The mean age of the first attack was in the 6th
decade. This outcome can be explained by an increasing
incidence of gallstone pancreatitis among white women
over the age of 60 years[9,10]. The most common causes
were gallstones (11%-56%), idiopathic (8%-44%) and
alcohol (3%-66%). However, occult microlithiasis is
probably responsible for most cases of idiopathic AP
Overa
ll, severe AP (SAP) occurs in 10%-20% of
patients and despite improvements in critical care
between 10% and 25% of patients with SAP die
The pathogenesis of AP is caused by an inappropriate
activation of trypsinogen to trypsin. Once activated
these enzymes are responsible of autodigestion of
pancreatic tissues resulting in necrosis of the acini
and pancreatic islets with interstitial fat necrosis and
necrotizing vasculitis[SIRS may develop into acute respiratory
distress syndrome or multiorgan dysfunction syndrome
This systemic inflammatory response to pancreatic injury
marks the “first or early phase” of the n
atural course of
SAP, which normally characterizes the first 14 d of the
disease[21,22]. In this phase, organ failure is common and
often is not associated with infection[23]. The “second
or late phase” which starts 14 d after the onset of th
e
disease, is marked by infection of the gland, necrosis
and septic systemic complications causing a significant
increase in mortality[
Abdominal pain together with elevation of plasma levels
of pancreatic enzymes is the cornerstone of diagnosis.
The pain normally is generalized in the upper abdomen
and occurs suddenly without a prodrome. The pain,
which tends to last a few days, is often radiated in a
bandlike manner to the lower thoracic region of the back.
Nausea and vomiting normally appear in about
90%
of patients and can be severe.
Physical signs of severe
disease such as ecchymoses in the flank (Gray-Turner’s
sign) or in the periumbilical region (Cullen sign) occurs in
less than 3% of patients, and have been associated with a
mortality of 37%
Levels peak early,
and decline over 3-4 d. As a consequence, the diagnosis
should not rely on arbitrary levels 3 or 4 times greater
than normal, but levels should be interpreted in light of
the time since the onset of abdominal pain.
Enzymes released by acinar cells during an attack of AP
are amylase and lipase, and their con
centration in the serum
is used to confirm the diagnosis[28]. The half-life of elevated
amylase is shorter than that of lipase: the diagnosis using
plasma lipase has slightly superior sensitivity and specificity
and greater overall accuracy than amylase
In order to optimize the instant management and prevent
recurrence of AP it is essential identify the aetiology.
In the Western world, biliary tract disease (38%)
and alcoholism (36%) are accountable for the majority
of cases of AP[33]. However, in up to 10% of cases, the
cause of AP remains unknown (idiopathic AP).
Gallstones
In patients with no history of alcohol consumption, an
increased level of serum alanine aminotransferase up to 3
times its normal value is indicative of g
allstone pancreatitis.
Gallstone pancreatitis, in most cases, is caused by
gallstones passing into the bile duct and temporarily
lodging at the sphincter of Oddi. However, duct
obstruction can also be localized in the pancreatic duct.
Although not completely proven, it is thought that duct
obstruction leads to increased pancreatic duct pressure
with subsequence injury to acinar cells and activation
of digestive enzymes. It is supposed that only gallstones
with a diameter up to 5 mm can migrate distally into the
biliary duct whilst gallstones with a diameter of 8 mm or
more remain in the gallbladder[
In cases where a biliary aetiology is
suspected, the
first line of investigation should be a trans-abdominal
ultrasound (T-A US). The value of U
S lies in its ability
to demonstrate gallbladder stones and dilatation of
the CBD as well as other pathology unrelated to the
pancreas. In the case of high clinical suspicion of a biliary
cause of AP with normal T-A US, magnetic resonance
cholangiopancreatography or endoscopic US should
be performed in order to visualize the presence of
microlithiasis or other causes of duct obstruction.
Alcohol
Alcohol consumption is the second cause of AP.
Although the acinar cell is considered the main target of
damage by ethanol, there is not an accepted explanation
for why some patients are more p
redisposed to developing
AP than others who consume similar quantities of
alcohol. The pathogenesis of alcohol pancreatitis can be
explained by a combination of environmental and genetic
factors. Genetic studies have suggested that, in hereditary
pancreatitis, mutation of the cationic trypsinogen gene
and serine peptidase inhibitor, Kazal type 1 (SPINK1)
genes can promote AP in the presence of alcohol[36].
Post-ERCP acute pancreatitis
The risk of developing AP after endoscopic retrograde
cholangiopancreatography (ERCP) is around 5%[37].
The main risk factors for post-ERCP AP incl
ude female
gender, presence of periampullary divertic
ulum, and
procedure-related factors such as a cannulation time of
more than 10 min and major papilla sphincterotomy.
However, the risk of developing asymptomatic hyperamylasemia,
which appears in 35%-70% of patients,
seems to be linked with procedure-related factors
Trauma
Drug-induced pancreatitis
Drug-induced pancreatitis is considered a rare event
(0.1%-2%) and is normally mild and self-limiting. In the
literature, the true incidence of drug-induced AP is not
known since the evidence is derived mainly from case
reports and the diagnosis is always challenging because
of the difficulty in distinguishing the effects of drugs
from other causes of AP[40].
Dr ugs strongly associated with AP include
azathioprine, sulfonamides, sulindac, tetracycline, valproic
acid, didanosine, methyldopa, estrogens, furosemide,
6-mercaptopurine, pentamidine, 5-aminosalicylic acid
compounds, corticosteroids, and octreotide.
Infections
Infections are accountable for less than 1% of all AP
and tend to be milder than biliary and alcohol-induced
AP[41]. Viral infections such as Epstein-Barr, coxsackie
virus, echovirus, varicella-zoster and measles are the most
common causes of infectious AP especially in children.
Bacterial causes include Mycoplasma pneumoniae,
Salmonella typhosa, Leptospira, Campyloba
cter and Mycobacterium
tuberculosis.
Worldwide, ascariasis can cause AP by migration of
worms in and out of the duodenal papillae.
Hereditary pancreatitis
Hereditary pancreatitis is an autosomal dominant gainof-
function disorder related to mutations of the cationic
trypsinogen gene (PRSS1), which has an 80% penetrance.
Mutations in this gene cause premature conversion
of trypsinogen to active trypsin causing pancreatic
autodigestion. This genetic syndrome is associated with a
high risk of developing chronic pancreatitis at a young age
and of developing pancreatic cancer[42].
Mutations in the SPINK1 gene, which blocks the
active binding site of trypsin, rendering
it inactive, are
associated with acute and chronic pancreatitis. Patients
who have severe SPINK1 mutations normally develop
chronic pancreatitis in childhood[43].
In patients with mild CFTR gene mutations, an
increased risk of developing acute and chronic pancreatitis
has been observed in comparison with the general
population.
Hypercalcemia
Hypercalcemia and primary hyperparathyroidism can
lead to AP. Hypercalcemia, which causes less than 1% of
all cases of pancreatitis, normally appears with excessive
doses of vitamin D, familial hypocalciuric hypercalcemia
and total parenteral nutrition.
Hypertriglyceridemia
AP usually does not occur until serum
triglyceride levels
reach 1000 mg/dL. Hypertriglyceridemia causes about 2%
of AP and it is normally associated with type Ⅰ, Type Ⅱ
and Type Ⅴ hyperlipidemia. The triglyceride level should
be measured as soon as clinical presentation of AP appears
since this level tends to decline during hospitalization
because of fasting and Ⅳ fluid resuscitation.
Acquired hypertriglyceridemia can appear in adults
because of alcoholism, obesity and poorly controlled
diabetes mellitus.
In order to prevent recurrent attacks of AP, the
patient should be placed on a low-fat diet, a re
gular
exercise regimen, and tight control of diabetes, with use
of lipid-lowering drugs such as statins.
Developmental abnormalities of the pancreas
The pancreas develops from two buds stemming from
the alimentary tract of the developing embryo.
Pancreas divisum is a failure of the dorsal and ventral
pancreatic ducts to fuse during embryogenesis and it occurs
in about 5%-7% of the healthy population. Pancreatitis
appears only in 5% of patients with pancreas divisum and
it is thought to be the result of ductal hypertension caused
Tumor
Obstruction of the pancreatic ductal system by a tumor
can increase the intraduct pressure and causing AP in
proximately 14% of patients suffering from pancreatic
tumors
Autoimmune pancreatitis
This relatively newly described entity is an extremely rare
cause of AP. The diagnosis of autoimmune pancreatitis
has to be confirmed by specific radiological and
histological findings. Radiologically, there is a focal mass in
the pancreatic head on computed tomography (CT) scan
and irregular narrowing of the proximal pancreatic duct
on ERCP.
PREDICTION OF SEVERITY
Although, the majority of patients have a mild episode of
AP, it is difficult to identify the patients who are at risk of
developing severe disease on admission to the hospital.
There is agreement that there is still a need for an
early objective measure of severity. Clinical examination
in the first 24 h of admission although specific, lacks
sensitivity and hence is unreliable and should be
supported by objective measures[46].
Although there is no ideal single serum marker for predicting
severity, C-reactive protein (cut-off of 150 mg/L)
is a useful indicator of necrosis with a sensitivity and
specificity of 80% but is required to be measured more
than 48 h after the onset of symptoms[
In 1974, John Ranson selected 11 prognostic signs
based on statistical analysis of 43 parameters gathered
retrospectively from 450 AP patients. Five of these
criteria are measured on admission and the remaining 11
are measured 48 h post admission (Table 1).
In most cases AP is mild and its initial management
is directed towards maintenance of adequate organ
perfusion in order to reduce the systemic complications
caused by the pancreatic injury. This consists of fluid
resuscitation, analgesia, oxygen administration, antiemetics
and repeated evaluation of the patient’s vital signs with
the intention of identifying early manifestations of organ
dysfunction.
Adequate pain control is essential. Parenteral analgesia
is usually needed with an advantage in using patientcontrolled
analgesia. Opiates are normally used including
morphine and meperidine. Since there are no studies
directly comparing the effects of meperidine or morphine
on sphincter of Oddi manometry, morphine seems to
Although antiprotease treatment has
been successful in experimental pancreatitis, it has not been
shown to offer a survival benefit, but only a reduction of
the incidence of complications in human disease
All patients (EARLY)should have thrombo-prophylaxis with
low molecular weight heparin; however the decision to
begin stress ulcer prophylaxis is still debatable.
An important issue in the early treatment of SAP is
the optimal delivery of nutrition. After initial enthusiasm
towards parenteral nutrition (PN), recent guidelines
advise early enteral nutrition (EN) through a nasojejunal
tube[88]. Patients with AP are characterized by loss of
the gut barrier function which is involved in both local
and systemic infectious complications[
However, a recent meta-analysis by Petrov et al[97]
demonstrated that early ERCP with or without ES had
no beneficial effect in patients with predicted mild or
severe ABP without cholangitis. The conclusion of this
study was partially supported by the 2007 guidelines of
the American Gastroenterology Association which stated
that early ERCP in patient with severe ABP without
signs of acute cholangitis is still not uniformly accepted
in the literatura
MANGEMENT OF SAP: “LATE PHASE”
The main life-threatening event which characterizes the
late phase of SAP is infection of the necrotic pancreatic
parenchyma. Infection tends to occur in 10% to 50% of
patients with necrotizing pancreatitis and develops 2-3
wk after the onset of symptoms[26,106-108]. The mortality
increases from 5%-25% in patients with sterile necrosis
to 15%-28% when infection occurs
Despite the requirement for further multicenter
double-blind studies, the use of prophylactic antibiotics
in patients with proven necrotic pancreatitis on CT
has been advocated. β-lactam agents are preferred to
quinolones and the length of the therapy has to be at
least 2 wk (
