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References 409
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Other Rare Causes
Pancreatic divisum
Pancreatic divisum (PD) is the most common congenital malformation of the pancreas. It involves a congenital disconnection between the main pancreatic duct
and the major papilla. PD is classified as an obstructive
cause of CP [3]. Although increased pressure in the
dorsal pancreatic duct and minor papilla have been
reported in PD, the majority of patients with PD are
asymptomatic. Therefore, there is considerable debate
as to whether it is causally associated with pancreatitis
or abdominal pain [39]. Some reports indicate that the
existence of a genetic cofactor plus PD leads to the
development of CP. Garg et al. reported SPINK1
mutations in 41.7% of patients with PD and ICP, which
was significantly higher than 2% in healthy controls.
They also reported that 41.7% of patients carried CFTR
gene polymorphisms [40]. Bertin et al. reported the
frequency of PD in patients with RAP or CP is sign
ificantly associated with CFTR mutations or polymorphisms [41].
Autoimmune Pancreatitis
Autoimmune pancreatitis (AIP) is a distinct form of pancreatitis. Therapeutically, AIP has a dramatic response to
steroids. AIP is classified into type 1, which is a type of
IgG4- related systemic disease, and type 2, which frequently accompanies inflammatory bowel disease [42].
Currently, the long- term prognosis of AIP is not well
understood. However, an international study group
reported pancreatic duct stones in 7% of patients with
type 1 AIP, but not in patients with type 2 AIP [43].
According to a report from Japan, among 52 patients
with type 1 AIP who had no pancreatic stones at diagnosis, 20 (38.5%) of them developed de novo pancreatic
-
stones after 3 or more years of follow- up [44]. The
relationship between AIP and classic CP will become
clearer in the future.
Hyperparathyroidism
The causal relationship between primary hyperparathyroidism (hypercalcemia) and RAP or CP is debatable. A
systematic review demonstrated AP or CP occurred in
1.5% to 15.3% of patients with primary hyperparathyroidism, but the included studies had confounding factors, biases, and a lack of appropriate controls. In addition,
the authors suggested the pancreatitis in this setting is
likely the result of additional genetic and environmental
factors [45]. Aslam etal. reported that hyperparathyroidism
accounted for 1.94% of RAP or CP cases. In patients with
CP associated with hyperparathyroidism, severe pain was
a predominant symptom. After parathyroidectomy and
subsequent decreases in serumcalcium levels, there was
a reduction in their symptoms[46].
Hyperlipidemia
Hypertriglyceridemia is a well- established but underestimated cause of AP and RAP. However, whether hypertriglyceridemia can cause CP has not been well studied
[47]. Vipperla etal. performed a retrospective study that
reviewed the medical records of 121 patients with serum
triglyceride levels of ≥500 mg/dL who experienced 225
attacks of AP between 2001 to 2013 at their institute in
the United States. They found 20 (16.5%) of 121 patients
were diagnosed with CP (9with preexisting CP, 11with
new- onset CP during follow- up) [48]. Their relatively
small single- center retrospective study needs to be validated in future prospective or large multicenter studies
with simultaneous analysis of confounding factors such
as alcohol intake and smoking.
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40 Garg PK, Khajuria R, Kabra M, Shastri SS. Association of
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412
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50
Early Chronic Pancreatitis
Kazuhiro Kikuta and Atsushi Masamune
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Miyagi, Japan
Concept/Definition
The concept of chronic pancreatitis was established by
Comfort etal. in 1946[1,2]. They proposed that chronic
pancreatitis was characterized by the progressive
destruction of the pancreas. In the subsequently defined
classification systems such as the Marseille classification [3], Cambridge classification [4], and MarseilleRoma classification [5], irreversible pancreatic changes
associated with chronic pancreatitis were considered to
cause permanent loss of pancreatic exocrine and endocrine functions. The conventional diagnostic criteria for
chronic pancreatitis only enable us to detect the disease
at the end stage, which ought to be irreversible. To
improve the prognosis of chronic pancreatitis patients, it
is indispensable to diagnose chronic pancreatitis in the
early stage and prevent its progression through early
interventions.
In 1996, the term “early- stage alcoholic chronic pancreatitis” was used to define a clinical stage linking alcoholic acute pancreatitis and alcoholic chronic pancreatitis
by Ammann etal.[6]. They emphasized that the diagnosis “earlyfirmed by criteria independent from histology, i.e., the
long- term follow- up that eventually revealed the typical
clinical features of chronic pancreatitis. It could only be
diagnosed in a retrospective manner.
The category of early chronic pancreatitis was the first
to be introduced into the diagnostic criteria proposed by
the Japan Pancreas Society in 2009 [7]. Early chronic
pancreatitis corresponds to the stage at which chronic
pancreatitis has already started with clinical symptoms
and signs of pancreatic injury; however, characteristic
morphological changes of the pancreas have still
not been detected clearly on conventional imaging
stage alcoholic chronic pancreatitis” was con-
modalities. Theoretically early chronic pancreatitis is
considered to be a reversible pathological condition[8].
A new mechanistic definition of chronic pancreatitis
was proposed by Whitcomb etal. in 2016[9]. A conceptual model of chronic pancreatitis was derived, recognizing that subjects may exist in: (A) “at- risk” state of chronic
pancreatitis, or in four active states; (B) acute pancreatitis recurrent acute pancreatitis; (C) early chronic pancreatitis; (D) established chronic pancreatitis; and (E) end- stage
chronic pancreatitis (Fig.50.1). Early chronic pancreatitis may overlap conceptually with “minimal change
chronic pancreatitis” or “pre- chronic pancreatitis,”
depending on eventual diagnostic criteria and distinctions from other states. The transition from “B” to “C”
involves detection of biomarkers of chronic pancreatitis
pathogenesis or pathology, but does not reach a state of
“D.” Biomarkers may be biochemical, structural or functional. The transition from “C” to “D” involves progression of disease to a persistent state of pathology or
dysfunction. This new definition of chronic pancreatitis
may allow for a rational approach to early diagnosis.
However, there still has not been international consensus on the definition of early chronic pancreatitis. In
2018, international consensus statements on early
chronic pancreatitis were developed by a working group
for the international consensus guidelines for chronic
pancreatitis in collaboration with the International
Association of Pancreatology, American Pancreatic
Association, Japan Pancreas Society, PancreasFest
Working Group, and European Pancreatic Club [10]:
morphology- based diagnosis of early chronic pancreatitis is not possible without additional information; new
approaches to the accurate diagnosis of early chronic
pancreatitis will require a mechanistic definition; such a
definition will require prospective validation.
The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler,
RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao.
© 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd.
Companion website: www.wiley.com/go/beger/thepancreas4e
Diagnosis 413
A. “At Risk”
B. “AP-RAP”
C. “Early CP”
D. “Established CP” E. “End-Stage CP”
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Injury
Susceptibility
factors
(asymptomatic)
Years Days Months Months to years Remainder of life
Figure50.1 A conceptual model of chronic pancreatitis used for definition development[9]. AP: acute pancreatitis; RAP: recurrent acute
pancreatitis; CP: chronic pancreatitis; SAPE: sentinel acute pancreatitis event; DM: diabetes mellitus; PDAC: pancreatic ductal
adenocarcinoma. Source: Whitcomb etal. 2016[9]. With permission of Elsevier.
SAPE,
then RAP
Susceptibility to
recurrence
CP
biomarkers
Resolve
Risk Factors/Etiology
Injury or
stress
Immune dysregulation
Acinar dysfunction
Islet dysfunction
Pathologic pain
Metaplasia
Therapeutic
approaches
Progression
pathways
Fibrosis/sclerosis
Exocrine insufficiency
DM(T3c)
Pain Syndrome
PDAC
Symptomatic and
supportive treatment
pancreatitis [9,10,14,15]. However, some patients with
chronic pancreatitis are asymptomatic during the early
Based on the new mechanistic definition of chronic pancreatitis[9], the risk factors of early chronic pancreatitis
can be considered similar to those of recurrent acute
pancreatitis and chronic pancreatitis. International classification systems such as TIGAR- O [11] and the
M- ANNHEIM classification system [12] incorporate
common etiological risks including alcohol and nicotine
consumption, genetic mutations and polymorphisms,
stage, and incidental imaging findings, steatorrhea, or
diabetes may be the first clinical manifestation of chronic
pancreatitis. According to a nationwide epidemiological
survey conducted in Japan, 91.4% of patients with early
chronic pancreatitis had recurrent upper abdominal
pain, and 81.5% had abnormal pancreatic enzyme levels
in the serum or urine. Only 13.9% were positive for
abnormal pancreatic exocrine function[13].
metabolic disorders, ductal obstruction, immunological
factors, and idiopathic pancreatitis.
Diagnosis
Epidemiology
A nationwide epidemiological survey of early chronic pancreatitis was conducted in Japan [13]. Patients with early
chronic pancreatitis who were diagnosed according to the
Japanese diagnostic criteria 2009 [7] and had visited the
selected hospitals in 2011 were surveyed. The estimated
prevalence and the annual incidence of early chronic pancreatitis were 4.2 and 1.0 per 100,000 persons, respectively.
The male- to- female sex ratio was 1.32 : 1. The mean age was
60.4 and the mean age at disease onset was 55.4. The common etiologies were idiopathic (47.7%) and alcoholic (45.0%).
Clinical Presentation
A history of acute pancreatitis, especially recurrent acute
pancreatitis, is a significant risk factor for early chronic
There still has not been international consensus on the
diagnostic criteria for early chronic pancreatitis.
In 2009, the Japan Pancreas Society proposed the
world’s first diagnostic criteria for early chronic pancreatitis in the Japanese clinical diagnostic criteria for chronic
pancreatitis 2009 (DC2009) [7]. In 2019, the Japan
Pancreas Society proposed the revised DC2009, namely,
“clinical diagnostic criteria for chronic pancreatitis 2019
(DC2019)” (Table50.1)[17]. Early chronic pancreatitis is
diagnosed using a combination of five clinical signs: (i)
repeated upper abdominal or back pain; (ii) abnormal
pancreatic enzyme levels in the serum or urine; (iii)
abnormal pancreatic exocrine function; (iv) continuous
heavy drinking of alcohol equivalent to or more than
60 g/day of pure ethanol or mutation in the pancreatitisassociated gene such as PRSS1 and SPINK1; (v) past
history of acute pancreatitis; and imaging findings on
EUS, MRCP, or ERCP. Imaging findings on EUS were
Early Chronic Pancreatitis
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414
Table50.1 Japanese clinical diagnostic criteria for chronic
pancreatitis 2019 Source: [16]/Springer Nature.
Diagnostic items for chronic pancreatitis
① Characteristic imaging findings
② Characteristic histological findings
③ Repeated upper abdominal or back pain
④ Abnormal pancreatic enzyme levels in the serum or urine
⑤ Abnormal pancreatic exocrine function
⑥
Continuous heavy drinking of alcohol equivalent to ≧60 g/
day of pure ethanol or mutation in the pancreatitisassociated gene
⑦ Past history of acute pancreatitis
Imaging findings of early chronic pancreatitis
Either (a) or (b)
a) More than two features among the following four EUS
findings including (1) or (2)
1) Hyperechoic foci (non- shadowing) or strands
2) Lobularity
3) Hyperechoic MPD margin
4) Dilated side branches
b) Irregular dilatation of more than three side branches on
MRCP or ERCP
Definite chronic pancreatitis: either (a) or (b)
a) Definite findings of ① or ②
b) Probable findings of ① or ②, plus more than two items
among ③, ④, and ⑤
Probable chronic pancreatitis
Probable findings of ① or ②
Early chronic pancreatitis
More than three items among ③~⑦ plus imaging findings of
early chronic pancreatitis
Note 1: Differential diagnosis from other pancreatic diseases
especially pancreatic cancer and intraductal papillary mucinous
neoplasm is important.
Note 2: If imaging findings of early chronic pancreatitis were absent, a
diagnosis of possible chronic pancreatitis could be made in the
patients without ① and ②, but with more than three items among ③~⑦
after ruling out other diseases. Imaging examinations including EUS
are recommended for the patients with possible chronic pancreatitis.
Note 3: Patients with only two items among ③~⑦ and imaging findings
of early chronic pancreatitis are regarded as possible early chronic
pancreatitis after ruling out other diseases, and require careful
follow- up. Footnote: Long- term prognosis should be clarified in
patients with early chronic pancreatitis.
It has also been reported that three or more attacks of
acute pancreatitis with no morphological changes to the
pancreas can be an improved diagnostic criterion for
early chronic pancreatitis[16].
Diagnostic Modalities forEarly
Chronic Pancreatitis
Transabdominal Ultrasonography (US)
Transabdominal US is recommended as the first- line
noninvasive imaging approach for evaluating patients
with suspected chronic pancreatitis. However, the ability
of transabdominal US to diagnose early chronic pancreatitis has not been fully validated. HaPanEU/UEG working
group indicated that abdominal US can only be used to
diagnose chronic pancreatitis at an advanced stage[17].
Computed Tomography (CT)
The ability of CT to diagnose early chronic pancreatitis
has not been fully validated as well as transabdominal US.
Magnetic Resonance Imaging (MRI)
Japanese clinical diagnostic criteria for chronic pancreatitis 2019incorporated a finding of irregular dilation of
more than three side branches on MRCP into diagnostic
criteria for early chronic pancreatitis [16]. This MRCP
finding has been defined in accordance with image grading “mild” of ERP defined in the Cambridge classification[4]. The ability of MRCP to diagnose early chronic
pancreatitis needs to be prospectively verified.
T1- weighted MR signal of the pancreas, which was
associated with pancreatic exocrine dysfunction[18] and
the grade of ductal changes under the Cambridge classification [19], may be helpful in the evaluation of suspected early chronic pancreatitis. Main pancreatic duct
irregularity, T1- weighted MR signal, and duodenal filling
after secretin injection may be predictors of pancreatic
fibrosis[20].
consolidated from seven items in DC2009 to four items:
hyperechoic foci (non- shadowing) or strands; lobularity;
hyperechoic MPD margin; dilated side branches. Early
chronic pancreatitis can be diagnosed if a patient does
not justify a diagnosis of definite or probable chronic
pancreatitis, but satisfies at least three of five clinical
signs and imaging findings of early chronic pancreatitis.
The approach by the Japan Pancreas Society still has
not been fully accepted internationally, while it provides a potentially useful definition of early chronic
pancreatitis.
Endoscopic Ultrasonography (EUS)
EUS is considered the most sensitive modality for detecting early chronic pancreatitis, although early chronic
pancreatitis may not be diagnosed by current imaging
techniques [10]. So far, there is no consensus cutoff of
EUS findings for establishing a diagnosis of early chronic
pancreatitis.
In 2009, Japanese clinical diagnostic criteria incorporated EUS findings into diagnostic criteria for early
chronic pancreatitis[7]. Considering the diagnosis of
Management/Treatment 415
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indeterminate for chronic pancreatitis based on the
Rosemont classification [21], five features of pancreatic parenchymal factors (lobularity with honeycombing; lobularity without honeycombing; hyperechoic
foci without shadowing; stranding; cysts) and two features of pancreatic ductal factors (dilated side branches;
hyperechoic MPD margin) were adopted for the EUS
findings of early chronic pancreatitis. In the 2019 revision of diagnostic criteria, EUS findings were consolidated from seven items to four items: lobularities with
and without honeycombing were consolidated to
lobularity; hyperechoic foci without shadowing and
stranding were consolidated to hyperechoic foci (nonshadowing) or strands; and cysts were removed from
the diagnostic items (Table 50.1) [16]. The interobserver reliability of EUS criteria of diagnostic criteria
2019 was higher than that of diagnostic criteria
2009[22].
Elastography
EUS- elastography has recently allowed the evaluation of
the elasticity of deep organs, such as the pancreas[23,24].
The usefulness of EUS- elastography for the diagnosis of
early chronic pancreatitis has yet to be established[25],
although there has been a single arm study that patients
with suspected early chronic pancreatitis had an abnormally high strain ratio at EUS- elastography[26].
tests for pancreatic insufficiency. The positive predictive
value of the secretin pancreatic function testing for the
subsequent development of chronic pancreatitis has been
reported to be 45% with a negative predictive value of
97%[27].
The Japanese clinical diagnostic criteria incorporated
a finding of abnormal results in BT- PABA test into diagnostic criteria for early chronic pancreatitis [7,16].
Based on this criteria, only 13.9% of early chronic pancreatitis was positive for abnormal pancreatic exocrine
function[13].
Fecal elastase- 1 is considered to be inappropriate for
the diagnosis of early chronic pancreatitis because the
correlation of fetal elastase- 1with mild ductal changes is
not strong[28,29].
Histological Evaluation
While conventional chronic pancreatitis has been diagnosed mainly on the basis of structural changes related
to fibrosis, histological findings for the diagnosis of early
chronic pancreatitis have not yet been established.
Furthermore, direct acquisition of pancreatic tissue for
the diagnosis of early chronic pancreatitis is limited. It
has been reported that EUS- guided fine- needle biopsy
provided inadequate material for the histological diagnosis of early chronic pancreatitis[30].
ERCP
The Japanese clinical diagnostic criteria incorporated a
finding of irregular dilation of more than three side
branches on ERP into diagnostic criteria for early chronic
pancreatitis[7,16]. This ERP finding has been defined in
accordance with image grading “mild” defined in the
Cambridge classification[4]. The ability of ERP to diagnose early chronic pancreatitis needs to be prospectively
verified.
Pancreatic Function Testing
Exocrine pancreatic insufficiency is a common complication of chronic pancreatitis. Conversely, early chronic
pancreatitis is considered to be a stage of chronic pancreatitis with preserved pancreatic function and potentially reversible features[10]. The usefulness of pancreatic
function testing for the diagnosis of early chronic pancreatitis still has not been established, although it is considered that early chronic pancreatitis can be diagnosed
by a combination of factors including pancreatic function testing[10].
Direct hormone- stimulated tests, using cholecystokinin
or secretin, are considered the most sensitive and specific
Biomarkers
So far, there are no widely accepted biomarkers for the
diagnosis of early chronic pancreatitis [10]. There is a
report that indicated the usefulness of blood- based
microRNA biomarker panel for the diagnosis of early
chronic pancreatitis[31].
Genetic Markers
Genetic variants are important risk factors for early
chronic pancreatitis and can add specificity to the likely
etiology, but they are neither necessary nor sufficient to
make a diagnosis of early chronic pancreatitis[10]. The
Japanese clinical diagnostic criteria has incorporated
mutations in the pancreatitis- associated genes such as
PRSS1 and SPINK1 for the diagnosis of early chronic
pancreatitis[16].
Management/Treatment
Evidence for the management of early chronic pancreatitis is insufficient.
In patients with acute pancreatitis or recurrent acute
pancreatitis, it is important to evaluate risk factors in
Early Chronic Pancreatitis
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416
order to prevent disease progression[11]. It is expected
that precision medicine will be established according to
risk factors in the future. Alcohol abstinence and smoking cessation can be the mainstays for preventing the
progression of early chronic pancreatitis.
It has been reported that a combination treatment of
proton pump inhibitor, camostat mesilate, and pancrelipase improved epigastric pain[32] and EUS findings[33]
in patients with early chronic pancreatitis.
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13 Masamune A, Kikuta K, Nabeshima T etal. Nationwide
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15 Hegyi PJ, Soos A, Toth E etal. Evidence for diagnosis of
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20 Trikudanathan G, Walker SP, Munigala S etal. Diagnostic
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the diagnosis of chronic pancreatitis: the Rosemont
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22 Yamamiya A, Irisawa A, Tominaga K etal. Interobserver
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51
Chronic Pancreatitis withInflammatory Mass inthe Pancreatic Head
Ulrich F. Wellner, Kim C. Honselmann, and Tobias Keck
Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
Definition
Chronic pancreatitis can present with enlargement and
mass- formation of the pancreatic head, mimicking virtually all symptoms of a malignant pancreatic head tumor
and confronting the clinician with significant diagnostic
and therapeutic challenges. This phenomenon has been
termed the “inflammatory (pseudo) tumor”[1], “tumorforming chronic pancreatitis”[2], and other. For the purpose of this article, we will use the term inflammatory
pancreatic head mass (IPHM).
From a pathophysiological point of view, IPHM is
thought to result from recurrent acute and chronic
inflammation of the pancreatic parenchyma, but at the
same time to perpetuate disease progression as a “pacemaker” by causing main pancreatic duct (MPD) obstruction leading to chronic ductal hypertension[3]. There is
no generally accepted definition of IPHM, but the following criteria may be applied: presence of an abnormally enlarged pancreatic head, often accompanied by
pancreatic calcifications, MPD dilatation, and irregularities and atrophy of the pancreatic parenchyma to the left
of the mesentericoportal axis[4–6] (Figs51.1 and51.2).
Incidence
The concept of the IPHM as a pacemaker of chronic pancreatitis has been established by Beger etal.[3] and followed mainly by European surgeons. The incidence of
IPHM in surgical patients is in the range of 85%; however, exact figures have rarely been reported in
detail[5,7]. The average size of the pancreatic head has
been shown to be significantly larger in a study comparing German (median 4.5 cm) and North American
(median 2.6 cm) patients undergoing surgery for chronic
pancreatitis [5]. The significance of this finding lies in
the fact that it explains regional differences in operative
procedures used to treat chronic pancreatitis; however,
the underlying cause is not clear. Reasons might be a pattern of clinical transfer of the patient from the gastroenterologist to the surgeon, genetic differences, or different
risk factors for the development of chronic pancreatitis.
Symptoms, Pathophysiology, and
Clinical Problems
An IPHM can cause many clinical symptoms and complications, which in principle constitute the classical
complications of chronic pancreatitis. Differential
diagnosis and decision- making may be complicated as
virtually all of these symptoms can also be caused by
pancreatic head cancer.
One of the most frequently reported symptoms is
pain[4,7]. Typically, the pain maximum is located to the
epigastric area and may radiate to the flanks and back. In
some cases, however, back pain may be the primary complaint. The pain can be episodic or continuous, with sudden exacerbations of variable frequency from daily to
once in several months, often triggered by alcohol or
food intake. Signs of acute pancreatitis like elevation of
serum amylase or lipase and edematous swelling of the
pancreatic head are often found associated with severe
acute pain attacks, but may as well be missing, especially
with longer duration of disease. In line with this, there is
good evidence from histopathological and experimental
studies that pancreatic pain is not only caused by acute
inflammation but also from chronic neuropathy of visceral nerves in the pancreas [8]. Importantly about
50–90% of patients will not become pain10years after disease onset[9].
free even
The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler,
RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao.
© 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd.
Companion website: www.wiley.com/go/beger/thepancreas4e
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