pathophysiology and management and treatment. newer insights

1.  CHRONIC PANCREATITIS: NEWER INSIGHTS
INTO PATHOPHYSIOLOGY AND MANAGEMENT
KUSH KUMAR BHAGAT
M.L.N MEDICAL COLLEGE ALLAHABAD

2.  Chronic pancreatitis is defined as permanent and
irreversible damage to the pancreas, with histologic
evidence of chronic inflammation, fibrosis, and
destruction of exocrine (acinar cell) and endocrine
(islets of Langerhans) tissue.

3.  Autopsy reports – 0.04-5%
 Retrospective studies – 3-9/100,000
 Prospective data
◦ among alcoholics – 8.2/yr/100,000;
 Alcohol abuse – 2/3 of causes
 Mortality 3.6 X age matched control.

4.  Incompletely understood
 Alcoholic chronic pancreatitis, being the most
common form, has received the most attention.
 No single theory explains adequately why only about
10% of heavy alcohol users develop chronic
pancreatitis
 In most studies, alcohol abuse accounts for two
thirds of all cases of chronic pancreatitis.

5.  Alcohol is metabolized by the liver and the pancreas.
In the liver the main end product of oxidative alcohol
metabolism is acetaldehyde.
 In the pancreas, an alternative pathway produces
fatty acid ethanol esters (FAEEs).
 Alcohol and its metabolites like FAEE, have direct
injurious effects on pancreatic acinar cells.
 Alcohol and its metabolites appear to stimulate the
pancreatic stellate cell. These cells appear to be the
final common pathway for fibrosis.
 When activated, they assume a stellate or
myofibroblastic appearance, express smooth muscle
actin, and lose the lipid droplets.

6.  This activation is necessary for the cell to begin to
secrete extracellular matrix and produce fibrosis
within the gland.
 Activation of pancreatic stellate cells is likely
occurring via at least two mechanisms in alcoholic
chronic pancreatitis: directly by alcohol and its
metabolites and indirectly by cytokines induced by
cellular necrosis.

7.  Chronic alcohol use
 acinar and ductal cell
 protein rich pancreatic juice, low in volume and
HCO3
 formation of protein precipitates – plug
 calcification of ppt. – ductal stone formation
 duct obstruction
 parenchymal damage
 Pancreatic ductal stone are seen in alcoholic,
tropical, hereditary and idiopathic pancreatitis.

8.  The toxic-metabolic hypothesis, focuses primarily on
the role of alcohol and its metabolites (or other toxins)
and their ability to damage the pancreas and activate
pancreatic stellate cells.
 Direct injurious effect on acinar and ductal cells
 Increased membrane lipid peroxidation (oxidative
stress), free radical production
 Activation of pancreatic stellate cells (alcohol,
cytokines) – begin to secrete extracellular matrix and
produce fibrosis.

9.  The occurrence of repeated episodes of acute
pancreatitis with cellular necrosis or apoptosis
eventually leads to the development of chronic
pancreatitis as the healing process replaces necrotic
tissue with fibrosis.
 The concept that multiple clinical or subclinical
attacks of acute pancreatitis lead to chronic
pancreatitis is certainly being reinforced by
observations in both animal models and in humans.

10.  Multiple mutations have been identified in several
forms of chronic pancreatitis, suggesting a complex
genetic background that provides the relative
predisposition to develop chronic pancreatitis.
 Mutations in the cystic fibrosis transmembrane
conductance regulator (CFTR), cationic trypsinogen
gene (PRSS1 gene), serine protease inhibitor Kazal
type 1 (SPINK1) a trypsin inhibitor have been
identified.
 CFTR - Cystic fibrosis is associated with abnormalities
of HCO3 secretion, ductal dilatation, ppt formation,
pancreatic atrophy. Seen in 50% of idiopathic CP.

11.  PRSS1 - Once trypsinogen is activated to trypsin, it
becomes resistant to inactivation and activate other
proenzymes leading to episodes of acute
pancreatitis. The mutant trypsin activate other
proenzymes and produce clinical or subclinical
episodes of acute pancreatitis, ultimately leading to
chronic pancreatitis in affected patients.
 SPINK1 - Seen in pediatric ICP, hereditary P, TP; but
not in chronic alcoholic pancreatitis. It is a trypsin
inhibitor. Mutation of this gene leads to non
inhibition of trypsin producing clinical or subclinical
episodes of acute pancreatitis.

12. Abbreviations: DBTC, dibutylin dichloride

13.  Alcohol is the cause of at least 70% of all cases of
chronic pancreatitis
 The risk of alcoholic chronic pancreatitis increases
with rising alcohol use, but there is no true threshold
value below which the disease does not occur.
 In nearly all patients, at least 5 years (and in most
patients more than 10 years) of intake is required
before the development of chronic pancreatitis.
 Only 3% to 15% of heavy drinkers ultimately develop
chronic pancreatitis, suggesting an important
cofactor for development of chronic pancreatitis
which include genetic polymorphisms and tobacco.

14.  Tropical pancreatitis is one of the most common
forms of chronic pancreatitis in certain areas of
southwest India.
 Tropical pancreatitis is generally a disease of youth
and early adulthood, with a mean age at onset of 24
years.
 Tropical pancreatitis accounts for about 70% of all
cases of chronic pancreatitis in southern India,
whereas alcohol is a more dominant cause in the
north.
 The disease classically manifests as abdominal pain,
severe malnutrition, and exocrine or endocrine
insufficiency.

15.  One striking feature is the propensity to diabetes,
and endocrine insufficiency appears to be an
inevitable consequence of tropical chronic
pancreatitis (often classified as a specific cause of
diabetes called fibrocalculous pancreatic diabetes).
 Pancreatic calculi develop in more than 90% of
patients.
 The pathology is characterized by large intraductal
calculi, marked dilation of the main pancreatic duct,
and gland atrophy.
 The pathophysiology of tropical pancreatitis is
unknown, a number of genetic mutations have been
identified, with mutations in the SPINK1 and
chymotrypsinogen genes being most common.

16.  Environmental triggers for the disease that have
been proposed include protein-calorie malnutrition,
deficiencies of trace elements and micronutrients
coupled with oxidative stress, cyanogenic glycosides
present in cassava (tapioca—a main dietary
component).

17. Clinical features of auto immune pancreatitis

18.  Idiopathic pancreatitis accounts for 10% to 30% of all
cases of chronic pancreatitis.
 Two forms, an early-onset type that manifests in the
late second or third decade of life and a late-onset
form that appears in the sixth or seventh decade of
life.

19. ABDOMINAL PAIN
 Abdominal pain is the most common symptom.
 Pain is most commonly described as being felt in the
epigastrium, often with radiation to the back.
 Pain is typically deep, boring and penetrating and is
often associated with nausea and vomiting.
 Pain may be relieved by sitting forward or leaning
forward, by assuming the knee-chest position on one
side, or by squatting and clasping the knees to the
chest.

20.  Severe pain decreases appetite and limits food
consumption, contributing to weight loss and
malnutrition.
 Intractable pain is the most common reason for
hospitalization and for surgery in patients with
chronic pancreatitis.

21. STEATORRHEA
 The human pancreas has substantial exocrine
reserve. Steatorrhea does not occur until pancreatic
lipase secretion is reduced to less than 10% of the
maximum output.
 Steatorrhea is therefore a feature of far-advanced
chronic pancreatitis, in which most of the acinar cells
have been injured or destroyed.
 Affected patients may present with diarrhea and
weight loss. Some patients may note bulky foul-
smelling stools.

22.  With very long follow-up, approximately 50% to 80%
of patients with chronic pancreatitis eventually have
exocrine insufficiency.
 Deficiencies of fat-soluble vitamins may develop in
patients with chronic pancreatitis and steatorrhea.
 Significant vitamin D deficiency and osteopenia and
osteoporosis occur in patients with chronic
pancreatitis.

23. DIABETES MELLITUS
 Like exocrine insufficiency, endocrine insufficiency is
a consequence of long-standing chronic pancreatitis
and is especially common after pancreatic resection
and in tropical (fibrocalcific) pancreatitis.
 Islet cells appear to be relatively resistant to
destruction in chronic pancreatitis.
 About half of patients with chronic pancreatitis who
develop diabetes will require insulin.
 Unlike type 1 diabetes, insulin-producing beta cells
and glucagon-producing alpha cells are injured.

24.  This combination increases the risk of prolonged and
severe hypoglycemia with overvigorous insulin
treatment, owing to the lack of a compensatory
release of glucagon
 Ultimately, 40% to 80% of patients with chronic
pancreatitis have diabetes after long follow-up.

25. Examination:
 During an attack, patients may assume a
characteristic position in an attempt to relieve their
abdominal pain (leaning forward).
 Occasionally, a tender fullness or mass may be
palpated in the epigastrium, suggesting the presence
of a pseudocyst or an inflammatory mass in the
abdomen.

26.  Patients with advanced disease (ie, patients with
steatorrhea) exhibit decreased subcutaneous fat,
temporal wasting, sunken supraclavicular fossa, and
other physical signs of malnutrition.
 Jaundice may be seen in the presence of coexistent
alcoholic liver disease or bile duct compression
within the head of the pancreas.
 A palpable spleen may also rarely be found in
patients with thrombosis of the splenic vein as a
consequence of chronic pancreatitis or in patients
with portal hypertension due to coexistent chronic
liver disease.

27.  The diagnostic tests are usually separated into those
that are designed to detect abnormalities of
pancreatic function and those that detect
abnormalities of pancreatic structure.

29.  Abnormalities of pancreatic structure or function
may take years or even decades to develop, or may
not develop at all.
 All available diagnostic tests are most accurate in far-
advanced disease, when obvious functional or
structural abnormalities have developed.
 Conversely, all diagnostic tests are less accurate in
less advanced or early chronic pancreatitis.
 Functional abnormalities in chronic pancreatitis
include exocrine insufficiency (maldigestion and
steatorrhea), and endocrine insufficiency (diabetes
mellitus).

30.  Structural abnormalities that can be diagnostic
include changes within the main pancreatic duct
(dilation, strictures, irregularity, pancreatic ductal
stones) or pancreatic parenchyma (lobularity of the
gland, alterations in echogenicity, cysts, enlargement
or atrophy, and others).

31.  Tests of pancreatic function can be divided into those
that directly measure pancreatic function by
measuring the output of enzymes or bicarbonate
from the pancreas and those that measure the
released enzymes indirectly (through its action on a
substrate or its level in blood or stool)
Direct Tests includes
 Direct hormonal stimulation by secretin or
cholecystokinin or both using oroduodenal tube,
Using endoscopy or Magnetic resonance
cholangiopancreatography with secretin stimulation

32. Indirect Tests
 Serum trypsinogen can be measured in blood and
provides a rough estimation of pancreatic function.
Very low levels of serum trypsinogen (<20 ng/mL)
can be seen in patients with advanced chronic
pancreatitis.
 Low concentrations of chymotrypsin or elastase in
stool can reflect inadequate delivery of these
pancreatic enzymes to the duodenum. Both can be
measured on random samples of stool.
 Faecal Fat Excretion : Maldigestion of fat occurs after
90% of pancreatic lipase secretary capacity is lost.

33.  Abdominal x-ray: The finding of diffuse (but not
focal) pancreatic calcifications on plain abdominal
films is quite specific for chronic pancreatitis.
 Focal calcifications may be seen in cystic and islet cell
tumours of the pancreas, and in peripancreatic
vascular calcifications.
 Pancreatic calcifications are observed in
approximately 30% of cases.

35. ABDOMINAL ULTRASOUND: Ultrasonographic findings
indicative of chronic pancreatitis include dilation of
the pancreatic duct, pancreatic ductal stones, gland
atrophy or enlargement, irregular gland margins,
pseudocysts, and changes in the parenchymal echo
texture.

36.  COMPUTED TOMOGRAPHY SCAN: Pseudocysts,
calcifications and pancreatic duct dilatation can be
observed in chronic pancreatitis.

39. In this CT scan of abdomen there is evidence of markedly dilated pancreatic duct with
calcification

41. MAGNETIC RESONANCE CHOLANGIO
PANCREATOGRAPHY (MRCP)
 Noninvasive
 It can assess both pancreatic parenchyma and ducts
at the same time.
 It can detect pancreatic duct dilatation, ductal
narrowing and filling defects.

42. Chronic pancreatitis on MRCP; dilated duct with filling defects suggestive of pancreatic ductal
calculi

43. ERCP:
 Provides the most accurate visualization of the
pancreatic ductal system and has been regarded as
the gold standard for diagnosing chronic pancreatitis.
 Findings include characteristic “chain of lakes”
beading of the main pancreatic duct, and intraductal
filling defects.

46.  ENDOSCOPIC ULTRASOUND (EUS): To diagnose
chronic pancreatitis requires the presence of at least
5 criteria of the followings:

48. Treatment consists of managing:
1. ABDOMINAL PAIN
2. STEATORRHEA
3. DIABETES MELLITUS

49. ABDOMINAL PAIN
 Pain is the most common and most debilitating
symptom.
 The initial evaluation of pain should focus on
identifying associated conditions for which specific
therapy exists.
 These conditions can include pancreatic pseudocyst,
duodenal compression, superimposed pancreatic
carcinoma and gastroparesis.

50. VARIOUS MODALITIES OF TREATMENT OF ABDOMINAL
PAIN
 MEDICAL TREATMENT
1. Analgesics
2. Cessation of Alcohol and Tobacco
3. Antioxidants
4. Pancreatic Enzyme Therapy
5. Octreotide
 ENDOSCOPIC THERAPY
1. Pancreatic Duct Sphincterotomy
2. Stent Placement
3. Pancreatic Duct Stone Removal
4. Combined Endoscopic Therapy

51.  SURGICAL THERAPY
 Drainage procedure: -
1. Lateral pancreaticojejunostomy (Puestow operation)
 Resective procedures :
1. Whipple’s procedure
2. Distal pancreatectomy
3. Total pancreatectomy

52.  Analgesics: The majority of patients with chronic
pancreatitis require some form of analgesia. Some
patients’ pain may be managed with
acetaminophen or aspirin, but most require more
potent narcotic agents.
 Cessation of Alcohol and Tobacco: Cessation of
alcohol consumption and tobacco smoking are
important. In early-stage pain relief can occur after
abstinence from alcohol, but, in advanced stages,
abstinence does not always lead to symptomatic
improvement.
 Pancreatic Enzyme Therapy: The use of pancreatic
enzymes to reduce pain is based on the ability of
these agents to reduce pancreatic secretion.

53.  Antioxidants: Patients with chronic pancreatitis
have evidence of oxidant stress and reduced
antioxidant capacity.
Oxidant stress is a strong activator of pancreatic
stellate cells. There are now several small
randomized trials of a mixture of antioxidants
(selenium, beta-carotene, vitamin C, vitamin E)
that indicate that this therapy reduces the pain of
chronic pancreatitis.
 Octreotide: Octreotide decreases pancreatic
secretion and reduces circulating CCK levels. This
agent therefore might reduce pain via the same
mechanisms invoked for the use of enzymes for
pain.

54. Endoscopic treatment:
 Papillary stenosis: In appropriately selected patients,
a pancreatic duct sphincterotomy will facilitate
drainage, reduce ductal pressures, and may help
alleviate pain.
 Pancreatic duct strictures: performing a pancreatic
sphincterotomy, dilating the stricture, and placing a
stent.
 Pancreatic duct stones: Requires a pancreatic duct
sphincterotomy and stricture dilation to enable their
extraction.

56. Surgical treatment:
I-Pancreatic duct drainage: In patients with a dilated
pancreatic duct, pancreaticojejunostomy is
indicated.
II-Pancreatic resection: If the disease is limited to the
head of the pancreas, a Whipple operation
(pancreaticoduodenectomy) can produce good
results.
 In patients with intractable pain and diffuse disease
with nondilated ducts, a subtotal or total
pancreatectomy can be offered.

57. III-Total pancreatectomy and islet autotransplantation:
 In selected patients, the long-term morbidity caused
by diabetes following total pancreatectomy can be
avoided.
 This involves harvesting the islets from the resected
pancreas and injecting them into the portal system,
which then lodges them in the liver.

58. IV- Drainage of pseudocyst:
The indications include rapid enlargement,
compression of surrounding structures (duodenal,
biliary obstruction or vascular occlusion), pain, or
signs of infection and abscess formation, suspected
malignancy, hemorrhage and intraperitoneal
rupture.

59.  Abdominal pain –
 R/o ddx – US (no mass) –
 3-4wk pancreatic enzyme –
 (4-8tablets at meals and at bed time) –
 minimal change CP pt get relief of pain –
 if not, ERCP/EUS –
 pseudocyst, obstruction, dilated duct – surgery,
octreotide –
 If No response
 subtotal pancreatic resection

60. STEATORRHEA
 Fat maldigestion is the principal clinical problem. It
has been estimated that 30,000 IU of lipase
delivered to the intestine with each meal should be
sufficient to eliminate steatorrhea.
 This corresponds to approximately 10% of the
normal pancreatic output of lipase.
 The goal of managing steatorrhea is to administer
30,000 IU of lipase in the prandial and postprandial
portions of each meal.

61.  If non–enteric-coated preparations are chosen,
concomitant suppression of gastric acid with a
histamine-2 (H2) receptor antagonist or proton pump
inhibitor is necessary
 There are several explanations for failure of enzyme
therapy for steatorrhea.
 The most common is inadequate dose, generally due
to patient noncompliance with the number of pills
that must be taken.

62. DIABETES MELLITUS
 Diabetes mellitus is an independent predictor of
mortality in patients with chronic pancreatitis.
 Ketoacidosis is distinctly unusual.
 Insulin is often needed and patients with chronic
pancreatitis tend to have lower insulin requirements
than patients with type 1 diabetes mellitus.
 Overvigorous attempts at tight control of blood
glucose value are often associated with disastrous
complications of treatment-induced hypoglycemia.

63.  DM – but end organ damages of DM and DKA are
rare
 Non DM retinopathy (peripheral) due to Vit A and Zn
defc.
 Pleural, peritoneal and pericardial effusions with
high amylase
 GI bleeding – PUD, gastritis, pseudocyst, varies (SV
thrombosis)
 Cholestasis, icterus, cholangitis, biliary cirrhosis
 Fistula – internal or external
 Subcutaneous fat necrosis – tender red nodules on
the shins
 Pseudocyst
 Pancreatic carcinoma – 4% life time risk
 Narcotic addiction

64. Prognosis:
 The prognostic factors associated with chronic
pancreatitis are age at diagnosis, smoking, continued
use of alcohol, and the presence of liver cirrhosis.
 The overall survival rate is 70% at 10 years and 45%
at 20 years.
 The risk of developing pancreatic cancer is
approximately 4% at 20 years.