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Indian J Pediatr (December 2016) 83(12):14591472

DOI 10.1007/s12098-016-2115-1

REVIEW ARTICLE

Pancreatitis in Children
Malathi Sathiyasekaran 1 & Vishnu Biradar 2 & Ganesh Ramaswamy 3 & S. Srinivas 1 &
B. Ashish 3 & B. Sumathi 4 & D. Nirmala 4 & M. Geetha 5

Received: 2 September 2015 / Accepted: 13 April 2016 / Published online: 6 June 2016
# Dr. K C Chaudhuri Foundation 2016

Abstract Pancreatic disease in children has a wide clinical


spectrum and may present as Acute pancreatitis (AP), Acute
recurrent pancreatitis (ARP), Chronic pancreatitis (CP) and
Pancreatic disease without pancreatitis. This article highlights
the etiopathogenesis and management of pancreatitis in children along with clinical data from five tertiary care hospitals in
south India [Chennai (3), Cochin and Pune].
Keywords Children . Pancreatitis . Acute . Recurrent .
Chronic

Acute Pancreatitis

for a cure) 2012 has recommended at least 2 of the following 3


criteria for the diagnosis of AP [1].
1. Abdominal pain suggestive of, or compatible with AP
(i.e., abdominal pain of acute onset, especially in the epigastric region).
2. Serum amylase and/or lipase activity at least three times
greater than the upper limit of normal (IU/L).
3. Imaging findings characteristic of, compatible with AP
[e.g., using Ultra sound (USG), Contrast Enhanced
Computerised Tomography (CECT), Endoscopic Ultra
Sound (EUS), Magnetic Resonance Imaging/Magnetic
Resonance Cholangio Pancreatography (MRI/MRCP)].

Definition
Epidemiology
Acute pancreatitis (AP) is an acute reversible inflammatory
process of the pancreas with variable involvement of other
regional tissues or remote organ systems. The INSPPIRE
(International Study Group of Pediatric Pancreatitis: In search
* Ganesh Ramaswamy
ganeped79@rediffmail.com

Department of Pediatric Gastroenterology, Kanchi Kamakoti


CHILDS Trust Hospital, Apollo & SMF Hospitals, Chennai, India

Department of Pediatric Gastroenterology, Deenanath Mangeshkar


Hospital, Pune, Maharashtra, India

Department of Pediatrics, Kanchi Kamakoti CHILDS Trust Hospital


& CHILDS Trust Medical Research Foundation, Chennai-34, India

Department of Pediatric Gastroenterology, Institute of Child Health


& Hospital for Children, Egmore, Chennai, India

Department of Pediatric Gastroenterology, Amrita Institute of


Medical Sciences, Cochin, Kerala, India

In children, AP is uncommon compared to adults. However,


over the last decade, there has been an universal increase in the
incidence of AP reported from major institutions. The incidence of AP in USA is 13.2 cases per 100,000 children per
year [2] and in Australia is 3.6 cases per 100,000/y [3]. There
is scarcity of data from India with 4 to 7 new cases reported
per year in referral centres. In Kanchi Kamakoti CHILDS
Trust hospital, a private tertiary care hospital for children in
Chennai, AP accounted for 48 (0.06 %) of the 80,157 admissions during the period January 2007 to June 2015 (67 cases/
year).
Etiopathogenesis
The common causes of AP in children are infections, abdominal trauma, medications, cholelithiasis, structural biliary/
pancreatic disease, metabolic, systemic diseases, and

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idiopathic (Table 1). The etiological break up figures differ


between the West and Asian countries [46] as shown in
Table 2.

Pathophysiology
The pathophysiology of AP remains obscure. However,
in spite of the varied etiology there seems to be a common inflammatory cascade pathway (Fig. 1). The first
trigger occurs within the pancreatic acinar cells and is
linked to non-physiological aberrant calcium signals
followed by premature activation of intra acinar pancreatic proenzymes or zymogens (cathepsin B, neutrophilic
enzymes). Pancreastasis with continued synthesis of enzymes occurs. Activated zymogens especially the protease trypsin plays a key role in acinar injury with production of cytokines such as tumor necrosis factor
and activation of inactive precursors of elastase, carboxypeptidase and phopholipase A 2 thereby resulting
in local or systemic complications. In severe acute pancreatitis the events may progress unchecked with release
of large amounts of histamine, bradykinin and cytokines. These cytokines trigger the systemic inflammatory response syndrome (SIRS) which results in hyperactivation of vascular endothelium, macrophages and neutrophils throughout the body resulting in multiorgan
failure syndrome (MOFS).
There are several protective mechanisms to limit this dynamic process such as compartmentalization of pancreatic enzymes, autodegradation of trypsin and endogenous trypsin
inhibitors like pancreatic secretory trypsin inhibitor (PST1),

Table 1 Etiology of acute and


acute recurrent pancreatitis

1-antitrypsin (1A) and 2 macroglobulin. In addition,


there is also a biological defense mechanism- Compensatory
Anti-inflammatory Response Syndrome (CARS) to prevent
prolongation of SIRS comprising of anti inflammatory cytokines [IL-4,IL-10,IL-1ra] and cytokine antagonists. Since
CARS inhibits new cytokine production, there is an increase
in susceptibility to sepsis, infected necrosis and pancreatic
abscess. The endotoxins stimulate neutrophil aggregation
and release of tissue injury mediators resulting in distant organ
failure [7, 8].
Diagnosis of Acute Pancreatitis
The diagnosis of AP is based on a combination of clinical
findings, biochemical tests and imaging studies.
Clinical Manifestations
This may differ with the age of the child and the underlying
etiology. The two classic symptoms of AP are abdominal pain
and nausea/vomiting.
Abdominal Pain In pediatric series of AP, 8095 % of children present with abdominal pain. The site of pain is usually
epigastric and back pain in <10 %. Infants and toddlers present
with irritability and less often with abdominal pain and
vomiting [9].
Nausea and Vomiting This is the second most common
symptom seen in 4080 %.

Category

Examples

Infections

Mumps, HIV, Coxsackie B, Hepatitis A,B, Varicella zoster,


Measles, Leptospirosis, Salmonella, Gram negative bacteria
Choledochal cysts, Cholelithiasis, Ascariasis, Pancreas divisuma, Sphincter of Oddi
dysfunctiona, Biliary sludgea
Valproic acida, Corticosteroidsa, L. Asparginasea,
Azathioprinea, 6 Mercaptopurinea
Tropical pancreatitisa

Biliary
Medications
Idiopathic
Genetic
Structural pancreatic
disorders
Mechanical
Metabolic
Systemic disease
Nutritional
a

Hereditary pancreatitisa, Trypsinogen gene mutationa,


SPINK 1 gene mutationa
Annular pancreasa, Pancreas divisuma, Sphincter of
Oddi dysfunctiona
Blunt abdominal trauma
Hypertriglyceridemiaa, Hypercalcemiaa
Hemolytic Uremic syndromea, Systemic Lupus
Erythematosusa
Malnutrition, Vitamin A and D deficiency

Includes causes of acute recurrent pancreatitis

Indian J Pediatr (December 2016) 83(12):14591472


Table 2

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Etiology of acute pancreatitis as reported from various studies

Study

Werlin et al., USA [4] Suzuki et al., Japan [5] Das et al., New Delhi [6] Chennai
KKCTHa

Chennai
ICHa

Cochina

Period/duration

6y

19852011

19942001

20072015 20062014

20032014

Number of cases
Etiology (%)

180

145

28

48

47

13

Infectious/viral

3.4

7.2; TB 7

21.8

6.3

15.3

Drugs
Systemic

12
14

13.1
8.9

14.3

23
4.34

17.02

7.7

Idiopathic

8.3

35.7

17.3

23.4

69.2

Structural/biliary/GS
Trauma

12
14

32.4; GS 6.2
9.6

10.7
14.3

17.4
17.4

2.1; GS/RW 4.2/6.3


25.5

Familial
Metabolic

3
5.5

2.1

7.2

8.5

7.7

Structural -pancreatic 7.5

6.9

4.2

GS Gallstones; RW Roundworm; TB Tuberculosis


a

Unpublished data

Abdominal distension and fever has been reported in 20


30 %. Other less common symptoms are jaundice, ascites,
pleural effusion and abdominal mass. In severe acute pancreatitis (SAP), children may present initially with shock, dyspnea, hemorrhage and mental confusion.
Biochemical Tests
Elevated serum amylase and/or lipase (>3 times upper limit of
normal) are the two important determinants of AP. Serum
amylase has a short half-life, levels rise within 6 to 12 h and
fall within 3 to 5 d of AP. However, elevated levels could also
be from non-pancreatic source such as salivary gland, intestine or due to reduced renal clearance and normal levels may
occur in acute on chronic pancreatitis. Plasma lipase, on the
other hand, rises on day one, persists longer and is organ
specific. In most studies the sensitivity of lipase was marginally higher than amylase alone and the combination is preferred for diagnosis [8]. However in infants and toddlers, lipase is often elevated 100 % compared to amylase (4060 %)
and is therefore, more sensitive [10]. Serum cationic trypsinogen, if available may be done since it is more sensitive than
amylase [11].
Imaging Studies
a) Plain radiograph of the chest and abdomen may identify
pleural effusion, generalized or local ileus, a colon cut off
sign and a renal halo sign. Identification of cholelithiasis
or pancreatic lithiasis may help in the etiological
diagnosis.

b) USG is a noninvasive ideal screening test for AP where


the pancreas may show diffuse enlargement with reduction in pancreatic echo texture, pancreatic hetetrogeneity,
edema and peripancreatic fluid collection. USG can also
identify choledochal cyst, gallstones, pancreatic calculi
and dilatation of pancreatico-biliary tree. It can also exclude other causes of acute abdomen such as intussusception, abscess or volvulus.
c) CT is occasionally indicated if clinical and biochemical
findings are not conclusive or there is a possibility of an
alternate diagnosis. CT helps in assessing the severity and
diagnosing complications.

Complications
The complications of AP may be either local or systemic.
Local complications are pseudocyst, pancreatic necrosis
and abscess.
Pseudocyst is a homogenous collection of amylase rich
pancreatic fluid that lacks an epithelial lining, which may be
complicated by infection, intracystic hemorrhage or rupture
leading to pancreatic ascites.
Pancreatic necrosis is diagnosed by the presence of non enhancement of >30 % of the pancreas on CECT or MRI and
may be either sterile or infected. Infection usually occurs after
the 10th day. Walled-off necrosis (WON) is a collection of
necrotic debris within a fluid filled cavity lined by fibrous
tissue [12].
Systemic complications include gastrointestinal bleeding,
pseudoaneurysms (direct injury to the blood vessels leading to pseudoaneurysms or arterial hemorrhage into

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Recovery and
regeneration

Mild
Pancreatitis

Pancreatic Acinar Cell

Inflammatory
Cytokines (IL-6, IL-8,
IL-, TNF-)

INSULT
Protease activation

Edema
Inflammation

Trypsinogen to trypsin

Protease activation
Protective
factors :

Anti-inflammatory
cytokines (IL-4,Il10,sTNF-R)

PST1
AIAT
A2M

SIRS

Compensatory antiinflammatory response


syndrome [CARS]

Recovery

Adequate CARS

Compromised
CARS

Multiorgan Dysfunction
Syndrome.
Pancreatic necrosis, abscess

Fig. 1 Pathophysiology of acute pancreatitis showing progress of the


event and the protective factors. SIRS Systemic inflammatory response
syndrome; TNF Tumor necrosis factor; IL Interleukin; AIAT Alpha 1

antitrypsin; A2M Alpha 2 microglobulin; PST-1 Pancreatic secretory


trypsin inhibitor-1; CARS Compensatory anti-inflammatory response
syndrome

p s e u d o c y s t t h u s c o n v e r t i n g th e m t o p a n c r e a t i c
pseudoaneurysms), splenic infarct, intestinal obstruction/
perforation, acute respiratory distress syndrome, pleural
effusion, pericardial effusion, shock, myocardial dysfunction, acute tubular necrosis, hyperglycemia, hypocalcemia, disseminated intravascular coagulation, pancreatic
encephalopathy and fat necrosis.

parenchymal necrosis or organ dysfunction with an


uneventful recovery and a low mortality (<1 %).
Severe acute pancreatitis (SAP) with local or systemic
complications is associated with high mortality
(<10 %) but is less common than in adults.
The assessment of severity is an essential step in
the management of AP and is done using a combination of parameters.

Management of Acute Pancreatitis


I. Assessment of Severity of Acute Pancreatitis
Based on the severity, AP is classified as mild AP
(no organ failure, no local/systemic complications),
moderately severe AP (organ failure that resolves
within 48 h and/or local or systemic complications
without persistant organ failure) and severe AP (single
or multiple persistant organ failure for >48 h). In majority (>90 %) of children, the course is mild without

a) Clinical Assessment: The presence of abdominal distension, absence of bowel sounds, tachycardia, hypotension and cutaneous bleeds point to a severe form of
illness. Obesity may be associated with a more complicated course.
b) Scoring Systems: Scoring systems such as
Ranson, Glasgow for adults and the De Banto
for pediatrics have a good specificity (85 %) with
a low sensitivity (55 %) for predicting severity of

Indian J Pediatr (December 2016) 83(12):14591472

AP but is not useful in Asian children. Recently


Suzuki M et al. [13] have modified the 2008 JPN
(Ministry of Health, Labour and Welfare of
Japan) scoring system and presence of 3 or more
of the 9 criteria indicate severity with a specificity of 96 % and sensitivity of 80 % for the pediatric JPN score (Table 3).
c) Hematological and Biochemical Parameters
i)

ii)

Hematocrit and C-Reactive Protein (CRP): A


high hematocrit and an elevated CRP >150 mg/
dl at 48 h predicts severity in adults.
Serum Lipase: Coffey et al. have reported that
serum lipase 7 upper limit of normal, performed
within 24 h of presentation has high sensitivity
(85 %) but low specificity (56 %).

d) Imaging: Plain radiograph of the chest and abdomen showing pleural effusion, infiltrates and atelectasis, colon cut off sign or sentinel bowel loops
may be indicative of severity. Scoring systems
only estimate the effect of AP whereas imaging
studies help in accurate visualization of the morphological alterations and grading the extent of
inflammation of the organ and the adjoining
tissues.
i)
ii)

iii)

Ultrasound, though useful as an initial screening


procedure, lacks sensitivity.
Contrast enhanced CT (CECT) is the imaging
modality of choice for staging the disease
and for the detection of complications such
as pseudocyst (Fig. 2), abscess and necrosis.
CECT detects parenchymal necrosis with a
sensitivity of 87 % and has an overall detection rate of 90 % [14, 15]. The scoring
index of Balthazar et al. by CT with pancreas protocol is considered sensitive to assess
severity.
MRI in AP has been evaluated as a sensitive
imaging modality with the advantage of
avoiding contrast media and radiation. The
sensitivity is 83 % and specificity is 91 %
[14].

II. Assessment of Etiology


a) History and Clinical Examination: A detailed history including blunt abdominal injury (handle bar),
medications, prodrome or exposure to viral illness,
jaundice, ascariasis, family history or symptoms of
systemic disease should be elicited.

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b) Laboratory Investigations: In the acute phase of


illness, a complete blood count, peripheral smear
and liver function test (LFT) should be done.
An increase in bilirubin, amino transferases, alkaline phosphatase and gamma glutamyl trans
peptidase (GGTP) is indicative of biliary disease. An elevated creatinine and thrombocytopenia points to hemolytic uremic syndrome.
During the recovery phase, fasting lipids and
plasma calcium should be estimated to exclude
metabolic cause.
c) Radiological Assessment: Plain radiograph and
USG of the abdomen help in diagnosing biliary diseases and gallstones. CECT helps not only in diagnosing complications and assessing the prognosis but
also in identifying the etiology such as disruption of
the pancreatic duct. Magnetic resonance cholangio
pancreatography (MRCP) helps in identifying pancreas divisum.
d) Endoscopic Assessment: Endoscopic retrograde
cholangio pancreatography (ERCP) is undertaken
for endotherapy in select cases such as pancreas
divisum, biliary pancreatitis and traumatic pancreatitis. Endoscopic ultrasound (EUS) may be useful in
older children as it has a very high sensitivity for
detection of stones at the lower end of common bile
duct (CBD).
e) Genetic Studies: Cationic trypsinogen mutations
p.R122H; N29I, CFTR mutations and SPINK1 may
be beneficial in children with a family history of acute
recurrent or chronic pancreatitis.
III. Management and Prevention of Complications
a) Initial Management of Mild AP Mild AP can be
managed with basic monitoring and supportive measures. Analgesics are prescribed, however there is no
role for prophylactic antibiotics. Prompt and adequate
fluid resuscitation is crucial to prevent systemic complications. There is no benefit of naso gastric tube
feeding or need for any dietary restrictions.
b) Management of Severe AP
i)

Naso gastric tube placement and Oxygen


therapy: Rest to the pancreas to prevent stimulation of the pancreas is obsolete. NG tube
placement is, however necessary if paralytic
ileus and delayed gastric emptying is associated with AP. It has been reported that oxygen
supplementation to maintain arterial oxygen
saturation > 95 % is associated with resolution
of organ failure.

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Table 3

Pediatric JPN scoring system

iii)
a

Parameter

Pediatric JPN scoring system

Base excess < 3 mEq or shock


PaO2 < 60 mmHg in room air or respiratory
failure requiring ventilation

2
3

BUN > 40 mg/dl or creatinine >2 mg/dl or urine


output <0.5 ml/kg/h

4
5

LDH > 2 times above the upper limit of normal


(age adjusted values)
Platelet count < 1,00,000 cells/cu.mm

Total serum calcium <7.5 mg/dl

7
8

C-reactive protein > 15 mg/dl


Number of positive measures in pediatric SIRS score > 3
[SIRS criteria
A: Core temperature > 38.53 C or <36 C
B. Tachycardia mean heart rate >2SD above
normal for age
C. Tachypnea mean respiratory rate >2SD above
normal for age
D. Leucocyte count either elevated or depressed
for age or >10 % immature neutrophils]

Age less than 7 y and/or weight below 23 kg

iv)

Presence of any three of the above criteria indicates severe pancreatitis

ii)

Fluid resuscitation and rehydration:


Maintaining an adequate intravascular volume is probably the most essential therapeutic measure in the treatment of SAP. Fluids
(Dextrose normal saline or Ringer lactate) are
given to maintain central venous pressure
(CVP) between 8 and 12 cm H2O, urine output >0.5 ml/kg/h and hematocrit between 30
and 35 %.

v)

vi)

Fig. 2 CECT abdomen showing acute pancreatitis with a large


pseudocyst. 1. Pseudocyst 2. Stomach with contrast 3. Pancreas

Pain relief with analgesics: Pain management


should be balanced between adequate control
and over sedation. There are no data regarding
optimal pain management in pediatric AP. The
commonly used analgesics are morphine
(0.05 mg/kg Q24 hourly), fentanyl (0.51 g/
kg Q12 hourly) and meperidine (0.5 mg/kg Q2
4 hourly).
Nutrition: Patients with SAP are frequently
hyper catabolic and hence, timely initiation
of feeding is important to prevent malnutrition. There are no data on the optimal
timing of nutritional intervention and mode
of nutrition in pediatric AP. Data from
adults is convincing that enteral nutrition
(EN) is safe, less costly and is well accepted
when compared to parenteral nutrition. It also reduces the complications by maintaining
the intestinal barrier and intestinal blood
flow and by preventing or reducing bacterial
translocation from the gut. EN should be
given by nasogastric or nasoduodenal/
jejunal tube to prevent atrophy of the intestinal mucosa and maintain the intestinal barrier if the caloric requirement is not met by
oral feeding. Early enteral feeding within
36 h results in improved nitrogen balance,
wound healing, host immune function, preservation of intestinal mucosal integrity and
decreased infections. It is recommended that
feeding should be started with readily digestible food once the child is free of pain.
Enteral feeding may be limited by ileus and
if persistent for more than 5 d, parenteral
nutrition will be required [15].
Role of Antibiotics: Routine use of prophylactic
antibiotics in patients with severe AP is not recommended. There is no recommendation to use
antibiotics in patients with sterile necrosis and for
those patients with infected necrosis, either initial
CT-guided fine-needle aspiration (for Gram stain
and culture to guide use of appropriate antibiotics) or empiric use of antibiotics (carbapenems,
quinolones, and metronidazole) after obtaining
necessary cultures without CT-guided fine-needle aspiration should be given for a period of
1014 d.
Drugs: There is no role for somatostatin or its
analogues in AP. These have been found useful
in some patients with pancreatic fistulae. Enzyme
replacement therapy is also not routinely prescribed in the resolving phase of AP except in
select situations.

Indian J Pediatr (December 2016) 83(12):14591472

IV) Specific Management of Pancreatic Complications


a) Endotherapy- Sphincterotomy and Basketting:
ERCP plays a therapeutic role in biliary pancreatitis
with cholangitis, jaundice or sonographically detected cholelithiasis or choledocholithiasis. According to
the American Gastroenterology Association recommendations, urgent ERCP (within 24 h) should be
performed in gallstone pancreatitis with cholangitis
and early ERCP (within 72 h) should be performed
in patients who present with a high suspicion of persistent common bile duct stone. Pancreatic trauma is
perhaps an unique diagnostic application of ERCP
that has been used to define the pancreatic ductal
injury and thereby stenting of pancreatic duct helping
to resolve a peripancreatic fluid collection. In pancreas divisum, minor ampulla papillotomy and in biliary
ascariasis, ERCP with basketting is recommended.
b) Pancreatic Stenting: In traumatic pancreatitis with
disruption of pancreatic duct, it is preferable to stent
across the disruption.
c) Endoscopic Drainage of Pseudocysts: Pancreatico
endotherapy such as cysto duodenostomy, cysto
gastrostomy with stenting is useful in managing
complications like pseudocyst. USG/CT guided
interventions also can be performed for drainage
of the cyst.
d) Surgical Management: In children with AP it is
rarely necessary to advocate necrosectomy or
debridement. Choledochal cyst, if identified,
needs surgical resection in view of it being
pre-malignant. If biliary pancreatitis is due to
gallstones, cholecystectomy should be done.
Surgery also plays a role wherever endotherapy
is not feasible.

Prognosis

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are at least 2 distinct episodes of AP (each as defined


above) along with:
Complete resolution of pain (1 mo pain-free interval between the diagnoses of AP)
OR
Complete normalization of serum pancreatic enzyme levels
(amylase and lipase), before the subsequent episode of AP is
diagnosed, along with complete resolution of pain symptoms,
irrespective of a specific time interval between AP episodes
[1].
ARP occurs in 15 to 36 % of children with AP.
Etiology
There is no clear distinction between diseases that cause recurrent attacks of acute pancreatitis and those causing chronic
pancreatitis. Thus this category is a phenotypic description
rather than a disease classification. The causes of ARP are
shown in Table 1. ARP has been reported from a very few
centres in India. In Cochin, out of 63 children with pancreatitis, 28 (44 %) were ARP and the identifiable causes were gall
stones (3.5 %), pancreas divisum (3.5 %) and 72 % were
idiopathic [16]. Poddar et al. has reported positive genetic
mutations in 45.4 % of children with ARP [17]. In an unpublished data from KKCTH, Chennai, (SPINK1 gene was positive in 36 % (4/12) of children with ARP.
Relevance of Acute Recurrent Pancreatitis
AP is not a benign disease and may present as ARP in a
significant number. AP may be managed by intensivists and
pediatricians but ARP should be referred to pediatric gastroenterologists and centres with facilities for endotherapy and
genetic studies. The pathologic changes in ARP are reversible
and therefore, steps should be taken to prevent further
progression.

Children with uncomplicated mild acute pancreatitis recover


within 57 d. In those with severe acute pancreatitis the prognosis is related to the complications and the underlying medical conditions. Children with AP may present with Acute
Recurrent Pancreatitis (ARP) which may eventually progress
to chronic pancreatitis.

The usefulness and drawbacks of various tests used for


evaluation of ARP are shown in Table 4. The management of ARP is based on a 3-tier structured approach
and is shown in Fig. 3.

Acute Recurrent Pancreatitis

Chronic Pancreatitis

Definition

Introduction

The INSPPIRE group has recommended that Acute


Recurrent Pancreatitis (ARP) be diagnosed when there

In India, tropical pancreatitis (TP), a form of chronic pancreatitis has been recognized as an important cause of morbidity

Approach to Management [18]

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Table 4

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Advantages and disadvantages of various evaluation methods for acute recurrent pancreatitis

Method

Usefulness

Drawbacks

Contrast enhanced CT

Easily available
Parenchymal and ductal abnormality
can be visualised

Poor sensitivity as compared to EUS


Misses early CP
Only morphological information (no pancreatic
exocrine function detail)

MRCP

Non-invasive
Better sensitivity than CT for ductal abnormality

EUS

Secretin-EUS/MRCP

Poorer parenchymal and no exocrine function information


Misses early CP
Highly accurate test for parenchymal and ductal morphology Requires high skill
Operator dependency
Semi-invasive
No exocrine functional detail
Other procedures can be done if needed like duodenal
bile aspiration, fine needle aspiration, trucut biopsy
Functional and morphological detail simultaneously
Poor sensitivity as compared to pancreatic
Provides non-invasive assessment of SOD
function test for functional details

ERCP

Most sensitive for ductal morphology


Therapeutic role

Sphincter of Oddi
manometry

Detects SOD

Invasive
Post ERCP complication risk
No parenchymal detail
Universal unavailability
Invasive
Post ERCP complication risk
Universal unavailability
No morphological detail

Pancreatic function test Most sensitive for functional detail

CT Computed tomography; MRCP Magnetic resonance cholangio pancreatography; EUS Endoscopic ultrasound; ERCP Endoscopic retrograde
cholangio pancreatography; SOD Sphincter of Oddi

since the initial reports by Zudeima in 1955 and later by Gee


Verghese in 1962. TP is an entity presenting as abdominal
pain in childhood, pancreatic calculi and diabetes mellitus in
puberty and death in the prime of life in individuals living in
the tropics. Over the years it became obvious that tropical
pancreatitis is only a part of the spectrum of chronic pancreatitis which encompasses several conditions.

Etiology
The etiology of CP is diverse and comprises of several conditions. The TIGARO classification proposed by Etemad &
Whitcomb in 2001 is based on the etiology [19] and is shown
in Table 5.
Epidemiology

Definition
Chronic pancreatitis (CP) is a progressive inflammation of the
pancreas characterized by fibrosis and irreversible acinar and
ductal changes (stricture, dilatation), resulting in endocrine
and exocrine insufficiency. The INSPPIRE has suggested that
a diagnosis of pediatric CP is made by clinical + radiologic
+/compatible histology (surgical resection, core biopsy).
Imaging modalities include CT, MRI/MRCP, ERCP,
transabdominal USG and EUS.
Clinical diagnosis is made with one of the following 3
situations:
A. Abdominal pain consistent with pancreatic origin AND
imaging findings suggestive of chronic pancreatic damage.
B. Evidence of pancreatic exocrine insufficiency AND suggestive pancreatic imaging findings.
C. Evidence of pancreatic endocrine insufficiency AND
suggestive pancreatic imaging findings [1].

Retrospective analysis of pediatric studies have documented


idiopathic, traumatic, biliary (including congenital)
malformations, medication related, hereditary-genetic, metabolic and others as the etiologies for CP which more or less
confines to the above classification. The clinico-etiological
profile of chronic pancreatitis from various centres [16, 20]
in south India is shown in Table 6.
Pathogenesis
Various hypotheses have been proposed such as the toxicmetabolic, obstructive due to protein hypersecretion, necrosis-fibrosis and oxidative hypothesis to
explain the events which result in CP. Several genetic
mutations like cystic fibrosis trans membrane conductance
regulator (CFTR) gene, pancreatic secretory trypsin inhibitor (PST1) or serine protease inhibitor kazal type 1
(SPINK1), chymotrypsin C (CTRC), calciumsensing receptor gene claudins (CLDN2), cationic trypsinogen gene

Indian J Pediatr (December 2016) 83(12):14591472

1467

Fig. 3 Algorithmic approach to


acute recurrent pancreatitis
(ARP). ARP Acute recurrent
pancreatitis; LFT Liver function
tests; USG Ultrasono gram; CP
Chronic pancreatitis; MRCP
Magnetic resonance cholangio
pancreatography; ERCP
Endoscopic retrograde cholangio
pancreatography; EUS
Endoscopic ultrasound

ARP as per INSPPIRE criteria

Obesity: Reduce weight

Complete history and through


physical examination

Offending drugs: Stop

Level I investigations
LFT, Lipid profile, Calcium
Repeat USG abdomen

Metabolic: Appropriate treatment


Microlithiasis (Biliary Stones < 3
mm): Sphincterotomy

Not contributory
Level II investigations
IgG subclass assay
MRCP, ERCP, EUS

Autoimmune: Steroids
Pancreas divisum: Papillotomy
Choledochal cyst: Complete excision

Not contributory
Level III investigations

Mutations identified:
Follow up for CP

Genetic studies

(PRSS1 gene) have also been implicated in pathogenesis


of CP. Few of the identified mutations are susceptibility
genes and may cause pancreatic damage (PRSS1).
However the majority act as disease modifiers lowering
the threshold for pancreatitis.

pancreas (trypsin) or prevent its breakdown and are


discussed below.
i)

Gene Mutations
The probable sites of action of the various genetic mutations resulting in CP are shown in Fig. 4. A gain of function (which occurs in PRSS1) or a loss of function (which
occurs in SPINK1, CTRC, and CFTR) leads to either the
premature activation of the enzymes that digest the

Table 5 Etiological classification


of chronic pancreatitis

ii)

Cationic Trypsinogen Gene Mutation: This is also


referred to as Serine protease I (PRSS 1) and is a
well recognized cause of HP with 80 % penetrance
rate. The most prevalent mutation worldwide is
p.R122H. The other mutations are P.N29I and
16 V. These mutations are associated with a gain
in function causing activation of the trypsinogen
molecule to trypsin [21].
SPINK 1 Gene Mutation: SPINK1, also known as
pancreatic secretory trypsin inhibitor (PSTI), is a specific inactivator of intrapancreatic trypsin activity. The

Category

Examples

Toxic-Metabolic

Alcohol, Tobacco smoking, Hypercalcemia, Hypertriglyceridemia,


Chronic renal failure

Idiopathic
Genetic
Autoimmune
Recurrent, Severe AP
Obstructive

Tropical, Early onset, Late onset


Cationic trypsinogen, SPINK 1 and CFTR mutations
Isolated, Syndromic: Sjogren, IBD
ARP, Severe acute-post necrotic, Vascular disease, Post radiation
Pancreas divisum, APBDU, Periampullary duodenal wall cysts, SOD disorders

SPINK-1 Serine Protease Inhibitor Kazal type 1; CFTR Cystic fibrosis trans membrane conductance regulator
gene; IBD Inflammatory bowel disease; AP Acute pancreatitis; ARP Acute recurrent pancreatitis; APBDU
Anomalous pancreatico biliary ductal union; SOD Sphincter of Oddi

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Table 6

Etiology of chronic pancreatitis (CP) as reported from various centres


Cochin [16]

CMC
Vellore [20]

Punea

Chennai ICHa

Period/duration

200310

200510

5y

5y

20062014

20092014

Number of cases
Age

37
218 y

99
Mean: 15.2 y

13
2.619 y (range)

30
Mean 7.84 y

58
55 % between 6 and 10 y

16
Median: 12 y

100
10.8

100
9.1

100
7.6

91.6
4.1

93.1
6.9

100
6.25

Chennai
KKCTHa

Chennai
Apolloa

Etiology (%)
Abdominal pain
Diabetes

Steatorrhea

45.5

12.5

27.5

6.25

Calculi
Metabolic

81.08
1.4

69.6

84.6
15.3

6.6

51.7

50

Gall stones
Biliary structural

46.15

12.5

Pancreas divisum (PD)

5.4

8.4

15.3

3.4

Idiopathic/tropical
Genetic

81

95.9

24

70
3

95

100

Trauma

8.1

4.0

Unpublished data

iii)

iv)

gene is located on chromosome 5 and N34S is the most


common mutation. Approximately 1 % of normal population are heterozygous for N3S4 mutation and 23
25 % of ICP display this mutation [22, 23]. This is
not a gain in function mutation but probably a disease
modifier.
CFTR Gene Mutation:There are more than 1000
mutations in Cystic fibrosis trans membrane conductance regulator gene. The most common
deltaF508 results in Cystic fibrosis. Compound heterozygotes of CFTR mutants with one of the three
common allele specific thymidines 5 T,7 T and 9 T
are seen in CP.
CTRC Gene Mutation: Trypsinogen-degrading enzyme Chymotrypsin C (CTRC) mutation has recently
been identified in children with CP.

Fig. 4 Mechanism of genetic


mutations causing chronic
pancreatitis. PRSS1 Serine
protease 1 mutation; SPINK 1
Serine protease inhibitor kazal
type 1; CFTR Cystic fibrosis
transmembrane conductance
regulator; CTRC
Chymotrypsinogen C

In CP, the initiating event (first hit) for necrosis is probably the premature activation of trypsin within the acinar
cell as seen in AP. While AP is an acute event, CP results
from an ongoing inflammatory process. The sentinel acute
pancreatitis event (SAPE) hypothesis was proposed in
1999 and still remains the prevailing concept [24]. This
event could be triggered by the toxic effect of the environmental insult or because of some genetic mutation resulting
in more inflammation. This necro inflammatory process
may either resolve or progress. When there is a continuing
metabolic and oxidative stress (second hit) it results in
repeated acinar, ductal injury with necrosis leading to an
increased number of activated lymphocytes, macrophages,
and stellate cells within the pancreas and finally, fibrosis. A
vicious cycle is set up with fibrosis causing acinar cell
ischemia which again drives the process.

PRSS1 +

Trypsin

CTRC +

Trypsinogen

Trypsin degradation

SPINK1-

Inflammation/injury

CFTR+

Flushes into duodenum


to breakdown food

Indian J Pediatr (December 2016) 83(12):14591472

The pathophysiology of CP may be considered as a disease


associated with a variety of disease triggers, different genetic
predispositions and multiple modifiers leading to similar final
common pathway producing pancreatic injury, fibrosis and
organ failure. The various triggers work in concert and individually may not cause disease.

Clinical Features
CP may occur in all age groups. Clinical examination of the
abdomen may be normal and the presence of a mass may
indicate pseudocyst and splenomegaly may indicate portal
hypertension. The common presentations in children with
CP are:
1. Abdominal Pain
This is the most common presentation and was
seen in (90100 %) of children from Chennai and
Cochin centres. CP usually manifests in early stage
by recurrent episodes of acute pancreatitis (ARP) that
eventually evolves over months or years into a late
painless stage dominated by progressive pancreatic
dysfunction/calcification. The pain in CP is usually
localized to the upper abdomen and may be mild or
severe. The pain is penetrating, post prandial, disturbs sleep and decreases on stooping and leaning
forward. The cause of pain is multifactorial and
may be due to increased ductular pressure, injury to
and alteration in peripheral and central nociceptive
nerves, pancreatic ischemia, substance P, CCK stimulated enzymes, pseudocyst, duodenal or CBD obstruction. The pain seems to burn off with time
perhaps due to loss of most parenchymal tissue.
2. Pancreatic Calculi
The three common causes of calcific pancreatitis in
pediatrics are Tropical (TCP), Idiopathic (ICP) and
Hereditary pancreatitis (HP). The calculi are large,
more than 10 mm, dense, solitary or multiple, discrete, well circumscribed, intraductal lying within a
dilated pancreatic duct in (TCP) whereas the size
and distribution remains variable in ICP. In HP with
ongoing disease, the pancreas may become fibrotic,
shrunken and calcified. Lithostatine, a protein secreted by the pancreatic duct which inhibits calcium carbonate precipitation and GP2 (glycosyl phosphatidyl
inositol) that is secreted into the duct during inflammation have been related to the formation of calculi.
These calculi do not cause the initial pancreatic injury
but may facilitate disease progression.

1469

3. Diabetes Mellitus
Glucose intolerance occurs in CP and overt diabetes
mellitus usually occurs later in the course of disease.
Children who develop calcifications early are more prone
for diabetes compared to non-calcific CP. The diabetes is
insulin dependent and brittle since there is a concomitant
loss of glucagon producing alpha cells and islet cells.
Fibrocalcalculous pancreatic diabetes (FCPD) denotes
calcification without significant abdominal pain, an
unique subset seen in TCP.
4. Exocrine Pancreatic Insufficiency
a) Malnutrition is an important feature of chronic pancreatitis and is explained by the reduced intake secondary to pain, diabetes mellitus and subclinical
steatorrhea.
b) Steatorrhea: Children with severe pancreatic exocrine
deficiency may develop fat and protein malabsorption. However significant steatorrhea do not occur
until >90 % of pancreatic function is lost.

Complications
The complications of CP include pseudocysts, splenic vein
thrombosis, GI bleeding, pancreatic fistulae, bile duct obstruction, duodenal obstruction, pancreatic cancer, Vitamin B12
deficiency and fat soluble vitamin deficiency.
Investigations
In chronic pancreatitis, serum amylase and lipase levels
may be normal, or mildly elevated or even reduced in the
advanced stages. Elevated bilirubin, serum alkaline phosphatase and transaminase levels are suggestive of biliary
obstruction. The panel of investigations that are performed in children with CP include imaging studies
pertaining to pancreatic structure, tests of exocrine/
endocrine function and for etiology.
I. Imaging Studies
1. Plain X-ray Abdomen: The visualization of pancreatic calculi to the right of L1,L2,L3 verebra extending
up to T10T11 verebrae supports the diagnosis of
chronic calcific pancreatitis (Fig. 5).
2. Transabdominal Ultrasonography: USG of abdomen can identify alterations of the pancreatic duct,
pancreatic calcification or stones and pancreatic cysts
or pseudocysts. The overall sensitivity in CP is 50
70 % and specificity is 8090 %.

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Indian J Pediatr (December 2016) 83(12):14591472

and patient motion. It also has limited application in


detecting milder form of disease. It is less sensitive
than EUS in evaluating early changes of CP. Secretin
induces fluid secretion in the pancreatic duct and
when administered with MRCP may improve visualization of the ducts [26].
5. Endoscopic Ultrasound: EUS is the diagnostic modality of choice to evaluate patients with early or mild
chronic pancreatitis. The high diagnostic accuracy
and low complication rate are the advantages over
ERCP. However, it is highly operator dependent.
II. Tests for Exocrine Function
Fig. 5 Plain X ray abdomen showing pancreatic calculi

3. Computerised Tomography: CT has better sensitivity over USG in visualization of the pancreas
and detection of abnormalities such as focal enlargement, atrophy, ductal dilation, pancreatic calculi, and pseudocysts. It can also delineate complications such as pseudoaneurysms, hemorrhage,
thrombosis of splenic vein and bile duct dilatation. CT has poor sensitivity to identify the early
parenchymal changes of CP or define the degree
of ductal abnormality. Sensitivity is 7590 % and
specificity is >85 % [25].
4. Magnetic Resonance Cholangio Pancreatography
(MRCP): This non-invasive non-radiation imaging has replaced ERCP in the evaluation of pancreatic diseases. MRCP can demonstrate the extent of dilated pancreatic ducts (Fig. 6), irregularities in the duct diameter and the exact site of
pancreatic stones. However, MRCP in children is limited by small caliber non-dilated ducts, poor signal

Pancreatic Exocrine Insufficiency (PEI) is usually diagnosed on the basis of patients clinical status assessment, self reporting of bulky, oily stools, as well as weight
loss and failure to thrive. A 72-h fecal fat estimation test is
considered as the gold standard for lab diagnosis. Fecal
chymotrypsin assay, fecal elastase assay and fecal acid
steatocrit tests are less cumbersome.
Fecal Pancreatic Elastase-1 (FPE-1) Assay:
Pancreatic elastase is released by the acinar cells and detected in the stool. An immunosorbent assay of elastase is a
non-invasive way of assessing the pancreatic exocrine functions. A fecal FPE-1 level of 200 mcg/g stool or more is
considered normal, 100200 mcg/g suggests mild to moderate PEI, and 100 mcg/g or less is indicative of severe
exocrine insufficiency. The sensitivity of FPE-1 to diagnose
moderate and severe PEI is close to 100 %, however in early
or mild disease, the results of the test are equivocal [27].
III. Tests for Endocrine Pancreatic Function
Fasting blood glucose, glucose tolerance test and Cpeptide assay are done to assess endocrine function.
IV. Tests for Etiology
Elevated serum triglyceride levels and serum calcium may be present in the metabolic forms of CP. If
type-1 autoimmune disease is suspected, -globulin,
IgG4, and various antibodies including
antilactoferrin, anti carbonic anhydrase, rheumatoid
factor, and antinuclear antibody should be checked.
Genetic studies should include mutation testing for
PRSS1, SPINK1 and CFTR genes.

Pancreatic stone

Fig. 6 MRCP showing dilation of main pancreatic duct (MPD) and


branches with stone at the lower end

Management
The goals of treatment in chronic pancreatitis are i) to relieve
acute or chronic pain ii) prevent recurrent attacks iii) treat

Indian J Pediatr (December 2016) 83(12):14591472

diabetes mellitus, steatorrhea and malnutrition iv) manage


complications and v) address the psychological problems.
The options available for management include medical, endoscopic, interventional radiology and surgical.

1471

pancreatitis. Denervation of splanchnic nerves and celiac


plexus have been reported to achieve pain relief, when
medications fail [28].
Management of Steatorrhea

Management of Pain
The management of pain in CP is probably the most difficult but very vital. Nonsteroidal anti-inflammatory drugs
and acetaminophen are the first line agents. Opioids
should be avoided as far as possible for fear of addiction
and drugs such as propoxyphene, tramadol, meperidine
may be considered in a step wise manner with non opioids. The dosage should be increased to achieve an acceptable pain level rather than complete pain relief. Some
of the non-pharmacologic treatments of chronic pain includes cognitive behavioral strategies, relaxation and distraction techniques and biofeedback. The role of oral pancreatic enzymes in reducing pain in chronic pancreatitis
remains unclear. In chronic pancreatitis, damage to acinar
cells results in decreased secretion of pancreatic trypsin
leading to increased release of CCK, which causes pancreatic pain related to an increase in pancreatic enzyme
output. When pancreatic enzymes are administered orally,
there is more complete denaturing of the CCK-releasing
peptide, thereby diminishing the release of CCK. A metaanalysis of the six randomized, double-blind, placebocontrolled trials for the treatment of chronic pancreatitis
with pancreatic enzymes showed no benefit in improving
pain. The usefulness of antioxidants in pediatric CP has
not yet been evaluated. However antioxidant supplementation significantly reduces analgesic requirements in
adult patients with alcohol induced chronic pancreatitis.
Pain modulators such as fluoxetene, gabapentin and
pregabalin have been tried in adults. Steroids are associated with rapid relief of symptoms in autoimmune
Fig. 7 ERCP showing stone
extraction and stenting

Pancreatic enzyme replacement therapy (PERT) is beneficial


for symptomatic patients as well as cases of subclinical deficiency. The dose is 1000 lipase units/kg per meal and 500
lipase units/kg per snacks in children below 4 y of age; 500
lipase units/kg per meal and 250 lipase units/kg per snack for
children over 4 y of age.
Management of Diabetes
Based on the blood sugar levels, dietary advice and insulin are
given [28].
Endotherapy
ERCP is a well accepted form of therapy for a subset of children with large duct CP. Decompression procedures;
sphincterotomy, stone removal and stenting (Fig. 7) are all
possible in centres performing these advanced and specialized
procedures. If CP is due to pancreas divisum, minor
papillotomy and stent placement is done. Complications of
CP such as pancreatic pseudocyst and fistula can be managed
by endotherapy.
Surgery
When endotherapy is not feasible, surgery is the option.
Pancreaticojejunostomy, cyst drainage, Beger and Frey
procedures for CP [29] and pancreaticoduodenectomy
have been performed in children with CP and have resulted in good pain relief on long term follow up. Pediatric

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Indian J Pediatr (December 2016) 83(12):14591472

Total pancreatectomyIslet auto transplantation


(Pediatric TP-IAT) is now recognized as the definitive
therapy for HP/genetic pancreatitis especially for those
with a high life time risk of pancreatic cancer [30]. The
published results had revealed improved quality of life
(QOL) with >60 % patients requiring insulin.
Contributions MS, VB and GR: Collected data, reviewed the literature
and drafted the manuscript; SS, AB, SB, ND and MG: Collected data,
reviewed the literature and assisted in manuscript drafting. MS will act as
guarantor for the paper.
Compliance with Ethical Standards
Conflict of Interest None.
Source of Funding None.

12.
13.

14.

15.

16.
17.

18.
19.

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