CHRONIC PANCREATITIS

INTRODUCTION

 Chronic pancreatitis is a syndrome involving progressive inflammatory changes

in the pancreas that result in permanent structural damage, which can lead
to impairment of exocrine and endocrine function. This disorder contrasts
with acute pancreatitis, which is an acute inflammatory response to
pancreatic injury and is usually nonprogressive, although the two conditions
may overlap. Recurrent episodes of acute pancreatitis may lead to chronic
pancreatitis over time
 Chronic and acute pancreatitis can be distinguished by several features.

Chronic pancreatitis may be asymptomatic over long periods of time, can present
with a fibrotic mass, or there may be symptoms of pancreatic insufficiency
without pain. Acute pancreatitis is almost always painful.
The serum amylase and lipase concentrations tend to be normal in patients with
chronic pancreatitis, but are almost always elevated with acute disease.
Morphologically, chronic pancreatitis is a patchy focal disease characterized by a
mononuclear infiltrate and fibrosis. In contrast, acute pancreatitis diffusely
involves a large portion of the entire pancreas with a predominantly neutrophilic
inflammatory response
Etiology

 Alcohol abuse
 Cigarette smoking
 Hereditary pancreatitis — Hereditary pancreatitis accounts for a small subset of
cases of chronic pancreatitis. It is transmitted as an autosomal dominant trait with a
penetrance rate of 80 percent
 Ductal obstruction — Obstruction of the pancreatic duct from strictures secondary
to trauma, pseudocysts, calcific stones, or tumors can lead to chronic pancreatitis.
The histologic abnormalities that are induced may persist after relief of the
obstruction
 Tropical pancreatitis — Tropical pancreatitis is a condition of unknown etiology that
is seen commonly in south India and other parts of the tropics, where it is the most
common cause of chronic pancreatitis. Children are commonly affected, and often
die in early adulthood from endocrine and exocrine dysfunction
 Systemic disease — Systemic diseases implicated as causes of chronic
pancreatitis include cystic fibrosis, systemic lupus erythematosus , and
perhaps primary hyperparathyroidism and hypertriglyceridemia
 Idiopathic pancreatitis — The majority of cases of chronic pancreatitis that
are not related to alcohol abuse are idiopathic
PATHOGENESIS
 there are two consistent findings that are characteristic and may help explain the
pathogenesis of this disorder:
There is hypersecretion of protein which is not compensated for by an increase in ductal
bicarbonate secretion
The inflammatory changes seen on histologic specimens are patchy within the exocrine
pancreas
 Proteinaceous ductal plugs — One theory regarding the pathogenesis of chronic
pancreatitis suggests that increased secretion of pancreatic proteins causes
proteinaceous plugs to form within the interlobular and intralobular ducts. These plugs
may act as a nidus for calcification, leading to stone formation within the duct system.
The net result is the formation of ductal epithelial lesions which scar and obstruct the
ducts, thereby causing inflammatory changes and cell loss
 Ischemia — Ischemia has been proposed as another factor in the pathogenesis of chronic
pancreatitis. Is important in exacerbating or perpetuating rather than initiating disease
 Antioxidants — Patients with chronic pancreatitis are frequently nutritionally depleted,
particularly with regard to antioxidants such as selenium , vitamins C and E, and
methionine. An imbalance between a decrease in antioxidants and an increased demand
for them in "stressed cells" may lead to elevations in free radical formation, which is in
turn associated with lipid peroxidation and cellular impairment
 Autoimmune disorders — Chronic pancreatitis has been found in association with other
autoimmune diseases such as Sjögren's syndrome, primary biliary cirrhosis, and renal
tubular acidosis
CLINICAL MANIFESTATIONS

 The two primary clinical manifestations of chronic pancreatitis are abdominal

pain and pancreatic insufficiency
 Abdominal pain — Abdominal pain is a dominant feature of chronic
pancreatitis. The pain is typically epigastric, often radiates to the back, is
occasionally associated with nausea and vomiting, and may be partially
relieved by sitting upright or leaning forward. The pain is often worse 15 to
30 minutes after eating. Early in the course of chronic pancreatitis, the pain
may occur in discrete attacks; as the condition progresses, the pain tends to
become more continuous
 Pancreatic insufficiency — Patients with severe pancreatic exocrine dysfunction
cannot properly digest complex foods or absorb partially digested breakdown
products. Nevertheless, clinically significant protein and fat deficiencies do not
occur until over 90 percent of pancreatic function is lost
 Fat malabsorption — Steatorrhea usually occurs prior to protein deficiencies since
lipolytic activity decreases faster than proteolysis. The clinical manifestations of
fat malabsorption include loose, greasy, foul smelling stools that are difficult to
flush. Malabsorption of the fat soluble vitamins (A, D, E, K) and vitamin B12 may
also occur, although clinically symptomatic vitamin deficiency is rare
 Pancreatic diabetes — Glucose intolerance occurs with some frequency in chronic
pancreatitis, but overt diabetes mellitus usually occurs late in the course of
disease. Patients with chronic calcifying disease, particularly those who develop
early calcifications, may develop diabetes more frequently than those with chronic
noncalcifying disease
 Diabetes which develops in patients with chronic pancreatitis is usually insulin
requiring
DIAGNOSIS

 The diagnosis of chronic pancreatitis can be challenging since laboratory

studies and imaging procedures may be normal. In addition, patients may
have symptoms suggestive of chronic pancreatitis but in fact have pancreatic
carcinoma
 On the other hand, the classic triad of pancreatic calcifications, steatorrhea,
and diabetes mellitus strongly suggests the diagnosis, but are usually seen
together only in late, very advanced disease
 The diagnosis is confirmed if there are calcifications within the pancreas on
abdominal plain films or computed tomography (CT) scan, an abnormal
pancreatogram revealing beading of the main pancreatic duct or ectatic side
branches, or an abnormal secretin pancreatic function test
Laboratory studies
 Serum concentrations of amylase and lipase may be slightly elevated in patients
with chronic pancreatitis, but are more commonly normal for the following
reasons:
Chronic pancreatitis is a patchy, focal disease, leading to a minimal increase in
pancreatic enzymes within the blood.
There is frequently significant fibrosis, resulting in decreased abundance of these
enzymes within the pancreas
 Thus, serum measurements of amylase or lipase should be reserved only for the
diagnosis of acute pancreatitis and not chronic pancreatitis where they are
neither diagnostic nor prognostic
 The complete blood count, electrolytes, and liver function tests are typically
normal. Elevations of serum bilirubin and alkaline phosphatase suggest
compression of the intrapancreatic portion of the bile duct by edema, fibrosis,
or pancreatic cancer
 Markers of autoimmune chronic pancreatitis include an elevated ESR, IgG4,
rheumatoid factor, ANA, and anti-smooth muscle antibody titer
Imaging studies
 Imaging studies that may be useful in chronic pancreatitis include abdominal plain
films, transabdominal ultrasound, CT scan, magnetic resonance imaging
(MRI/MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and
endoscopic ultrasound
 Plain films — Calcifications within the pancreatic duct are present on plain film in
approximately 30 percent of patients with chronic pancreatitis. Calcium
deposition is most common with alcoholic pancreatitis, but is also seen in the
hereditary and tropical forms of the disorder; it is rare in idiopathic pancreatitis
 CT, MRI, and US — Transabdominal ultrasonography (US), CT scan, and MRI may
show calcifications, ductal dilatation, enlargement of the pancreas, and fluid
collections (eg, pseudocysts) adjacent to the gland . The sensitivity and specificity
of ultrasound for the diagnosis of chronic pancreatitis are 60 to 70 percent and 80
to 90 percent, respectively. The corresponding values for CT scanning are 75 to 90
and 85 percent, respectively. Magnetic resonance cholangiopancreatography
(MRCP) is becoming the diagnostic test of choice since it can demonstrate
calcifications and pancreatic duct obstruction consistent with chronic pancreatitis
 ERCP — ERCP has frequently been the test of choice for the diagnosis of
chronic pancreatitis when calcifications are not present on a plain film of the
abdomen and there is no evidence of steatorrhea. However, with the
advances in the quality of MRCP in visualizing the pancreatic ducts (with or
without secretin ), many centers are limiting the use of ERCP to cases with
the potential need of therapeutic intervention
 Characteristic beading of the main pancreatic duct and ectatic side branches
is diagnostic of chronic pancreatitis
 Endoscopic ultrasonography — Endoscopic ultrasonography (EUS) may be as
sensitive as ERCP or pancreatic function testing, but requires a highly skilled
gastroenterologist
 The most predictive endosonographic feature is the presence of stones.
Other suggestive features include: visible side branches, cysts, lobularity, an
irregular main pancreatic duct, hyperechoic foci and strands, dilation of the
main pancreatic duct, and hyperechoic margins of the main pancreatic duct
 GENETIC TESTING — In the past few years, genetic mutations have been
associated with chronic pancreatitis. These genes include the CFTR gene
responsible for cystic fibrosis, SPINK-1, which encodes for trypsin inhibitor,
and the PRSS-1 gene linked to hereditary pancreatitis
Treatment of chronic pancreatitis

 PAIN MANAGEMENT — The principal symptom of chronic pancreatitis is

abdominal pain. The pain may range from occasional postprandial discomfort
to debilitating persistent pain associated with nausea, vomiting, and weight
loss. Pain control can be difficult in some cases
 The first step in alleviating pain is to recognize the underlying cause of
chronic pancreatitis and to treat the underlying etiology to reduce progressive
pancreatic damage
 As a general rule, pain management should proceed in a stepwise approach
beginning with general recommendations followed by pancreatic enzyme
supplementation and then judicious use of analgesics. Patients with continued
symptoms may be candidates for more invasive options
 General recommendations — Many patients will improve with these measures
early in the course of illness, requiring only occasional non-opioid analgesics:
Cessation of alcohol intake — Cessation of alcohol intake is imperative,
particularly if this is the underlying etiology of pancreatitis. Abstinence can but
does not always lead to symptomatic improvement; however, patients with
alcohol-induced chronic pancreatitis who continue to drink have increased
mortality
Small meals and hydration — Small meals that are low in fat may also help to
varying degrees. Although the evidence is anecdotal, keeping patients well
hydrated may help prevent flares of pancreatitis
Cessation of smoking — Smoking may accelerate the progress of chronic
pancreatitis and may increase the risk of pancreatic cancer
 Pancreatic enzyme supplements — Pancreatic enzyme supplements to
suppress pancreatic exocrine secretion relieve pain in some patients.
Rationale for this therapy is based upon suppression of feedback loops in the
duodenum that regulate the release of cholecystokinin (CCK), the hormone
that stimulates digestive enzyme secretion from the exocrine pancreas
 High doses of the non-enteric coated enzymes were used in the clinical trials.
The two clinical trials that demonstrated improvement of pain with
pancreatic enzyme supplements used non-enteric coated preparations with
each meal, although the newer enteric-coated preparations have not been
adequately tested. Patients taking non-enteric coated pancreatic enzyme
supplements should also be treated with acid suppression (either with an H2
receptor blocker or a proton pump inhibitor) to reduce inactivation of the
enzymes from gastric acid
 Analgesics — Analgesia can be considered if pancreatic enzyme therapy fails
to control pain. Amitriptyline and nortriptyline have been shown to reduce
daily pain from neuropathic conditions
 Chronic opioid analgesia may be required in patients with persistent
significant pain. Long-acting agents such as morphine sulfate continuous
release or fentanyl patches are generally more effective than short acting
medications, which last only three or four hours
 Antioxidant therapy — There is insufficient evidence to support the use of
antioxidants in patients with chronic pancreatitis. Studies evaluating the
efficacy of antioxidant therapy in reducing pain in patients with chronic
pancreatitis have had conflicting results
Specialized approaches
 Other treatments have been evaluated in patients who were suffering from
severe pain refractory to the above measures:
Celiac nerve block — Percutaneous or endoscopic celiac nerve blocks with either
alcohol or steroids have had only limited success in chronic pancreatitis and
should be considered to be an unproven therapy
Endoscopic therapy — Although randomized trials are lacking, several reports
have suggested that endoscopic therapy aimed at decompressing an obstructed
pancreatic duct can be associated with pain relief in some patients
Extracorporeal shock wave lithotripsy — Pancreatic duct stones are found in
approximately 22 to 60 percent of patients with chronic pancreatitis. The stones
can lead to obstruction of the outflow of pancreatic secretions, causing increased
intraductal pressure. Because the pancreas is relatively noncompliant, the rise in
intraductal pressure can induce tissue hypertension and ischemia, which may be
a major factor causing pain in patients with chronic pancreatitis. Extracorporeal
shock wave lithotripsy (ESWL) creates millimetric fragmentation of pancreatic
stones, which has improved the results of endoscopic therapy and may have
additional indications in the treatment of patients with chronic pancreatitis
Surgery

 Surgery has generally been considered for patients who fail medical therapy,
or as first line therapy if there is suspicion of pancreatic cancer. Notably, up
to 15 percent of patients in surgical series had unrecognized pancreatic
cancer at the time of the procedure, underscoring the need for a firm
diagnosis prior to surgery
 When choosing among surgical options, one must consider the areas of the
pancreas that are involved in chronic pancreatitis and whether the pancreatic
duct is dilated
 Three surgical approaches have been described: decompression/drainage
operations; pancreatic resections; and denervation procedures. Some surgical
procedures employ a combination of these approaches
 Decompression — Decompression procedures have generally been
recommended for patients with refractory pain who have a dilated main
pancreatic duct. The normal pancreatic duct ranges from 2 to 4 mm in
diameter (most narrow in the tail, enlarging as it passes toward the ampulla).
A dilated duct (from a surgical standpoint) is one that would permit
anastomosis to a loop of jejunum
 Some surgeons will perform such a procedure in those with ducts that are only
5 to 6 mm in diameter, while others require dilation to around 10 mm
 However, pain relief persists for more than two years in only about 60
percent of patients. Patients with recurrent pain may require additional
surgery. The cause of pain recurrence is unclear. It may be related to
progressive pancreatic injury or inadequate drainage of secondary ducts
 Resection — This surgical approach involves resection usually of a portion of
the pancreas (typically the tail or head) and less commonly the entire
pancreas. Several specific procedures have been described including the
Whipple, pylorus-preserving pancreaticoduodenectomy, distal
pancreatectomy, total pancreatectomy, and a duodenal-preserving resection
of the pancreatic head
 Resection is considered in patients who have failed other forms of therapy
and in those who are not candidates for a drainage procedure (usually
patients with predominantly small duct disease)
 Denervation procedures — Most afferent nerves emanating from the pancreas
pass through the celiac ganglion and splanchnic nerves. Thus, interruption of
these nerve fibers has the potential to alleviate pain originating from the
pancreas. Interruption of these pathways also occurs with
pancreaticoduodenectomy and with resection of the pancreatic head, which
may in part explain the pain relief achieved with these procedures
STEATORRHEA
 Patients with severe pancreatic exocrine dysfunction cannot properly digest
complex foods or absorb digestive breakdown products
 Treatment of pancreatic exocrine insufficiency with pancreatic enzyme
supplementation in chronic pancreatitis is dependent on the size and nature
of the meal (fat content), the residual function of the pancreas (which may
be progressively lost), and the goals of therapy (elimination of steatorrhea,
reduction in the abdominal symptoms of maldigestion (bloating, diarrhea), or
improvement in nutrition, depending on the size and condition of the patient)
 Dietary modification — One approach in patients with steatorrhea is to
restrict fat intake. The degree of restriction depends upon the severity of fat
malabsorption; generally intake of 20 grams per day or less is sufficient.
Patients who continue to suffer from steatorrhea following fat restriction
require medical therapy
 Lipase supplementation — Since all of the digestive enzymes are secreted in
parallel, lipase can be used to titrate pancreatic enzyme supplement doses
GLUCOSE INTOLERANCE

 A trial of oral hypoglycemic agents followed by insulin therapy when the need
arises has been the line of management in these patients
Complications of chronic pancreatitis

 PSEUDOCYSTS — Pseudocysts develop in approximately 10 percent of patients

with chronic pancreatitis. They develop as a result of ductal disruptions
rather than from peripancreatic fluid accumulations that lead to pseudocyst
formation in the setting of acute pancreatitis
 Treatment — The indications for drainage of pseudocysts have evolved. It
used to be thought that drainage was indicated if they become greater than 6
cm in diameter or persisted for more than six weeks. However, that approach
was challenged by studies which found that pseudocysts can be safely
followed up to one year and up to 12 cm in size. Indications for drainage
include rapid enlargement, compression of surrounding structures, pain, or
signs of infection
 BILE DUCT OR DUODENAL OBSTRUCTION — Symptomatic obstruction of the
bile duct and/or duodenum develops in 5 to 10 percent of patients with
chronic pancreatitis. Postprandial pain and early satiety are characteristic of
duodenal obstruction, while pain and abnormal liver function tests (including
hyperbilirubinemia) are suggestive of a bile duct stricture. These
complications are most commonly seen in patients with dilated pancreatic
ducts; they are due to either inflammation and fibrosis in the head of the
pancreas or to a pseudocyst
 Treatment — Drainage should be performed if a pseudocyst is obstructing the
duct. Otherwise, a gastrojejunostomy or choledochoenterostomy is typically
performed. Endoscopic stenting may be an option for benign bile duct
strictures, but frequently requires several stent changes
 PANCREATIC ASCITES AND PLEURAL EFFUSION — Pancreatic ascites and
pleural effusion may develop following disruption of the pancreatic duct,
leading to fistula formation in the abdomen or chest, or rupture of a
pseudocyst with tracking of pancreatic juice into the peritoneal cavity or
pleural space. Analysis of fluid obtained at paracentesis or thoracentesis is
diagnostic; the amylase concentration in the fluid is very high, typically >1000
IU/L
 Treatment — Nonoperative therapies of pancreatic ascites and pleural
effusion include repeated aspiration, diuretics, octreotide (a long-acting
somatostatin analogue), or parenteral nutrition to decrease pancreatic
secretion
 SPLENIC VEIN THROMBOSIS — The splenic vein courses along the posterior
surface of the pancreas where it can be affected by inflammation leading to
thrombosis. Affected patients can develop gastric varices as a result of
associated portal hypertension. Splenectomy is usually curative for patients
who develop bleeding from gastric varices
 PSEUDOANEURYSMS — Pseudoaneurysm formation is a rare complication of
chronic pancreatitis. Affected vessels are in close proximity to the pancreas,
including the splenic, hepatic, gastroduodenal, and pancreaticoduodenal
arteries. Computed tomography (CT) scan (with and without contrast) or MRI
may detect the pseudoaneurysm, which appears as a cystic structure in the
pancreas. Doppler ultrasound can show blood flow within the pseudoaneurysm
 Mesenteric angiography permits confirmation of the diagnosis, and also
provides a means of therapy since embolization of the pseudoaneurysm can
be accomplished during the procedure. Surgery for bleeding pseudoaneurysms
is difficult and associated with a high morbidity and mortality
EPIDEMIOLOGY

 Overall prevalence ranges around 40 to 50 per 100,000 population in USA

 Prevalence is low below age of 35 years
The end

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