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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
Acute Pancreatitis
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
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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),
Category
Examples
Infections
Biliary
Medications
Idiopathic
Genetic
Structural pancreatic
disorders
Mechanical
Metabolic
Systemic disease
Nutritional
a
1461
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
Familial
Metabolic
3
5.5
2.1
7.2
8.5
7.7
6.9
4.2
Unpublished data
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
1462
Recovery and
regeneration
Mild
Pancreatitis
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
Recovery
Adequate CARS
Compromised
CARS
Multiorgan Dysfunction
Syndrome.
Pancreatic necrosis, abscess
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.
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
ii)
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)
1463
1464
Table 3
iii)
a
Parameter
2
3
4
5
7
8
iv)
ii)
v)
vi)
Prognosis
1465
Chronic Pancreatitis
Definition
Introduction
In India, tropical pancreatitis (TP), a form of chronic pancreatitis has been recognized as an important cause of morbidity
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Table 4
Method
Usefulness
Drawbacks
Contrast enhanced CT
Easily available
Parenchymal and ductal abnormality
can be visualised
MRCP
Non-invasive
Better sensitivity than CT for ductal abnormality
EUS
Secretin-EUS/MRCP
ERCP
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
CT Computed tomography; MRCP Magnetic resonance cholangio pancreatography; EUS Endoscopic ultrasound; ERCP Endoscopic retrograde
cholangio pancreatography; SOD Sphincter of Oddi
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].
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Level I investigations
LFT, Lipid profile, Calcium
Repeat USG abdomen
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
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
ii)
Category
Examples
Toxic-Metabolic
Idiopathic
Genetic
Autoimmune
Recurrent, Severe AP
Obstructive
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
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
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)
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+
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.
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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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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
Management
The goals of treatment in chronic pancreatitis are i) to relieve
acute or chronic pain ii) prevent recurrent attacks iii) treat
1471
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
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12.
13.
14.
15.
16.
17.
18.
19.
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