Lecture 19 pancreatitis - Pathology

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Pancreatitis
Lecture 19
Pancreas Physiology & Anatomy

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 The pancreas is a narrow retroperitoneal structure, 15 cm long gland that lies posterior
and inferior to the stomach on the left side of the abdominal cavity.
 The pancreas extends laterally and superiorly across the abdomen from the curve of the
duodenum to the spleen.
 The head of the pancreas, which connects to the duodenum, is the widest and most
medial region of the organ.
 Extending laterally toward the left, the pancreas narrows slightly to form the body of the
pancreas.
 The tail of the pancreas extends from the body as a narrow, tapered region on the left side
of the abdominal cavity near the spleen.
 The pancreas is a glandular organ in the upper abdomen, it serves as two glands in one:
 A digestive exocrine gland: excretes enzymes to break down the proteins, lipids,
carbohydrates, and nucleic acids in food.
 A hormone-producing endocrine gland: (Will be discussed in Diabetes Mellitus)
o The islets of Langerhans have different cells types that are responsible for the
synthesis and secretion of : insulin (B cell), glucagon (A cell), and somatostatin (D
cell) and amylin (amylin cell) that together modulate energy metabolism; and
pancreatic polypeptide (PP cell), which is a regulator of GI function.
 Both of these diverse functions are vital to the body’s survive
Endocrine Function
Pancreatic Enzymes Exocrine Function
 Amylase (which digests carbohydrates): it splits molecules of Starch or Glycogen into
Disaccharides.
 Lipase (which digests fats); it breaks Triglycerides molecules into Fatty acids &
Monoglycerides.
 Protease (which digests protein) such as Trypsinogen . Proteases are the most abundant
class of enzymes.
 Bicarbonate is also produced in large amounts to neutralize the acid produced by the
stomach.
 Trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase and
prophospholipase A2 are stored in the pancreas and secreted into the duodenal lumen as
Inactive proenzymes forms.
 If these enzymes were active in the pancreas, they would digest the pancreatic gland.
 Amylase and Lipase are stored and secreted in their active forms. The active forms of
these enzymes (amylase and lipase) have no effect on the pancreatic gland because it
does not contain starch or triglyceride.

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Pancreatitis Overview
Pancreatitis is classified as either acute or chronic.
 Acute Pancreatitis refers to an acute inflammation that resolves both clinically and
histologically.
o The acute inflammatory process of the pancreas that may also involve peripancreatic
tissues and/or remote organ systems (involvement of other regional tissue).
o Severe pancreatitis is characterized by the presence of organ failure (including
Shock: systolic blood pressure <90 mm Hg , Pulmonary insufficiency: Pao2 ≤60
mm Hg, Renal failure: serum creatinine >2 mg/ld., Gastrointestinal bleeding: >500
mL/24 hr ) and/or
o The presence of local complications (pancreatic necrosis, abscess or pseudocyst).
 Chronic Pancreatitis is characterized by histologic changes that persist even after the
cause has been removed. The histologic changes in chronic pancreatitis are irreversible and
tend to progress, resulting in serious loss of exocrine and endocrine pancreatic function and
deterioration of pancreatic structure.
 When the pancreatic fluid extravasates out of the pancreas, it collects in the anterior
pararenal space and other areas. This is acute fluid collection.
 If it persists for > 4 weeks, it becomes encapsulated in a wall and develops into a pseudocyst.
 Pancreatic necrosis is defined as one or more areas of nonviable pancreatic parenchyma
and is usually associated with peripancreatic fat necrosis.
 2 types of pancreatitis
o Interstitial (80%) (edematous) mild, self-limiting (3-5 days), fluid accumulation
with swelling and edema
o Necrotizing (20%) (death of tissue) hemorrhagic with cellular death and systemic
complications

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 Prevalence: There are >100,000 hospital admissions for pancreatitis in the U.S. per year.
 Approximately 2,000 of these patients will die from severe pancreatitis.
Acute Pancreatitis Causes
 Gallstones: 45%
 Alcohol abuse: 35% Idiopathic: 10%
 Other 10%
 Drugs: azathiprine, thiazide, valproate, sulfasalazine, bactrim, pentamidine,
tetracycline
 Blunt and penetrating Trauma
 Postoperative (particularly of stomach and biliary tract and after coronary artery
bypass grafting), ERCP.
 Hyperlipidemia (hypertriglyceridemia), Hypercalcemia &
Hyperparathyroidism
 Infectious agents: mumps, Coxsackie B, CMV, Candida, HIV, salmonella,
shigella, E. coli, legionella, leptospira
 Ductal obstruction , Structural abnormalities of the pancreatic duct (eg,
stricture, cancer, pancreas divisum) & Structural abnormalities of the common
bile duct and ampullary region (eg, choledochal cyst, sphincter of Oddi
stenosis),
 Hereditary, Vascular disease (especially severe hypotension) & Renal
transplantation.

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Pancreatitis Pathophysiology
 Normally, the pancreatic enzymes are stored in an inactive precursor form intracellularly
(within the acinar cell).
 In acute pancreatitis, pancreatic proenzymes are exposed to the lysosomal enzymes such
as Cathepsin B (an enzymatic protein belonging to the peptidase “or protease” families),
which activate trypsinogen to trypsin.
 This initiates premature activation of other pancreatic enzymes and autodigestion.
 The activated enzymes enter the systemic circulation and cause widespread systemic
toxicity.
 Recent evidence focuses on the role played by leukocytes and their products such as
cytokines, enzymes and nitric oxide in the mediation of systemic and local inflammation.
Acute Pancreatitis signs and symptoms
 Typical symptoms of acute pancreatitis are :
o Epigastric pain (95%) usually radiating to the back,
o Nausea and vomiting (80%).
o Symptoms persist for several hours without relief.
 Physical examination reveals
o Epigastric tenderness,
o Guarding and reduced bowel sounds due to ileus.

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 Ecchymosis in the flanks (Grey Turner sign : reddish-purple or greenish-brown color to
the flank area (the area between the ribs and the hip bone) or
 in the periumbilical region (Cullen's sign :bluish color around the navel) reflecting the
extravasation of hemorrhagic pancreatic exudate to these areas.
 Rarely: Nodules of subcutaneous fat necrosis may be found on the extremities.

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Laboratory Diagnosis (Pancreatic Enzymes)
Diagnosis of acute pancreatitis relies on at least a three-fold elevation of amylase or lipase in the
blood.
Serum Amylase (30-180 IU/L)
 It rises within 6 to 12 hours of onset (half-life, 10 hours).
 The serum amylase is usually increased on the first day of symptoms, and it remains
elevated for three to five days in uncomplicated attacks.
 Sensitivity is greater than 85%, the serum amylase may be normal or minimally elevated
in fatal pancreatitis, during a mild attack or an attack superimposed on chronic
pancreatitis, or during recovery from acute pancreatitis also in hypertriglyceridemia-
associated pancreatitis.
 Hyperamylasemia is not specific for pancreatitis because it occurs in: intestinal
ischemia, renal insufficiency, small bowel obstruction, parotitis & macroamylasemia (is
a benign condition caused by circulating macroamylase complexes of pancreatic or
salivary amylase bound to plasma proteins, which cannot be cleared by the renal
glomeruli).
Serum Lipase (0-160 IU/L)
 The sensitivity of serum lipase is similar to that of serum amylase and is between 85%
and 100%.
 Lipase may have greater specificity for pancreatitis than amylase.
 Serum lipase always is elevated on the first day of illness and remains elevated longer
than does the serum amylase.
Secretin-pancreozymin (CCK) test
 Secretin leads to increased output of pancreatic juice and HCO3; CCK leads to increased
output of pancreatic enzymes.
 Sensitive enough to detect occult disease; involves duodenal intubation and fluoroscopy
only role in acute on chronic pancreatitis.
Other blood test
 White blood cell count -Increased
 Monitor daily : Hematocrit->44 show poor prognosis, Serum Creatinine and serum
electrolytes
 Other laboratory features include hyperglycemia, hypocalcemia, hyperbilirubinemia and
mild elevations in serum alanine aminotransferase (ALT) and alkaline phosphatase.
 A bilirubin >two and half times the normal and a serum ALT > twice the normal are
suggestive of gallstone pancreatitis.

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 MCV- Alcoholic patients tend to have a higher MCV.
 Serum triglyceride levels- increase in acute pancreatitis, but also with alcohol use,
uncontrolled diabetes mellitus, or defective triglyceride metabolism
Acute Pancreatitis Diagnosis
AP established by the presence of 2 of the 3 following criteria:
 Abdominal pain consistent with the disease
 Serum amylase and / or lipase greater than three times the upper limit of normal
 Characteristic findings from abdominal imaging
 Ultrasound –Most useful initial test for common bile duct dilation and gallstones
 Contrast CT Scan
o Not necessary for diagnosis of acute pancreatitis
o May help identify etiology in rare instances (tumor)
o Useful to assess complications-fluid collections or pancreatic necrosis
 ERCP’s are done frequently for both diagnostic and treatment reasons, especially with
gall stones as the responsible cause can create additional problems with manipulation and
trauma
Acute Pancreatitis Treatment
1) Goals of treatment include:
 Supportive care,
 Limitation of systemic complications and
 Prevention of pancreatic necrosis or abscess formation.
2) Treatment of acute interstitial pancreatitis:
 Is supportive with intravenous fluids and
 Adequate analgesia.
3) A nasogastric tube is needed only for vomiting or for gastric decompression in ileus.
4) Refeeding is instituted once the pain subsides and the patient is hungry.
5) Treatment of severe pancreatitis requires:
 Aggressive fluid resuscitation,
 Appropriate respiratory care,
 Cardiovascular support including maintenance of Hematocrit around 30 (for adequate
microperfusion of the pancreas)

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 Pain relief. (Morphine ,Hydromorphone-Dilaudid®-& Fentanyl)
6) Nutritional support with parenteral nutrition may be necessary.
7) Endoscopic sphincterotomy within 72 hours was shown to reduce morbidity—but not
mortality—of severe gallstone pancreatitis in the elderly.
8) Use of antibiotics: In acute pancreatitis, antibiotics are used for two major indications.
 The Prophylactic use of antibiotics may reduce the number of pancreatic infections and
non-pancreatic infections (UTI), but are usually reserved for those with severe disease.
 Antibiotics are used Therapeutically for the treatment of cholangitis or other infections(
Infected Necrosis, Pancreatic Abscess, Infected Pseudocyst)
9) If there is no improvement in the first 7-14 days, then pancreatic necrosis is suspected.
– If necrosis is seen, a CT-guided percutaneous aspiration should be performed and
sent for gram stain and culture to rule out infection.
10) If infection is documented, then surgical debridement should be performed.
11) In the absence of infection, choices include medical therapy or debridement of sterile
necrosis.
12) Severe pancreatitis may also be complicated by pseudocyst or pancreatic abscess formation.
– Pseudocysts occur in approximately 20% of cases and should be drained only if causing
symptoms.
– Pancreatic abscesses are collections of pus that usually occur 4 to 6 weeks after the onset
of acute pancreatitis. Treatment options include surgical drainage and percutaneous
catheter drainage, which are equally effective.

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 AST, aspartate aminotransferase; BUN, blood urea nitrogen; LDH, lactate dehydrogenase;
Pao2, partial pressure of arterial carbon dioxide; WBC, white blood cell.
 Sequestration :Loss of blood or of its fluid content into spaces within the body so
 that it is withdrawn from the circulating volume, resulting in hemodynamic impairment,
hypovolemia, hypotension, and reduced venous return to the heart.
 The table lists 11 signs that Ranson and colleagues identified as early prognostic criteria
that predict the severity of outcome in acute pancreatitis.
 These signs are obtained during the first 48 hours of acute pancreatitis.
 Mortality increases with an increase in the number of abnormal values in the list of
Ranson’s early prognostic criteria.
 Most of the patients who develop a severe disease outcome have 3-5 abnormal Ranson
early prognostic criteria.
 5% mortality risk with <2 signs
 15-20% mortality risk with 3-4 signs
 40% mortality risk with 5-6 signs
 99% mortality risk with >7 signs
Chronic pancreatitis Overview
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.
Prevalence:
 The true prevalence of the disease is not known; it is estimated to range from 0.04% to
5% of the general population.
 In developed countries, 60% to 70% of chronic pancreatitis is due to alcohol abuse.
 It is most frequent in men, with a peak incidence between 35 to 45 years of age.
 Tropical pancreatitis also called Fibrocalculous pancreatitis, on the other hand, occurs
in young children in areas of Africa and Asia.
 Idiopathic pancreatitis, which accounts for 30% of cases of chronic pancreatitis, occurs
in two distinct subgroups of patients—a younger group 15-30 years of age and an older
group 50-70 years of age.
Chronic pancreatitis Pathophysiology
 The underlying pathophysiology of chronic pancreatitis involves basal hypersecretion of
pancreatic proteins with a concomitant decrease of protease inhibitors.
 This changes the pancreatic juice biochemical composition and leads to protein plugging
and pancreatic stone formation.

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 Blockage of small ducts results in:
o Premature activation of pancreatic enzymes with development of acute
pancreatitis. This leads to permanent damage of the gland over time.
 One of the more popular hypotheses is that chronic pancreatitis and especially the fibrotic
response arises from the summation episodes of acute pancreatitis.
Chronic pancreatitis Etiology
 The most common cause is alcohol consumption
 Alcohol abuse: 70%
 Idiopathic: 20%
 Other 10%
 Tropical pancreatitis
 Hereditary pancreatitis
 Hyperparathyroidism
 Cystic fibrosis & Pancreas divisum
 Pancreas divisum is a congenital anomaly in the anatomy of the ducts of the pancreas in
which a single pancreatic duct is not formed, but rather remains as two distinct dorsal and
ventral ducts.

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Cystic fibrosis
 Cystic fibrosis is a genetic disorder that affects function of exocrine glands throughout
the body.
 Caused by a defect in the CFTR gene that provides instructions for making a cell
membrane–associated protein called the cystic fibrosis transmembrane conductance
regulator (CFTR). This protein is embedded in lipid membrane of epithelial cells, sweat
glands, pancreas and lungs.
 Lack of this protein results in production of overly thick mucus that cannot be cleared
from the respiratory passages and accumulates to form mucous plugs.
 In this subset of patients (Chronic pancreatitis), there is no evidence of cystic fibrosis
lung disease.

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Chronic pancreatitis signs and symptoms
 After a subclinical phase, recurrent attacks of pain are noted and symptoms of
exocrine and endocrine deficiency appear.
 Patients commonly present with abdominal pain and weight loss.
 Abdominal pain may be due to:
o May involve pancreatic inflammation,
o Increased intrapancreatic pressure,
o Neuroinflammation or
o Extrapancreatic causes such as obstruction of the common bile duct or
duodenum.
 Weight loss during the initial course of the disease is due to:
o Decreased caloric intake for fear of precipitating abdominal pain.
o Later, as the gland is progressively destroyed, patients develop fat
malabsorption.
o Diabetes develops when more than 80% of the gland has been destroyed.

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 The physical examination may reveal epigastric tenderness during acute exacerbations.
Otherwise, it may be entirely normal in mild chronic pancreatitis.
 In advanced cases, there may be an abdominal mass from a pseudocyst or pancreatic
cancer or splenomegaly from splenic vein thrombosis.
Chronic pancreatitis Clinical Features
1) 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.
 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.
2) Steatorrhea
 Steatorrhea is not a really a condition but a symptom in which fecal matter is frothy,
foul-smelling and floats because of a high fat content.
 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.

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 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.
3) 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.
 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.
Chronic pancreatitis Diagnosis
 Is based on history and confirmed by laboratory and imaging studies.
 Serum amylase and lipase may be normal or slightly elevated.
 In 5% to 10% of the patients with chronic pancreatitis, compression of the distal common
bile duct leads to elevation of serum bilirubin and alkaline phosphatase.
 Fat malabsorption leads to elevated fecal fat excretion (Steatorrhea), more than 7
gm/day.
 The appearance of pancreatic calcifications on X-ray, ultrasound or CT scan is
diagnostic of chronic pancreatitis.
 They are found in about 25% to 60% of cases of chronic alcoholic pancreatitis and
35% to 80% of pancreatitis due to other causes.
 In addition, CT scan may show focal pancreatic enlargement, atrophy, pancreatic
ductal dilatation or pseudocysts.
 ERCP is the most sensitive and specific imaging study for the diagnosis of chronic
pancreatitis. (It should be undertaken only if other non-invasive studies are inconclusive).
 Other imaging studies such as MRCP and endoscopic ultrasound (EUS) are equally
sensitive.
 If the imaging studies are not informative, then pancreatic function tests such as secretin
or cholecystokinin (CCK) stimulation tests can be performed.

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Chronic pancreatitis complications
The most common complications seen in chronic pancreatitis are:
 Pseudocysts,
 Ascites,
 Splenic vein thrombosis.
1) Pancreatic pseudocysts occur in 25% of patients: can cause:
 Abdominal pain; can cause Nausea and vomiting by obstructing the stomach or
duodenum
 Jaundice by obstructing the common bile duct.
 In about 10% of cases, pseudocysts are associated with pseudoaneurysms, which can
cause life-threatening bleeding.
 Asymptomatic pseudocysts can be observed.
 Symptomatic pseudocysts need to be drained by surgical, endoscopic or radiological
means.
2) Pancreatic ascites:
 Is diagnosed by high amylase levels in the ascitic fluid. This is most likely due to duct
disruption and may respond to total parenteral nutrition, pancreatic stent placement and
octreotide injections. If not responding, then surgery may be indicated.

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3) Splenic vein thrombosis:
 Occurs in about 2% to 4% of patients. This leads to isolated gastric varices with resulting
gastrointestinal hemorrhage. The diagnosis is confirmed by mesenteric angiography. In
the event of hemorrhage, splenectomy is curative.
4) Other complications:
 Include pancreatic cancer, common bile duct obstruction, duodenal obstruction and
pancreatic fistula formation.
Chronic pancreatitis Outcomes
 The treatment of pain in chronic pancreatitis is unsatisfactory.
 Most patients continue to experience pain.
 Pancreatic surgery leads to relief of pain for a variable period of time.
 Chronic alcoholic pancreatitis is associated with a mortality rate that approaches 50% in
20 to 25 years. Of these, 15% to 20% of the deaths are directly related to pancreatitis. The
rest are due to smoking, alcohol or trauma.
 Pancreatic cancer develops in 4% of the patients within 20 years of diagnosis of chronic
pancreatitis.
 The prognosis for tropical pancreatitis and idiopathic pancreatitis is generally more
favorable than for alcoholic pancreatitis.
Pancreatic Exocrine Cancer
 75% of pancreatic cancers involve the head of the pancreas, 25% involve the body and
tail of pancreas, so jaundice d/t blocking of the ampulla of vater may be the earliest sign
 90% die within first year of Diagnosis. 4th leading cause of cancer death both genders
 Incidence in men is 20% higher than in women
 Incidence in blacks is 40-50% higher than in whites; men d/t smoking and diabetes,
women d/t obesity
 Survival – 24% of patients with CA pancreas survive at least one year after diagnosis
(5% five years after diagnosis). 20% long term survival with localized disease.
 Primary prevention is key, especially smoking cessation.
 Secondary and tertiary prevention is difficult d/t poor outcome.

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Risk factors:
 Smoking/Alcohol.
 diets high in fat, beef, pork & processed meats
 diabetes
 chemical exposure
 chronic pancreatitis
Complications:
 abdominal pain,
 anorexia, nausea,
 jaundice, diarrhea
 Metastasis by time of diagnosis
Diagnosis:
 tumor markers- CA19-9, CEA (markers do not rise high enough to detect until cancer
is far advanced)
 CT with biopsy, ERCP with biopsy
 Staging by TNM (Tumor, nodes, mets)
Treatment:
 Some treatment protocols are showing promise.
 Surgical resection possible in only 5-15% and may be followed by chemo and radiation
 Chemo and radiation for inoperable, locally advanced disease (chemo improves survival
slightly)
 Chemo and supportive care for patients with metastasis
 5-FU
 Gemcitabine (Gemzar) better results
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