme replacement
A weight loss of more than 10% of the body weight, steatorrhea with a fecal fat
excretion of more than 15 g/die (or a pathological pancreatic function test) in combi-
nation with clinical signs of malabsorption (dyspeptic symptoms with severe
meteorism or diarrhea) are a clinical indication for pancreatic enzyme replacement
therapy. Abdominal complaints (diarrhea/steatorrhea, abdominal distension/
meteorism and pain) may be due to intestinal motility disorders caused by
maldigestion and malabsorption [91]. Enzyme supplements are administered by
gastric-acid-protected encapsulated microsphere and contain pancreatin, with the
main components being lipase, amylase, trypsin and chymotrypsin. A successful
treatment is measured by improvement of the disease symptoms. Therapy with
pancreatin purely as a trial for 4–6 weeks may also be beneficial if symptoms are
unclear [91–94].
An untreated severe EPI results in a severe malabsorption syndrome that manifests
in the form of steatorrhea, deficiency of fat-soluble vitamins, weight loss and finally
cachexia [71, 95, 96]. The success of enzyme replacement therapy should be moni-
tored using clinical parameters (weight gain, long-term normalization of the vitamin
status, cessation of abdominal symptoms).
3.6 Surveillance
Incidence of pancreatic cancer is increased in long-lasting CP. Several studies have
addressed this topic. The paper by Bansal and Sonnenberg in 1995 found a clear
relationship between CP and pancreatic cancer (OR 2.23; 95% CI 1.43–3.49) [97].
Should patients with CP be screened for pancreatic cancer? The United States
Preventive Task force has stated that screening the general population for pancreatic
cancer by current modalities is not recommended.
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4. Surgical treatment of complications
Local complications such as pancreatic and/or peripancreatic fluid collections can
occur after an episode of AP or after recrudescence of CP or a blunt, penetrating,
iatrogenic pancreatic trauma. Peripancreatic fluid collections, with or without a
necrotic component, are early manifestations of the pancreatic inflammatory process.
In asymptomatic patients, clinical observation and periodic imaging follow up repre-
sent the most successful management. Prognosis and management are greatly affected
by the recognition between sterile and infected pancreatic necrosis. In symptomatic
patients, with rapidly enlarging pseudocysts or systemic manifestations of organ failure
sustained by an infectious process, an interventional treatment is indicated. In this case
endoscopic drainage approach is the first choice, especially when fluid collection is close
to gastroduodenal lumen. A combination of techniques is possible in patients with large
collections, extended in pelvis and paracolic gutters, or multiple collections [98].
Endoscopic management of pseudocysts and walled-off pancreatic necrosis
(WOPN) has been described in a dedicated chapter of this Book.
Endoscopic drainage techniques consist in [99]: transmural or transpapillary drainage.
Percutaneous drainage remains an important treatment modality for patients with
symptomatic collections. It may be used both as primary therapy and as an adjunct to
other techniques. According to the last International [3], American [100] and
Japanese [24] guidelines, percutaneous catheter (or endoscopic transmural drainage)
should be the first step in the treatment of patients with suspected or confirmed
(walled-off) infected necrotizing pancreatitis. This is applied to decompress retroper-
itoneal fluid collections, to provide a rapid and effective means for source control in
patients with infected pancreatic necrosis. The positioning can be performed via the
transperitoneal or retroperitoneal approaches. Retroperitoneal route is generally pre-
ferred because it avoids peritoneal contamination, enteric fistulas and facilitates a
possible step-up approach.
The surgical odyssey in managing necrotizing pancreatitis is a notable example of
how evidence-based knowledge leads to improvement in patient care. In the begin-
ning of the 20th century surgeons such as Mayo Robson, Mickulicz, and Moynihan, in
the context of the progression of anesthesia, were induced to deploy laparotomy in an
effort to treat complications of severe AP [101]. Over the next decades surgical
intervention became the therapy of choice despite a mortality rate greater than 50%.
Extensive pancreatic resection became the treatment of choice in the 1960s and 1970s.
Innovations and increased accuracy in radiological techniques led to new approaches
for management. Since 1990s several studies proved that nonoperative management
of patients with sterile pancreatic necrosis was superior to surgical intervention, and
that delayed intervention provided improved surgical mortality rates. The treatment
of infected necrosis shifted to a more conservative approach also thanks to a compre-
hensive knowledge of the physio-pathological process of the systemic inflammatory
response and the adoption of novel antibiotics in curbing systemic toxicity and
protecting against organ failure.
According to the last guidelines of the Working Group of the IAP/APA published
in 2013 [3] and of the AGA published in 2020 [100], a symptomatic sterile pancreatic
necrosis is an indication for intervention (either radiological, endoscopical or surgi-
cal). In case of infected pancreatic necrosis invasive procedures (e.g. percutaneous
catheter drainage, endoscopic transluminal drainage/necrosectomy, minimally inva-
sive or open necrosectomy) should be delayed, where possible, until at least 4 weeks
after initial presentation to permit the collection to become “walled-off”.
22
Multidisciplinary Management of Pancreatitis

Percutaneous drainage, alone or in combination with other minimally invasive
approaches, can be an effective means for source control in patients with infected
pancreatic necrosis. A significant number of patients (23–47%) will resolve their
necrosis with percutaneous drainage alone. In those with persistent disease, a step up
to operative intervention may be undertaken. The tract of the drain is utilized to
access the retroperitoneal space for an intracavitary videoscopic necrosectomy by
which drains are left in the cavity for lavage and fistula control [102–104].
Open debridement with external drainage still plays an important, albeit limited,
role. After access to retroperitoneum, fluid is evacuated and necrotic dissection and
debridement is made. In biliary pancreatitis, cholecystectomy should be practiced but
it is associated with increased incidence of postoperative bile leak or biliary injury.
Colon resection and colostomy have to be considered if mesocolon is involved in
peripancreatic necrosis. A feeding enteral tube and at least two-four drainage tubes
should be placed [105].
Each approach has distinct peculiarities with pros and cons that must be weighted
in each case planning: pattern of disease, physiology of the patient, expertise of the
multidisciplinary team, and the resources of the center [100].
Conflict of interest
The authors declare no conflict of interest.
Author details
Tommaso Stecca*, Cristina Nistri, Bruno Pauletti, Adriana Di Giacomo, Flavio Colaut,
Mariangela Ruperto, Ezio Caratozzolo, Luca Bonariol and Marco Massani
Surgery Department, First Surgical Unit, Treviso Regional Hospital, Azienda ULSS2
Marca Trevigiana, Italy
*Address all correspondence to: tommaso.stecca@aulss2.veneto.it
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
23
Management of Acute and Chronic Pancreatitis
DOI: http://dx.doi.org/10.5772/intechopen.109115

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