Disorders of the Pancreas

Harrison’s Principles of Internal Medicine

Approach to a patient with pancreatic
disease
General consideration

 The pancreas has a large reservoir of exocrine function

 More than 90% of the pancreas must be damaged for
maldigestion of fat and protein to manifest
 Noninvasive, indirect tests of pancreatic exocrine function are
much more likely to give abnormal results in patients with obvious
advanced pancreatic disease than occult disease
 Invasive, direct tests are the most sensitive and specific tests to
detect early chronic pancreatic disease when imaging is equivocal
or normal
 Amylase and lipase elevate within 24
hours and return to normal within 7
Diagnostic tests days. Maybe normal when
(1)Delay before blood is obtained
(2)Chronic pancreatitis
(3)Hypertriglyceridemia
 Click icon to add picture
Elevations of lipase
can occur:
• Hepatobiliary and gastrointestinal
malignancy
• Septicemia
• Liver cirrhosis
• SLE, DM
• Severe head injury
• Chronic alcoholism
• Post ERCP without any associated
evidence of pancreatitis
 EUS is the test of choice for
Major benefit of CT in acute MRI with MRCP is the
acquisition of diagnostic
pancreatitis is the diagnosis preferred modality for
tissue and cyst fluid in those
of pancreatic necrosis evaluating pancreatic cystic
with masses or cysts.
lesions
Click icon to add picture

• ERCP is the most sensitive

modality for the detection of
bile duct stones
• Double duct sign noted when
the pancreatic duct and CBD
are stenosed or obstructed
• Stents and rectal indomethacin
has been used to prevent post
ERCP pancreatitis
Secretin test:
• Normal values for the secretin test are
• Volume output >2mL/kg/hr
• HCO3 concentration >80 mmol/L
• HCO3 output >10 mmol/L in 1 hour

• The most reproducible measurement is the maximal HCO3 concentration

• <80 mmol/L is considered abnormal and commonly seen in early chronic pancreatitis
• Steatorrhea does not occur until intraluminal levels of lipase are markedly reduced,
underscoring the fact that only small amounts of enzymes are necessary for intraluminal
digestive activities
• Decreased fecal elastase (FE-1) activity in stool is a test to detect EPI in patients with
chronic pancreatitis and cystic fibrosis
• FE-1 levels > 200 ug/g are normal
• 100-200 ug/g are mild to moderate EPI
• <100 ug/g are severe EPI
• False positive in diarrhea, diabetes, irritable bowel syndrome
Acute Pancreatitis
Biochemistry and physiology of
pancreatic exocrine secretion

General considerations Regulation of pancreatic secretion

 1500-300 mL of isosmotic alkaline fluid  Gastric acid – stimulus for release of secretin
per day containing 20 enzymes from the duodenal mucosa (S cells) which
stimulates secretion of water and
electrolytes from pancreatic ductal cells
 Cholecystokinin – from the duodenal and
jejunal mucosa (Ito cells) is triggered by long
chain fatty acids, essential amino acids and
gastric acid
 CCK – evokes release of enzymes from
pancreas
 Secretin > CCK – release of water & HCO3
 Water and electrolyte secretion Enzyme secretion
 CCK and VIP promotes secretion  Acinar cells
 Acetylcholine also promotes secretion  Amylolytic enzymes: (amylase)
 hydrolyze starch to oligosaccharides
Intraluminal bicarbonate secreted from
and to the disaccharide maltose
the ductal cells helps neutralize gastric
acid, increases the solubility of fatty  Lipolytic enzymes: lipase,
acids and bile acids, maintains an phospholipase A and cholesterol
optimal pH for pancreatic and brush esterase
border enzymes, and prevents intestinal  Bile salts prevent lipase but colipase
mucosal damage. prevents that inhibition
 Bile salts activate phospholipase A and
cholesterol esterase
 Enzyme secretion
 Proteolytic enzymes:  Enterokinase on the duodenal brush
 endopeptidases (trypsin, chymotrypsin), border activates trypsinogen to trypsin
act on internal peptide bonds of proteins which activates the inactive zymogens
and polypeptides;  Nervous system also participates in
 exopeptidases (carboxypeptidases, pancreatic enzyme secretion
aminopeptidases), act on the free  Cholinergic through the vagus nerve
carboxyl- and amino-terminal ends of
peptides  Stimulatory neurotransmitters are the

acetylcholine and gastrin releasing
Enzymes are secreted as inactive peptides
zymogens
 Enteropancreatic axis and
Auto-protection of the pancreas feedback inhibition
 (1) the packaging of pancreatic proteases in  CCK RF also stimulates CCK release
the precursor (proenzyme) form  Serine proteases inhibit pancreatic secretion by
 (2) intracellular calcium homeostasis (low inactivating CCK
intracellular calcium in the cytosol of the  Acidification of the duodenum releases secretin,
acinar cell promotes the destruction of which stimulates vagal and other neural
spontaneously activated trypsin) pathways to activate pancreatic duct cells,
 which secrete bicarbonate. This bicarbonate
(3) acid-base balance
then neutralizes the duodenal acid, and the
 (4) the synthesis of protective protease feedback loop is completed
inhibitors (pancreatic secretory trypsin  Dietary proteins bind proteases, thereby leading
inhibitor [PSTI] or SPINK1), which can bind to an increase in free CCK-RF
and inactivate ~20% of intracellular trypsin
 Additional hormonal feedback inhibition occurs
activity
via peptide YY and glucagon-like peptide-1
 Chymotrypsin C can also lyse and inactivate following lipid or carbohydrate exposure to the
trypsin ileum
Etiology and
pathogenesis
 Gallstone is the leading cause
 4x risk in patients with stone <5mm than
larger
 Alcohol is the 2nd most common cause
 Incidence surprisingly low in alcoholics
 Additional factors: smoking, genetics
 Post ERCP
 minor papilla sphincterotomy, suspected
sphincter of Oddi dysfunction, prior history of
post-ERCP pancreatitis, age
 Hypertriglyceridemia
 Usually >1000 mg/dL
 Alcohol, drugs such as OCPs
Etiology and
pathogenesis

 Ranges from interstitial pancreatitis

(pancreas blood supply maintained),
generally self-limited, to necrotizing
pancreatitis (pancreas blood supply
interrupted)
 Pathogenic theory: autodigestion due to
activation of the enzymes within the
pancreatic acinar cells instead of the
intestinal lumen
 Activated proteolytic enzymes, especially
trypsin, not only digest pancreatic and
peripancreatic tissues but can also activate
other enzymes, such as elastase and
phospholipase A2
Activation of Genetic factors that increase
pancreatic susceptibility
 (1) cationic trypsinogen gene
enzymes (PRSS1) – capable of
precipitating acute pancreatitis
 Initial phase: intrapancreatic digestive in the absence of other factors
enzyme activation ad acinar cell injury  (2) pancreatic secretory trypsin
 Trypsin activation appears to be mediated by
lysosomal hydrolases such as cathepsin B
inhibitor (SPINK1)
  (3) the cystic fibrosis
Second phase: activation, chemoattraction,
and sequestration of leukocytes and transmembrane conductance
macrophages in the pancreas, resulting in regulator gene (CFTR)
an enhanced intrapancreatic inflammatory
reaction  (4) the chymotrypsin C gene
 neutrophils can activate trypsinogen (CTRC)
 Third phase: effects of activated proteolytic  (5) the calcium-sensing
enzymes and cytokines, released by the
receptor (CASR)
inflamed pancreas, on distant organs
 (6) claudin-2 (CLDN2)
Approach to the Physical examination
 Distressed and anxious, low grade fever,

patient 
tachycardia, hypotension
Shock
 Hypovolemia from exudation of blood and
plasma proteins into the retroperitoneal space
 Increased formation of kinin peptides that
Abdominal pain cause vasodilation and permeability
  Systemic effects of proteolytic and lipolytic
Major symptom
enzymes released into the circulation
 Mild to severe, constant and incapacitating  jaundice, erythematous skin nodules,
distress pulmonary findings (rales, atelectasis,
 Characteristically stead and boring, effusion)
epigastric, radiating to the back, chest,  Abdominal pain and rigidity
flanks and lower abdomen  Diminished or absent bowel sounds
 Nausea, vomiting, and abdominal  Cullen’s sign: hemoperitoneum producing
distention due to gastric and intestinal bluish discoloration around the umbilicus
hypomotility  Turner’s sign: tissue breakdown of Hgb
from necrotizing pancreatitis with
hemorrhage hence blue-red-purple or
green-brown discoloration of the flanks
  Hyperbilirubinemia: >4mg/dL

Laboratory data 
 Normalized in 4-7 days
Transiently elevated ALP and
transaminases
 ALT >3x ULN is associated with gallstone
etiology
 Amylase and lipase >3 ULN  Hypoxemia which may herald the onset
 No correlation with severity of ARDS
 ECG: ST segment and T wave
 Amylase usually returns to normal after 3-7
days abnormalities simulating MI
  UTZ: checks for gallstone and CBD
Lipase may remain elevated for 7-14 days

dilatation
Lipase is more sensitive for pancreatitis
 Revised Atlanta Criteria outlines the
 Leukocytosis: 15,000-20,000 features of acute pancreatitis on CT
 Hemoconcentration  Interstitial pancreatitis
 Harbinger of severe disease  Necrotizing pancreatitis
  Acute pancreatic fluid collection
Azotemia is a risk factor for mortality
 Pseudocyst
 Hyperglycemia
 Acute necrotic collection
 Hypocalcemia  Walled off necrosis
 Differential diagnosis should
Diagnosis include the following disorders:
 perforated viscus, especially
peptic ulcer
 acute cholecystitis and biliary
The diagnosis is established by two of the colic
following three criteria:  acute intestinal obstruction
 (1) typical abdominal pain in the  mesenteric vascular occlusion
epigastrium that may radiate to the back
 renal colic
 (2) threefold or greater elevation in serum
lipase and/or amylase  inferior myocardial infarction
 (3) confirmatory findings of acute  dissecting aortic aneurysm
pancreatitis on cross-sectional abdominal
imaging  connective tissue disorders with
 Markers of severity: hemoconcentration vasculitis
(Hct >44%), admission azotemia  Pneumonia
(BUN>22), SIRS, signs of organ failure
 diabetic ketoacidosis.
Clinical course, definition and
classification

Phases of acute pancreatitis

 Early (<2 weeks)  Late (>2 weeks)
 Severity defined by the clinical parameters  Characterized by protracted illness
 Most patients have SIRS may predispose to  May need imaging to evaluate for local
organ failure complications
 Respiratory, cardiovascular and renal  Clinical parameter of severity is
 Organ failure defined by a score of 2 or more persistent organ failure
for one of these 3 organ systems on the
modified Marshall scoring system  Radiographic feature of greatest
 Persistent organ failure (>48 hours) is the importance is development of necrotizing
most important clinical finding regarding pancreatitis on CT
severity  Necrosis is associated with prolonged
 CT imaging usually not needed during first hospitalization and if infected, may
48 hours require intervention
Clinical course, definition and
classification

Severity of acute pancreatitis

 Mild  Severe
 Without local complications or organ  Persistent organ failure (>48 hours)
failure involving one or more organs
 Most with interstitial acute pancreatitis  CT or MRI should be obtained to check for
have mild pancreatitis necrosis or other complications
 Self limited and subsides spontaneously,  If local complication is encountered,
usually 3-7 days management is dependent on symptoms,

evidence of infection, maturity of fluid
Moderate collection and clinical stability of the
 Transient organ failure (<48 hours) or patient
local or systemic complications in the  Prophylactic antibiotics are not
absence of persistent organ failure recommended
Clinical course, definition and
classification

Imaging in acute pancreatitis

 2 types of pancreatitis on imaging:  Those with only extrapancreatic
interstitial or necrotizing necrosis have a more favorable
 prognosis than patients with pancreatic
CT with IV contrast is best on 3-5 days
necrosis
into hospitalization it patients are not
responding to supportive care  CT identification of local complications,
 particularly necrosis, is critical in
Interstitial pancreatitis: 90-95% of
patients who are not responding to
admissions, symptoms usually resolve
therapy because patients with infected
within the week of admission
and sterile necrosis are at greatest risk
 Necrotizing pancreatitis: may not evolve of mortality
until several days  Single-organ system failure, the
mortality is 3–10%, but increases to
nearly 50% with multiorgan failure
  LR has been shown to decrease
Management systemic inflammation (lower
CRP)
 Targeted resuscitation strategy
with measurement of Hct and

BUN q8-12 hours
85-90% of cases are self limited and
subside spontaneously, usually within 3-7  Decrease in Hct and BUN in the
days, and do not exhibit organ failure or first 12-24 hours strong evidence
local complications of adequate resuscitation
Fluid resuscitation  Rise in Hct and BUN should be
 Most important treated with volume challenge
 NPO to prevent nutrient induced with 2L crystalloid bolus and
stimulation of the pancreas increasing fluid rate by 1.5

mL/kg/hr
IV narcotic analgesic to control abdominal
pain  If the Hct and BUN failed to
 O2 support as needed respond to the challenge,

consider transferring the patient
IV or LR or NSS bolus 15-20 mL/kg then 2-
to the ICU
3ml/kg/hr to maintain UO of 0.5 mL/kg/hr
Management

Assessment of severity
 BISAP: >25 mg/dL BUN, impaired mental
status, SIRS, age >60, pleural effusion
 3 or more is associated with increase risk of
mortality
 Hct > 44 and BUN >22 mg/dL is associated
with more severe pancreatitis
 Helps to triage the patient to where they
should be admitted: regular room, step-
down unit, or ICU
 Nutritional therapy

Management 


Low fat solid diet in mild cases
Enteral nutrition in 2-3 days with more
severe cases, instead of TPN
 Maintains the gut barrier integrity, limits
bacterial translocation, less expensive, fewer
complications
Special consideration based on etiology
Local complications
 Gallstone: if with evidence of ascending  Necrosis
cholangitis should undergo ERCP in the first  No role for prophylactic antibiotics
24-48 hour  Empiric antibiotics for those with clinical
 Increase risk of recurrence hence ideally for decompensation
cholecystectomy  Repeat CT or MRI should be considered with
 any change in the clinical course to monitor
Hypertriglyceridemia: >1000 mg/dL the complications
 Focus on treating hyperglycemia with IV  Sterile necrosis: conservative
insulin which often correct high TG  Infected necrosis: targeted antibiotics,
 Hypercalcemia: treat hyperparathyroidism consider pancreatic drainage and or
debridement (necrosectomy)
or malignancy to decrease levels  If conservative management considered, do so for
 4-6 weeks to allow the collection to either resolve
Post ERCP: stenting, rectal indomethacin or evolve to develop a more organized boundary
so that surgical or endoscopic intervention is safer
 Drug associated with pancreatitis and more effective
  Perivascular complications

Management
 Splenic vein thrombosis with gastric varices and
pseudoaneurysms as well as portal ad SMV
thrombosis
 Gastric varices rarely bleed
 Rupture pseudoaneurysm can be diagnosed with
mesenteric angiography and embolization
 Extrapancreatic infections
Local complications cont…  Hospital acquired infections occur in 20%
 Pseudocyst  Must monitor for pneumonia, UTI, line infection

 After 4 weeks persistent fluid collections Follow-up care

would meet the definition of pseudocyst  Hospitalization of severe pancreatitis can be
prolonged and last weeks to months and often
 Only symptomatic cysts require intervention involve periods of ICU admission and subacute
 Pancreatic duct disruption nursing care
 Assess development of DM, exocrine pancreatic
 Abdominal pain or shortness of breath with
insufficiency, recurrence cholangitis, infected
enlarging fluid collection resulting in ascites
fluid collections
 Diagnosis through MRCP or ERCP  Cholecystectomy at the initial hospitalization for
 Placement of a stent for at least 6 weeks is gallstone pancreatitis with mild severity
effective in resolving the leak with or without  For those with necrotizing gallstone pancreatitis,
TPN and octreotide the timing need to be individualized
 Recurrent acute pancreatitis Pancreatitis in patients with AIDS
 25% of cases  Incidence has increased due to
 2 most common factors: alcohol and  High incidence of infections involving the
cholelithiasis pancreas including CMV,
cryptosporidium, and Mycobacterium
 If with recurrence pancreatitis without avium complex
obvious cause:  Frequent use of medications such as
 Occult biliary tract disease, including pentamidine, TMP SMX and protease
microlithiasis, hypertriglyceridemia, inhibitors
pancreatic cancer, hereditary pancreatitis  Incidence has since decreased due to
disuse of didanosine
Chronic pancreatitis
Pathophysiology

 Characterized by irreversible damage to the

pancreas
 Irrespective of the mechanism of injury, the
stellate cell activation lead to cytokine
expression and production of extracellular
matrix protein that contribute to the acute
and chronic inflammation and collagen
deposition on the pancreas
 Defined by the presence of histologic
abnormalities, including chronic inflammation,
fibrosis, and progressive destruction (atrophy)
of both exocrine and endocrine tissue
 Strong association with smoking:
independent, dose dependent risk factor for
CP and RP
Etiologic  It is estimated that in patients with
idiopathic pancreatitis, the
considerations frequency of a single CFTR
mutation is 11 times the expected
frequency and the frequency of two
mutant alleles is 80 times the
 In the US, alcoholism is the most common expected frequency
cause in adults, while cystic fibrosis is the 
most common cause in children CFTR mutations are common in the
general population, so it is unclear
 Prototypical genetic defect: PRSS1 whether the CFTR mutation alone
 Defect prevents the destruction of can lead to pancreatitis as an
prematurely activated trypsin and allows it
to be resistant to intracellular protective
autosomal recessive disease.
effect of trypsin inhibitor  The presence of a separate genetic
 CFTR gene mutation (N34S SPINK1) increased
 Functions as the cyclic AMP regulated the risk twentyfold.
chloride channel  A combination of two CFTR
 Those with CF, the high concentration of mutations and an N34S SPINK1
macromolecules can block the pancreatic mutation increased the risk of
ducts
pancreatitis 900-fold.
Autoimmune
 A type of chronic pancreatitis with distinct
histopathology

pancreatitis
 2 types
 Type 1: pancreatic manifestation of IgG4
related disease
 including bilateral submandibular gland
enlargement, characteristic renal lesions,
retroperitoneal fibrosis, and stricturing of the
suprapancreatic biliary tree
 Type 2: idiopathic duct centric chronic
pancreatitis
 pancreas-specific disorder that is associated with
inflammatory bowel disease in ~10% of patients

 Sx: jaundice, weight loss, new onset diabetes

 Elevated IgG4 levels supportive of diagnosis
 CT: inflammatory rim (capsule sign) specific
but not sensitive for AIP
 ERCP or MRCP: strictures in bile duct in 1/3,
some with isolated intrahepatic bile duct
strictures (type 1 AIP only), which can mimic
primary sclerosing cholangitis, and is referred
to as IgG4-related sclerosing cholangitis
Autoimmune  Relief of symptoms, liver
biochemistries, and abnormal imaging

pancreatitis of the pancreas and bile ducts are

followed to assess for treatment
response.
 A poor response to glucocorticoids
 The Mayo Clinic HISORt criteria provide a should raise suspicion of an alternate
helpful mnemonic to remember the key diagnosis, such as pancreatic cancer.
diagnostic features of this disease, including
 A recent multicenter international
 (1) histology
study examined >1000 patients with
 (2) imaging
AIP. Clinical remission was achieved in
 (3) serology (elevated serum IgG4 levels) 99% of type 1 AIP and 92% of type 2
 (4) other organ involvement AIP patients with steroids.
 (5) response to glucocorticoid therapy  However, disease relapse occurred in 31
 Glucocorticoids and 9% of patients with type 1 and type

2 AIP, respectively.
Alleviates symptoms and decrease size of
pancreas and reverse histopathologic features  Multiple relapses may be managed with
 2-4 week period an immunomodulator (e.g., azathioprine,
6-mercaptopurine, or mycophenolate
 Prednisone: 40mg/d for 4 weeks then taper by54 mofetil) or B-cell depletion therapy (e.g.,
mg per week
rituximab).
Clinical features of  Low serum pancreatic enzyme levels are

chronic
moderately specific for a diagnosis of
chronic pancreatitis but have poor
sensitivity
pancreatitis  Elevated bilirubins and ALP may indicate
cholestasis
 Abdominal pain or maldigestion  Prevalence of the exocrine pancreatic
insufficiency is >80%
 Abdominal pain: variable in location,  Steatorrhea is suggestive
severity and frequency
 CT is the initial modality of choice followed
 Pain can be constant or intermittent with by MRI, endoscopic ultrasound and
pain free intervals pancreas function testing
 Eating may exacerbate pain hence fear of  Secretin test is the most sensitive
eating and weight loss  Abnormal with >60% of the exocrine function
 Fat soluble vitamin deficiency has been lost
 Correlates well with onset of chronic abdominal
 Metabolic bone disease pain
 Diagnosis of early or mild chronic  Abdominal Xray: diffuse calcification is
pancreatitis is challenging due to no pathognomonic
accurate biomarker  Alcohol is most common cause but can be seen
in hereditary pancreatitis, posttraumatic
 Amylase and lipase are not strikingly pancreatitis, idiopathic chronic pancreatitis and
elevated tropical pancreatitis
Complications of
chronic
pancreatitis
 Life time prevalence of pancreatitis related  Jaundice, cholestasis, and biliary
diabetes >80%
cirrhosis: from the chronic
 DKA and diabetic coma is uncommon inflammatory reaction around the
 Along with end organ damage intrapancreatic portion of the
 Nondiabetic retinopathy may be due to vitamin common bile duct
A and/or zinc deficiency
 Twenty years after the diagnosis of
 Osteoporosis and osteopenia: shared risk factors
(e.g., alcohol use, cigarette smoking), vitamin D
chronic calcific pancreatitis, the
deficiency, and detrimental effects on the bone cumulative risk of pancreatic cancer
from chronic inflammation is 4%
 Gastrointestinal bleeding: peptic ulceration,  Patients with hereditary PRSS1 or
gastritis, a pseudocyst eroding into the tropical pancreatitis have an increased
duodenum, arterial bleeding into the pancreatic risk for pancreatic cancer compared to
duct (hemosuccus pancreaticus), or ruptured other forms of chronic pancreatitis.
varices secondary to splenic vein thrombosis.
  Steatorrhea
Treatment  start at a dosage of 25,000–
50,000 units of lipase
 dose may need to be increased
up to 100,000 units

There are currently no  Abdominal pain

therapies to reverse or delay  Endoscopic: sphincterotomy,
pancreatic duct stenting, stone
the disease progression of extraction and drainage of
chronic pancreatitis, so pancreatic pseudocyst
management is primarily  Celiac plexus block
focused on screening for and  Total pancreatectomy with or
management of disease- without autologous islet cell
transplant: in lieu of ductal
related complications. decompression surgery or partial
pancreatic resection or hereditary
pancreatitis
Hereditary Pancreatitis

 Rare, early age of onset with familial aggregation

 Chromosome 7
 Mutations in ion codons 29 (exon 2) and 122 (exon 3) of the
cationic trypsinogen gene (PRSS1) cause an autosomal
dominant form of pancreatitis
 Eliminates a fail-safe trypsin self-destruction site
 Pancreatic calcification, diabetes mellitus, and steatorrhea,
10% increased risk of pancreatic cancer
Annular pancreas

 Ventral pancreatic anlage fails to

migrate correctly
 Resulting in a ring of pancreatic
tissue around the duodenum
 Sx: Post prandial fullness, epigastric
pain, nausea, vomiting, intestinal
obstruction
 Increased risk of pancreatitis and
peptic ulcer
 Tx: Retrocolic duodenojejunostomy
Pancreatic Divisum

 Embryologic ventral and dorsal

pancreatic anlagen fail to fuse
 Pancreatic drainage is accomplished
mainly through the accessory minor
papilla
 Most common pancreatic variant
 High risk of post-ERCP pancreatitis
 Tx: endoscopic or surgical intervention
when the pancreatitis recurs and no
other cause can be found
Macroamylasemia

 Amylase circulates in the blood in a polymer form too

large to be easily excreted by the kidney
 High serum amylase, low urinary amylase
 1.5% of nonalcoholic adults
 Usually an incidental finding
 Macrolipasemia: lipase is complexed with IgA, seen in
cirrhotics and non-Hodgkin’s lymphoma
Thank you Questions?