Transcript Aute, chronic Pancreatitis - University of Yeditepe Faculty of

Acute Pancreatitis
Umit Akyuz, MD
Gastroenterology Department,Yeditepe University
Istanbul
Acute Pancreatitis - Objectives
Discuss basic physiology
Etiology
Clinical Presentation
Diagnosis
Prognosis
Management
Complications
Pancreatic Physiology
(1) Production of bicarbonate-rich fluid to
neutralize gastric fluid in the duodenum –
duct cells primarily (CFTR gene =
chloride / bicarbonate channel)
(2) Synthesis of digestive enzymes –
acinar cells
(3) Insulin production = islet cells
Pancreatic Physiology
Most of the pancreas is made of acinar
cells
The duct cells connect the acinar cells to
the duodenum and as noted produces a
bicarbonate rich fluid to “wash” the
enzymes into the duodenum (3000cc/day)
The islet cells function independently but
need remain in close proximity to the
acinar cells to maintain normal gene
expression
Pancreatic Physiology
Acinar enzymes are produced as
zymogens
Zymogens are proenzymes that require
cleavage of a peptide by trypsin to
become active
Trypsinogen (zymogen of trypsin) is
activated by the intestinal brush boarder
enzyme enterokinase or by another trypsin
molecule
Acute Pancreatitis
Acute Pancreatitis –
Epidemiology
>200,000 Hospital Admissions / Year
20% have a severe course
– 10-30% mortality for this group, which has not
significantly changed during the past few
decades despite improvement in critical care
and other interventions
Acute Pancreatitis –
Pathophysiology
An acute inflammatory process within the
pancreas with variable involvement of
localized tissues and remote organ
systems
It can range from Mild  Severe with
MOSF, necrosis, abscess, or a myriad of
other complications
Vigorous immune response
– By the time pancreatitis is recognized
clinically the inflammatory consequences
dominate the clinical picture
Acute Pancreatitis
The vast majority of protection centers on
trypsin activation (or lack thereof)
– (1) preventing trypsinogen activation (2)
inactivating trypsin (3) “sweeping” trypsin out
of the pancreas
Acute Pancreatitis
Etiology
Etiology
Alcohol (40%)
– Mechanism not fully understood
– Not all alcoholics get pancreatitis (only about
15%)
– This suggests a subset of the population
predisposed to pancreatitis, with alcohol
acting more as a co-precipitant
Alcohol related pancreatitis CASE
26M presents for pseudocyst drainage –
four weeks after severe pancreatitis
Has had “abdominal symptoms” since
childhood
Does admit to heavy alcohol use as young
adult
– Strong family history of alcoholism and
pancreatitis
– Family history reveals a possible autosomal
dominant abnormality
ERCP reveals chronic pancreatitis
Alcohol related pancreatitis CASE
Answer:
– A mutation (PRSS1) was found that alters the
protein structure of trypsin producing a
constant ON trypsin (auto-activation within the
pancreas), resulting in frequent bouts of
pancreatitis.
Etiology
Gallstones (35%)
– Gallstone pancreatitis risk is highest among
patients with small GS < 5mm and with
microlithiasis
– GS pancreatitis risk is also increased in white
women > 60 yrs
Etiology – Drugs and Toxins
(5%)
Azathioprine
Cimetidine
Estrogens
Enalapril
Erythromycin
Furosemide
Multiple HIV medications
Scorpion Bites
Sulfonamides
Thiazides
TMP/SMX
Etiology – Trauma
Blunt Trauma
– Automobile
– Bicycle handlebar injuries
– Abuse
Iatrogenic – ERCP (1-7%)
– Likely secondary to contrast but also very
operator dependant
– Risk is also increased with Sphincter of Oddi
manometry
Etiology – Multi-System Disease
Diabetic Ketoacidosis (10-15%)
Hemochromatosis
HUS
Hypercalcemia
Hyperparathyroidism
Hypertriglyceridemia
IBD
Malnutrition
Severe PUD
Renal Failure
SIRS
SLE and other connective tissue dissorders
Status-Post solid organ and BM transplant
Vasculitis
Etiology – Multi-System Disease
Cystic Fibrosis
– 2-15% of patients
– Ductal obstruction from thickened secetions
Etiology – Multi-System Disease
Malnutrition and Re-feeding
Anorexia Nervosa
– Pancreatic acinar cells atrophy but true cause
of pancreatitis unknown
Etiology – Infection
Ascaris
Campylobacter
CMV
Coxsackie B
EBV
Enterovirus
HIV/AIDS
Influenza
MAC
Measles
Mumps Rubella
Mycoplasma
Rubeola
Viral Hepatitis
Varicella
Etiology – Anatomical
Anomalies
Pancreas Divisum
– Failure of dorsal and ventral fusion (5-15% of
population)
Annular Pancreas
Any Ductal Anomalies
Sphincter of Oddi dysfunction
Always consider a primary malignancy as
a possible cause of new onset pancreatitis
in older patients without other obvious risk
factors
Etiology – Genetic
CFTR heterozygote – “atypical” CF
Other CFTR mutations – found in many
adult patients with more severe forms of
pancreatitis (we can test for a few hundred
of the more than 1200 different mutations)
SPINK1 mutations – most common cause
of familial pancreatitis; causes a
predisposition for pancreatitis (other
trigger is usually present)
PRSS1 gene – Self-activating trypsin
Etiology - Autoimmune
Primarily a pancreatic disorder but . . .
Can be associated with other diseases of
presumed autoimmune etiology including
sclerosing cholangitis, primary biliary
cirrhosis, retroperitoneal fibrosis,
rheumatoid arthritis, sarcoidosis, and
Sjögren's syndrome - some authors have
proposed that AIP represents a systemic
autoimmune disease
Etiology - Autoimmune
(1) Diagnostic histology - dense
lymphoplasmacytic infiltrate of the pancreatic
parenchyma with secondary fibrosis
(2) Characteristic imaging with elevated IgG4
– focal or diffuse enlargement of the pancreas that is
often sausage-shaped
– minimal pancreatic stranding
– calcifications or peripancreatic fluid
– uniform narrowing of the main pancreatic duct
– rim-like enhancement of the pancreatic head
(3) Response to steroid therapy
Etiology – Idiopathic
Still accounts for ~20% of cases
Etiology – Idiopathic
Experts suggest that idiopathic
pancreatitis should account for no more
than 5-10% of the total cases, yet the
broadly quoted percentage in the literature
at this time in the US is currently 20-25%.
Acute Pancreatitis
Clinical Presentation
Clinical Presentation
Clinical
– Continuous mid-epigastric / peri-umbilical
abdominal pain  Radiating to back, lower
abdomen or chest
– Emesis
– Fever
– Aggravated by eating
– Progressive
– Restless and uncomfortable
Clinical Presentation
More severe cases
– Jaundice
– Ascites
– Pleural effusions – generally left-sided
– Cullen’s sign – bluish peri-umbilical
discoloration
– Grey Turner’s sign – bluish discoloration of
the flanks
Diagnosis – Initial work-up
GS history
Drug intake
Family History
Alcohol intake
Viral exposures
Lipase
LFTs
GB US
Diagnosis – Follow up
investigations
Fasting liver profile
Fasting plasma calcium – when well
Viral titers as indicated by clinical
presentation
GB US – consider repeating
MRCP
CT pancreas (pancreas protocol)
Diagnosis – Further
investigations
Appropriate for recurrent idiopathic acute
pancreatitis
– GB US
– EUS / ERCP – biliary and pancreatic cytology
– Autoimmune markers
– Sphincter of Oddi manometry
– Functional testing / History to screen for
sequela of chronic pancreatitis
Diagnosis – Amylase
Elevates within HOURS and can remain
elevated for 4-5 days
High specificity when using levels >3x
normal
Many false positives (see next slide)
Most specific = pancreatic isoamylase
(fractionated amylase)
Diagnosis – Amylase Elevation
Pancreatic Source
–
–
–
–
–
–
Biliary obstruction
Bowel obstruction
Perforated ulcer
Appendicitis
Mesenteric ischemia
Peritonitis
Salivary
–
–
–
–
–
Parotitis
DKA
Anorexia
Fallopian tube
Malignancies
Unknown Source
–
–
–
–
Renal failure
Head trauma
Burns
Postoperative
Diagnosis – Lipase
The preferred test for diagnosis
Begins to increase 4-8H after onset of
symptoms and peaks at 24H
Remains elevated for days
Sensitivity 86-100% and Specificity 6099%
>3X normal S&S ~100%
Diagnosis
Elevated ALT > 3x normal (in a nonalcoholic) has a positive predictive value of
95% for GS pancreatitis
Diagnosis – Imaging
CT
– Excellent pancreas imaging
– Recommended in all patients with persisting
organ failure, sepsis or deterioration in clinical
status (6-10 days after admission)
– Search for necrosis – will be present at least 4
days after onset of symptoms; if ordered too
early it will underestimate severity
– Follow-up months after presentation as
clinically warranted for CT severity index of >3
Diagnosis - Imaging
ERCP / EUS
– Diagnostic and Therapeutic
– Can see and treat:
Ductal dilatation
Strictures
Filling defects / GS
Masses / Biopsy
Diagnosis – Imaging
ERCP indications (should be done in the first 72hr)
– GS etiology with severe pancreatitis – needs sphincterotomy
– Cholangitis
– Jaundice
– Dilated CBD
– If no GS found sphincterotomy is indicated anyway
– Poor surgical candidate for laparoscopic cholecystectomy
– Clinical course not improving sufficiently to allow timely laparoscopic
cholecystectomy and intraoperative cholangiogram
– Pregnant patient
– Uncertainty regarding biliary etiology of pancreatitis
Acute Pancreatitis
Prognosis
Prognosis – Ranson’s (Severe > 3)
Ranson’s Score
– 5 on Admission
Age > 55 y
Glucose >200
WBC > 16000
LDH > 350
ALT > 250
– 6 after 48 hours from presentation
Hct > 10% decrease
Calcium < 8
Base Deficit > 4
BUN > 5
Fluid Sequestration > 6L
PaO2 < 60
Prognosis – Atlanta Criteria
Severe Acute Pancreatitis
– Early Prognostic Signs
Ranson signs ≥3
APACHE-II score ≥8
Organ Failure and/or Local Complications (persist >48
hr after admission)
Necrosis
Abscess
Pseudocyst
Organ Failure as Defined by Atlanta Symposium
–
–
–
–
Shock–systolic pressure <90 mmH
PaO2 ≤60 mmHg
Creatinine >2.0 mg/L after rehydration
Gastrointestinal bleeding >500 cc/24 h
Prognosis – CT Severity Index
CT Grade
– Normal
– Focal or diffuse enlargement
point
– Intrinsic change or fat stranding
– Single ill-defined fluid collection
– Multiple collections of fluid or gas
0 points
1
2 points
3 points
4 points
Necrosis Score
–
–
–
–
None
1/3 of pancreas
1/2 of pancreas
> 1/2 of pancrease
0 points
2 points
4 points
6 points
Severe = Score > 6 (CT Grade + Necrosis)
Prognosis – CRP
Santorini consensus and the World
Association guidelines recommend a cut
off of 10 - 15 mg/dl
– This is checked 48 hours after admission
Management
All patients with biliary pancreatitis should
undergo definitive treatment of gallstones
during the same hospital admission,
unless a clear plan has been made for
definitive treatment within the next two
weeks
Delay exposes the patient to the risk of
potentially fatal recurrent acute
pancreatitis
Surgery should be delayed in severe
pancreatitis and ERCP is preferred
Management
Mainly supportive
– Hydration, pain relief, and pancreatic rest
– NPO – to decrease pancreatic secretion
– Remember stress ulcer prophylaxis always
– Look for complications!!!
– No magic bullet – antiproteases, octreotide
(antisecretory) or lexiafant (anti-inflammatory)
have all been disappointing in large trials
Management - Antibiotics
Infected necrosis has significant mortality (40%)
No consensus at this time for prophylactic
antibiotics but the literature leans toward using
them in severe pancreatitis with necrosis
– Imipenum, cefuroxime, ceftazidime + amikacin +
metro, Ofloxacin + metro, cipro + metro  your
choice
If used, it should be given no longer than 7 to 14
days
Gut decontamination is not recommended
Management - Feedings
Enteral nutrition is preferred
There is a push for nasojejunal feeds
however nasogastric feeds have been
shown to be effective in 80% of cases¶
NGTs should be used with caution in
patients with AMS however
More risk with TPN / IL but if cannot feed
enterally >5 days may be needed
¶ Eatock FC. Nasogastric feeding in severe acute pancreatitis. Radiology 1994:
193, 297-306.
Management – Necrosis
All severe pancreatitis should be managed
in the ICU or Stepdown Unit
FNA recommended when >30% necrosis or
clinical suspicion of sepsis for a culture 7-14
days after onset, if gas present assume
infected necrosis and treat
Infection generally requires debridement
(surgical or IR)
Management – Pain
Morphine not ideal but can still be used – it
can theoretically worsen symptoms by
increasing spasm of the Sphincter of Oddi
Demerol is a good opiate agonist
Hydromorphone is also an excellent option
PCA is generally preferred in the
beginning
Always use the gut if you can to transition
off IV pain meds
Don’t forget aggressive bowel care
Infliximab in Acute Pancreatitis

Infliximab, a monoclonal TNF antibody, was tested in
100 rats randomly assigned to 10 groups

In acute edematous pancreatitis and in severe
necrotizing pancreatitis, the drug significantly
decreased serum amylase activity and the
histopathologic score

In severe necrotizing pancreatitis, it ameliorated both
parenchymal and fatty tissue necrosis of the pancreas

It also alleviated alveolar edema and ARDS-like
pulmonary complications, but this difference was not
significant
Oruc N, et al. Pancreas 2004; 28:E1-8. [26]
Treatment of Acute
Pancreatitis with Protease
Inhibitors




Ten articles of randomized controlled trials evaluating
the effects of protease inhibitors (Aprotinin and
Gabexate) for acute pancreatitis were retrieved by
systematically searching Medline, Cochrane Library and
Ovid databases published from January 1966 through
December 2003.
The main outcome of interest was the overall mortality
rate from acute pancreatitis
When protease inhibitors were given to patients with
mild pancreatitis, they were not significant (pooled RD
0.00; 95% CI from -0.04 to 0.05)
When protease inhibitors were given to patients with
severe pancreatitis, the mortality rate decreased
significantly (pooled RD -0.07; 95% CI from -0.13 to 0.01)
Seta T, et al. Eur J Gastroenterol Hepatol 2004; 16:1287-93. [37]
Interleukin-10 in Acute
Pancreatitis
No effect in humans
New organ failure (%)
Efficacy in experimental
study
100
Survival (%)
100
P<0.05
80
60
40
IL-10
Untreated
20
P NS
80
60
40
20
0
0
1
2
3
4 5
Days
6
7
8
Zou WG, et al. J Surg Res 2002; 103:121-6. (modified) [29]
0
IL-10
Placebo
Villoria A, et al. Pancreatology 2003; 3:466. [30]
Limitations of Experimental Models for
the Treatment of Acute Pancreatitis
The utility of such experimental models might have limitation, and a full
extrapolation of experimental data from laboratory animals to humans must be done
Pastor CM, Frossard JL. FASEB J 2001; 15:893-7. [28]
with caution
Complications – Local
Necrosis
– Sterile
– Infected - abscess
Pseudocyst
Ascites
Intraperitoneal hemorrhage
Thrombosis
Bowel infarction
Obstructive jaundice
Complications – Systemic
Pulmonary
–
–
–
–
Pleural effusions
Atelectasis
Mediastinal abscess
ARDS
Cardiovascular
– Hypotension
– Sudden death
– Pericardial effusion
Hematologic
– DIC
Gastrointestinal
–
–
–
–
PUD
Erosive gastritis
Blood vessel erosion
Portal vein thrombosis
Renal
– Oliguria
– Azotemia
– Renal artery/vein
throbosis
– ATN
Complications – Long Term
Chronic Pancreatitis
– Abdominal Pain
– Steatorrhea
– Exocrine insufficiency (pancreas has a 90%
reserve for the secretion of digestive
enzymes)
– Endocrine Insufficiency – less common
– Pseudocyst
Conclusions
Do not assume alcohol is the primary cause of
pancreatitis
Always consider further work-up for “idiopathic”
pancreatitis
Severe acute pancreatitis should be managed in
ICU/SD
Infected necrosis carries a high mortality
Antibiotics for suspected infected necrosis
Tube feedings preferred
Always look for the myriad of complications
CHRONIC
PANCREATITIS
Progressive – Destructive
Inflammation
 Permanent parenchymal loss
 Pancreatic endo + exo insufficiency
Causes
• Alcohol
80 %
(Ten years 60
gdL)
• Idiopathic
10%-20%
• Rare biliary, pHTP
Chronic Pancreatitis
Classic triad
Steatorrhea
Calcification
Diabetes
Symptoms + Signs
Abdominal Pain
Malabsorption
Diabetes
Jaundice
Pain
Mid-epigastrium;
Upperquadrant
periumbilical
Steady, boring, achy,
radiating to the back.
Better! When Sitting.
Diagnostic Laboratory
Amylase Slightly
Lipase
Liver Fu. Tests
Glucose
AP
Protrombin time





Diagnostic Imaging
CT: Ductal dilatation
Calcification
Pseudocysts
ERCP
Diagnostic Tests
Pancreolauryl-Test
Secretin – Pancreocymin Test
PANCREATIC NLP
1. Adeno – ca
2. Acinal cell
Giant cell
Epidermoid
Sarcoma
3. Islet cell
- 90%
 10%
- 5%