Review of Literature

REVIEW OF LITERATURE :

Introduction :

History offers numerous accounts of disease that might have been acute pancreatitis, an
early example being the fatal illness of Alexander the Great ( 323 BC) . This has been
mentioned by Sbarounis CN in 1997.1

The earliest case reports of patients dying of suppurative inflammation or tumours of the
pancreas were presented by S. Alberti (1578),J. Schenck (1600), and N. Tulp (1641)
(Sachs 1993)

Definition :

Currently , most pancreatologists use the 1992 Atlanta Symposium definition of acute
pancreatitis , which is an acute inflammatory process of the pancreas with variable
involvement of other regional tissues or remote organ system.

Prevalence and Incidence :

AP is a common emergency presentation, being responsible for 3% of all hospital
admissions with acute abdominal pain (Banerjee et al. 1994). The incidence rate of AP
varies considerably in different countries. Low figures have been reported in England
(10/100,000) (Corfield et al. 1985,Giggs et al. 1988) and Germany (15/100,000) (Assmus
et al. 1996). In USA, AP affects around 40-80 per 100,000 of the general population
(Lankisch 1999). In Finland, AP is a common disease, and its incidence has been
increasing from 47 to 73 per 100,000 inhabitants/year in 1970-1989, and the increase
correlates with alcohol consumption (Jaakkola and Nordback 1993)
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Trapnell JE in 1975 reviewed the incidence of acute pancreatitis occurring over a 20-
year period in the Bristol with 590 cases. The yearly incidence was 53-8 per million
population at risk, with a mortality of 9-0 per million. This compares favourably with 11-
4 deaths per million for England and Wales as a whole during the same period but the
difference is not statistically significant.. (Br Med J. 1975 Apr 26;2(5964):179-83.

The incidence of acute pancreatitis has been studied extensively in the United Kingdom.
Several authors have noted that the incidence of the disease has increased by a factor of
10 from the 1960s to the 1980s (  Thomson SR, Hendry WS, McFarlane GA, Davidson
AI. Epidemiology and outcome of acute pancreatitis. Br J Surg 1987;74:398-401. 
Bourke JB. Variation in annual incidence of primary acute pancreatitis in Nottingham,
1969-74. Lancet 1975;2:967-969.  Wilson C, Imrie CW. Changing patterns of
incidence and mortality from acute pancreatitis in Scotland, 1961-1985. Br J Surg
1980;77:731-734.)

The incidence of acute pancreatitis varies according to geographical locations. The

incidence in England , Denmark and in the United States varies from 4.8 to 24.2 per
100,000 patients. ( Go. VLW,Everhart JE:Pancreatitis , In Everhart JE (ed): Digestive
disease in United States : Epidemiology and Impact. NIH publication NO 94 – 1447 .
Washington DC , 1994 , p 693)

Michael J Goldacre in 2004 found that in England the incidence of acute pancreatitis
with admission to hospital increased from 1963-98: age standardised incidence rates were
4.9 per 100 000 population in 1963-74, 7.7 in 1975-86, and 9.8 in 1987-98 (Michael J
Goldacre BMJ 2004;328:1466-1469 (19 June), doi:10.1136/bmj.328.7454.1466)

Reports of incidence of acute pancreatitis from India are inadequate . However there are
some reports of chronic tropical pancreatitis which may have acute presentations
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H. Ramesh , S study revealed a prevalence of 1 in 500 while V Mohan in 1994 reported

an incidence of 50 to 60 new cases of TCP each year at Madras. In that centre 4% of all
diabetic presenting before the age of 30 years had pancreatic calculi.

The prevalence of chronic pancreatitis in south India is estimated to be 125 per 1,00,000
population in one survey.The majority of cases were calcific pancreatitis ,qualifying as
TCP (Tandon & Sato ,2002)

CLASSIFICATION OF ACUTE PANCREATITIS :

Acute pancreatitis has been classified as mild and severe form based on the 1992 Atlanta
symposium definitions. Mild Acute pancreatitis consists of minimal or no organ
dysfunction and an uneventful recovery. Sever pancreatitis manifests as organ failure and
or local complications such as necrosis , abscess or pseudocyst.

Race , Age and Sex in AP

In 1994 NIH USA showed in its study that the incidence of acute pancreatitis increases
with age and is three times more common in black men than in white men ( 1994
slesinger 1))

There is very little information in literature describing ethnic variations in etiologic and
clinical outcome of acute pancreatitis in the Asian population. Kandasami P ,in 2002
described the demographic, etiologic and clinical course of acute pancreatitis among the
three main races in Malaysia namely, the Malays, Chinese and Indians. One hundred and
thirty-three consecutive patients were admitted for acute pancreatitis for the period
January 1994 to July 1999 and they consisted of 77 males and 56 females The racial
breakdown of acute pancreatitis was: Malays 38 (28.6%), Chinese 19 (14.3%), Indians 75
(56.4%) and 1 (0.8%) patient was an orang asli. The incidence of alcohol association with
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was significantly increased in the males, while gallstone pancreatitis was principally a
disease of the female. Alcoholic pancreatitis was mainly among the Indians (73.3%) and
in contrast, gallstone was the commonest associated etiologic factor for the Malays and
Chinese. No etiologic factor could be identified in a substantial proportion of the Malay
patients (60.5%) when compared to the Chinese (36.8%) and Indians (35%)...( Singapore
Med J. 2002 Jun;43(6):284-8.)

Floyd A, in 2002 showed that incidence rate of acute pancreatitis in women increased
from 17.1 per 100,000 person-years in 1981 to 37.8 per 100,000 person-years in 2000.
The corresponding increase in men was from 18 per 100,000 person-years in 1981 to 27.1
per 100,000 person-years in 2000. The incidence rate of acute pancreatitis increased with
age in both sexes..( Scand J Gastroenterol. 2002 Dec;37(12):1461-5.)

Mark R. Burge, in 2003 showed that patients Hispanic would have an increased
incidence of diabetes following hospitalization for acute pancreatitis compared with non-
Hispanic white patients. The main outcome measure for the study was the frequency of
occurrence of post-pancreatitis diabetes according to ethnicity. Thirty seven (8.8%) of the
421 non-Hispanic white patients had post-pancreatitis diabetes compared with 61
(13.1%) of the 466 Hispanic patients (p < 0.05 by χ2) (Apr 2003, Vol. 5, No. 2: 183-188)

Michael J Goldacre in 2004 showed that the incidence rates for acute pancreatitis with
admission to hospital rose in both men and women from 1963 to 1998, particularly
among younger age groups in England. This probably reflects, at least in part, an increase
in alcoholic pancreatitis.( BMJ. 2004 June 19; 328(7454): 1466–1469)

AETIOLOGY OF ACUTE PANCREATITIS:

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Reginald Huber Fitz ( 1843 – 1913)2 , a pathologist at the Massachusetts General

Hospital , in his landmark paper published in Boston Medical and Surgical Journal in
1889 presented detailed clinical characteristics of fifty three patients , distinguishing
between haemorrhagic , suppurative and gangreneous forms of the disease. On treatment
he proclaimed that pancreatitis has been reportedly confounded with acute intestinal
obstruction , and thus has led …to an ineffective laparotomy , an operation which , in the
early stages of the disease is extremely hazardous. Mistakenly however , he believed that
acute pancreatitis was a complication of gastroduodenitis and “originates by the
extension of a gastroduodenal inflammation along the pancreatic duct”.

It was Chiari who in 1896 , postulated that the underlying pathophysiological mechanism
of the disease was pancreatic autodigestion – ie “that the pancreas succumbs to its own
digestive properties”3
Gallstones are the most common cause in the United Kingdom(Leese et al. 1988) and
Asia (Fan et al. 1993), whereas in USA (Steinberg and Tenner 1994) and Finland
(Jaakkola and Nordback 1993) alcohol is the most common causative factor.

Pancreas and biliary system:

The work of Fitz greatly facilitated other late nineteenth and early twentieth century
investigators , not least Eugene Lindsay Opie ( 1873 – 1971) , who in 1901 proposed that
gallstone lodged in the ampulla might occlude both the common bile duct and the
pancreatic duct , so forming a common channel that would allow reflux of bile into the
pancreatic duct with activation of pancreatic enzymes and pancreatitis. 4

Opie hypothesis dominated greater part of the twentieth century thinking regarding the
pathogenesis of pancreatitis ,but today it is regarded as a myth. By experiments on
opossum ( an animal with long and accessible pancreatobiliary channel) , Lerch et al in
1993 demonstrated that obstruction of the pancreatic duct alone causes necrotizing
pancreatitis indistinguishable from that seen when the bile duct is simultaneously
obstructed . 5
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Pancreas and Alcohol:

The earliest link between pancreatic disease and alcoholism was by Crawley who in 1788
described a thirty four year old man who was accustomed to free living and strong
corporeal exertions in the pursuit of country amusement 6 This patient died of diabetes
and emaciation , and at necropsy had pancreas studded with calculi.

However it was not until 1878 that chronic inflammation of the pancreas was linked to
alcoholism by Freidrich , who designated the condition as drunkard’s pancreas.

Alcohol was firmly established as an important pathogenetic factor in1917 (Symmers

1917)

Astonishingly , it was not until 1946 that Comfort et al from the Mayo clinic provided the
first detailed description of chronic pancreatitis as an disease entity. Alcohol was
implicated in 68% of cases , and on the basis of surgical specimen and necropsy reports ,
the authors speculated that chronic relapsing pancreatitis may represent summation of
repeated attacks of acute interstitial pancreatitis.

Pancreas and Genetics:

In 1952 , comfort and steinberg were the first to describe hereditary pancreatitis.

The aetiology remained obscure until modern molecular genetic techniques were applied
and Whitcomb and colleagues identified the disease gene as cationic trypsinogen. The
discovery not only elucidated the underlting cause of hereditary pancreatitis , an
uncommon form of the disease , but has also offered new insights into the pathogenesis
and natural history of acute and chronic pancreatitis and pancreatic cancer. The finding
that the disease causing gene in HP is a trypsinogen gene places this pivotal pancreatic
 Review of Literature

peptide and the acinar cell that produces it center stage in research into the pathogenesis
of acute pancreatitis.

In 1998 , Sharer N and Cohn JA reported a strong association between idiopathic chronic
pancreatitis and mutation of cystic fibrosis transmembrane conductance regulator
(CFTR) gene. These may in early part be responsible for relapsing attacks of acute
pancreatitis.

Pancreas and Hypocalcemia:

Any condition that can cause hypercalcemia can be a precipitating cause of acute
pancreatitis .This has been elicited by Brandwein et al in 1994 ( Am J Med Sci 308:173 ,
1994 , Branddwein K..)

Frick et al in 1994 showed that in vivo calcium-treated animals showed accumulation of

zymogen granules in the cytoplasm, cytoplasmic vacuolization, focal acinar cell
depolarization, acinar necrosis, and edema. Calcium causes amylase release from rat
pancreatic lobules in vitro (Frick TW, Wiegand D, Bimmler D, Fernandez-del Castillo C,
Rattner DW, Warshaw AL. Int J Pancreatol. 1994 Apr;15(2):91-6. )

Mithofer K in 1995 showed that acute experimental hypercalcemia induces dose-

dependent morphological alterations characteristic of acute pancreatitis, acute
hyperamylasemia, and early ectopic trypsinogen activation. (Gastroenterology. 1995
Jul;109(1):239-46. )

Frick TW in 1997 showed that increased intracellular trypsinogen activation is an early

step in the pathogenesis of hypercalcaemia induced pancreatitis and elevated cytosolic
calcium is thought to be an early event in the pathogenesis of acute pancreatitis .( Frick
TW, Fernandez-del Castillo C, Bimmler D, Warshaw .Gut. 1997 Sep;41(3):339-43.)
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Robert Sutton et al in 2003 showed that abnormal calcium signals induce intracellular
activation of digestive enzymes, and of nuclear factor B, as well as the morphological
changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and
mitochondrial membrane potential may contribute to further cell injury (Robert Suttona,
David Criddle , Michael G.T. Raraty, Alexei Tepikin, John P. Neoptolemos, Ole H.
Petersen Pancreatology 2003;3:497-505 (DOI: 10.1159/000075581)

Pancreatitis and drugs:

Mallory et al in 1980 showed that drug induced pancreatitis has same clinical feature as
other pancreatitis except that withdrawal of the drug cause decrease in the disease and the
reintroduction of the offending drug increases the disease process. ( Mallory A : Drug
induced pancreatitis : A critical review : Gastroenterology 78:813 1980)

Lankisch et al in 1995 established the incidence of drug induced pancreatitis to be 1.4%

and he mostly implicated azathioprine, mesalazine/sulfasalazine, 2',3'-dideoxyinosine
(ddI), oestrogens, frusemide, hydrochlorothiazide, and rifampicin.

Pancreatitis and Infectious diseases:

. The association of falciparum malara with pancreattis dates back to 1997 when Jhonson
et al reported attacks of acute pancreattis in PF positive patients (Post graduate Med 1977
Jun;61(6):181-3)

Pateron D in 1990 showed cases of acute pancreatitis attributable to tuberculosis .He also
concluded that tuberculous pancreatitis should be considered in subjects with acute
pancreatitis according to the epidemiological context, once the most frequent causes of
pancreatitis have been eliminated(Pateron D, Naveau S, Brivet F, Bedossa P, Poynard
T, Chaput JC. Gastroenterol Clin Biol. 1990;14(1):80-3.)

Pateron D in 1990 showed cases of acute pancreatitis attributable to tuberculosis .He also
concluded that tuberculous pancreatitis should be considered in subjects with acute
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pancreatitis according to the epidemiological context, once the most frequent causes of
pancreatitis have been eliminated(Pateron D, Naveau S, Brivet F, Bedossa P, Poynard
T, Chaput JC. Gastroenterol Clin Biol. 1990;14(1):80-3.)

AP has also been shown to be associated with AIDS as has been reported by Capepeli et
al in 1993. AP in HIV is related both to the virus itself and the drugs used in treatment of
HIV. ( Cappeli MS , Hassan T : Pancreatic diseases in AIDS ;J Clin Gastroenterol
17:254 1993)

Parenti et al in 1996 showed that pathologic or radiologic evidence of pancreatitis

associated with well-documented infection was noted with viruses (mumps, coxsackie,
hepatitis B, cytomegalovirus, varicella-zoster virus, herpes simplex virus), bacteria
(Mycoplasma, Legionella, Leptospira, Salmonella), fungi (Aspergillus), and parasites
(Toxoplasma, Cryptosporidium, Ascaris). Clues to the infectious nature of pancreatitis
lay in the characteristic signs and symptoms associated with the particular infectious
agent. (Parenti DM, Steinberg W, Kang P 1996 Nov;13(4):356-71.)

Pancreatitis and Hypertriglyceridemia:

Toskes PP in 1990 showed that marked elevation of triglyceride levels appears to be
causally linked to acute pancreatitis and is found in 12% to 38% of patients presenting
with acute pancreatitis. Elevated cholesterol levels are not associated with pancreatitis.
The pathogenesis of pancreatitis associated with hypertriglyceridemia is not clear.
( Toskes PP Gastroenterol Clin North Am. 1990 Dec;19(4):783-91.)

Hyperlipedemic AP is particularly associated with patients having associated diabetes

mellitus , alcohol intake and ingestion of drugs or diet indeuced hypertriglyceridemia
aswas shown by Glueck et al in 1994 ( Glueck Cj , Lang J , J Lab Clin Med 123:18 ,
1994)

Fortson et al in 1995 has put the incidence of acute pancreatitis due to

hypertriglyceridemia to be 1 to 4% of all pancreatitis cases. They also found levels >
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1000mg to be mostly associated with AP. ( Fortson MR , Freedman SN , Webster PD 3rd

Clinical assessment of hyperlipedemic pancreatitis ; Am J Gastroenterol 90:2134 , 1995)

Peter Simson in 2001 has convincingly linked lipoprotein lipase and apolipoprotein C-II
deficiency with acute pancreatitis .( Peter Simon, F. Ulrich Weiss, Klaus-Peter Zimmer,
Hans Georg Koch, Markus M. Lerch Pancreatology 2001;1:448-456 (DOI:
10.1159/000055846)

Clinical presentation

The diagnosis of AP is problematic while there are no specific clinical signs. Patients
with AP may suffer from a multitude of symptoms, including upper abdominal pain,
meteorism, abdominal resistance, fever, nausea and vomiting, ileus and jaundice
(Steinberg and Tenner 1994). None of these frequent symptoms are related to the severity
of the disease. Rare clinical findings, such as ecchymosis of the flank (Grey Turner sign)
or periumbilical area (Cullen sign), which occur in 1- 3% of patients, also fail to
effectively predict the severity of AP (Büchler 1991). Within the first days of admission
patients with severe AP may develop SIRS characterized by a combination of fever,
tachycardia, and tachypnoea (Bone 1996).

ASSESMENT OF SEVERITY OF ACUTE PANCREATITIS:

According to the Atlanta classification system

Pitchumoni CS in 1991 commented that - Assessment of severity of acute pancreatitis

(AP) is a key determinant in the management of a patient. Various methods of
assessment: clinical assessment, biochemical tests, Ranson's and Imrie's multiple
prognostic criteria, simplified prognostic criteria, APACHE II, peritoneal lavage, and
computed tomography. Although all of the above criteria can identify most of the
seriously ill patients, each has some drawbacks. Individual preference and available
institutional facilities greatly influence the method used for prognostic assessment in AP.
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However, some type of predictive assessment is possible in any hospital, and should be
used in the management of patients with AP.
(Assessment of severity in acute pancreatitis, Agarwal N, Pitchumoni CS. ; Am J
Gastroenterol. 1991 Oct;86(10):1385-91.)

CLINICAL CRITERIA :

Bank et al in 1983 proposed the Bank’s criteria for defining the severity of Acute
Pancreatitis

Organ System Finding

cardiac severe hypotension or shock
tachycardia > 130 beats per minute
arrhythmia
ECG changes
pulmonary dyspnea
rales, pulmonary edema
PaO2 < 60 mm Hg
adult respiratory distress syndrome
renal urine output < 50 mL/h
increasing BUN and/or creatinine
metabolic low or falling calcium
low or falling pH
decreased albumin
hematologic falling hematocrit
DIC (low platelet counts, fibrin split products)
neurological irritability
confusion
localizing signs on neurological examination
hemorrhagic pancreatitis Grey-Turner or Cullen signs; evidence on peritoneal tap
tense distension (abdomen) severe ileus, fluid 2+

Number of Bank's criteria = SUM(findings present)

Interpretation:

• minimum number = 0
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• maximum number = 20

• Severe disease (potentially lethal) may occur if 1 or more of these findings is present.

(Bank S, Wise L, Gersten M. – Risk factors in Acute Pancreatitis : Am J Gastroenterol.

1983 Oct;78(10):637-40. ; )

Simplified prognostic criteria (SPC) was developed for evaluating patients with acute
pancreatitis by Agarwal et al in 1986. This was based on modification of the Rank criteria
and included only the Cardiac. Pulmonary, renal and metabolic parameters:

(Pancreas. 1986; 1(1):69-73. Agarwal N, Pitchumoni CS, Simplified prognostic criteria in

acute pancreatitis)

However both these studies needed a 48 hours observation and were dependent on the
expertise of the clinical teams and were difficult to standardize.

( Raffaele Pezzilli and Francesco Mancini : World J of Gastroenterology : August

5(4):283-285)

CLINICAL AND LABORATORY CRITERIA:

John H C Ranson in 1974 designed his prognostic signs for early detection of patients
with severe pancreatitis in 1974 and he did this to evaluate the role of early operative
intervention. After evaluating 100 consecutive cases of acute pancreatitis , he selected the
nowadays well known eleven “ Ranson prognostic signs”

At Admission :

• Age over 55 years.

• White blood cell count over 16,000/uL.
• Blood glucose over 200 mg/dL.
• Serum lactate dehydrogenase (LDH) over 350 units/L.
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• Aspartate aminotransferase (AST, SGOT) over 250 units/L.

Development of the following in the first 48 hours indicates a worsening prognosis:

• Hematocrit drop of more than ten percentage points.
• Blood urea nitrogen (BUN) rise greater than 5 mg/dL.
• Arterial PO2 of less than 60 mm Hg.
• Serum calcium of less than 8 mg/dL.
• Base deficit over 4 meq/L.
• Estimated fluid sequestration of more than 6 L.

Mortality rates correlate with the number of criteria present:

Number of Mortality rate

criteria
0-2 1%
3-4 16%
5-6 40%
7-8 100%

(Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and
the role of operative management in acute pancreatitis.Surg Gynecol
Obstet,1974;139:69-81)

Imrie CW et al in 1978 proposed “The Glasgow system” which is a simple prognostic

system that uses the data collected during the first 48 hours following an admission for
pancreatitis. It is applicable to both biliary and alcoholic pancreatitis.The original system
used 9 data elements. This was subsequently modified to 8 data elements, with removal
of assessment for transaminase levels (either AST (SGOT) or ALT (SGPT) greater than
100 U/L).

Parameters used:

(1) age in years

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(2) serum albumin

(3) PaO2 on room air

(4) serum calcium

(5) blood glucose

(6) serum LDH

(7) BUN

(8) WBC count

Parameter Finding at any time duringPoints

1st 48 hours
age > 55 years 1
<= 55 years 0
serum albumin < 3.2 g/dL 1
>= 3.2 g/dL 0
arterial pO2 on room air < 60 mm Hg 1
>= 60 mm Hg 0
serum calcium < 8 mg/dL 1
>= 8 mg/dL 0
blood glucose > 180 mg/dL 1
<= 180 mg/dL 0
serum LDH > 600 U/L 1
<= 600 U/L 0
serum urea nitrogen > 45 mg/dL 1
<= 45 mg/dL 0
WBC count > 15,000 per µL 1
<= 15,000 per µL 0

Modified Glasgow prognostic criteria = SUM(points for all 8 parameters)

Interpretation:

 minimum score 0
 maximum score 8
 If the score >=3, severe pancreatitis likely.
 If the score < 3, severe pancreatitis is unlikely.
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(Imrie CW, Benjamin IS, Ferguson JC, McKay AJ, Mackenzie I, O＇Neill JO, Blumgart
LH.A single center double blind trial of Trasylol therapy in primary acute
pancreatitis.Br J Surg,1978;65:337-341)

Another simplified score was set up by Fan et al in 1989, utilizing only two biochemical
parameters (azotemia and glycemia). This score system has a sensitivity of about 75% in
the assessment of the severity of acute pancreatitis.
(Fan ST, Choi TK, Lai ECS, Wong J. Prediction of severity of acute pancreatitis: an
alternative approach.Gut,1989;30:1591-1595)

The APACHE II scoring system was introduced in the assessment of severity of acute
pancreatitis by Knaus WA et al in 1985 which takes into consideration age, presence of
chronic associated diseases and some biochemical parameters .Wilson et al in 1990 have
reported a score of 6.3 in patients with mild acute pancreatitis, of 9.4 in those with severe
pancreatitis and of 14.1 in those with fulminant pancreatitis.
Components:

(1) acute physiology score (APS)

(2) age points

(3) chronic health points

Data collection:

• The data for the acute physiology is collected during the initial 24 hour period after ICU
admission.

• The worst (most deranged) physiologic value is selected for grading.

Acute Physiology Score (APS)

Parameter Finding Points -1 1 2 3 4 5

rectal temp in C° >= 41 +4

39-40.9 +3
38.5-38.9 +1
36-38.4 0
34-35.9 +1
32-33.9 +2
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30-31.9 +3
<= 29.9 +4
mean arterial >= 160 +4
pressure mm Hg
130-159 +3
110-129 +2
70-109 0
50-69 +2
<= 49 +4
heart rate in >= 180 +4
beats/minute
140-179 +3
110-139 +2
70-109 0
55-69 +2
40-54 +3
<= 39 +4
respiratory rate in >=50 +4
breaths/min
35-49 +3
25-34 +1
12-24 0
10-11 +1
6-9 +2
<= 5 +4
oxygenation A-aDO2 >= 500 and FIO2 >= 0.5 +4
A-aDO2 350-499 and FIO2 >= 0.5 +3
A-aDO2 200-349 and FIO2 >= 0.5 +2
A-aDO2 < 200 and FIO2 >= 0.5 0
PaO2 > 70 and FIO2 < 0.5 0
PaO2 61-70 and FIO2 < 0.5 +1
PaO2 55-60 and FIO2 < 0.5 +3
PaO2 < 55 and FIO2 < 0.5 +4
arterial pH >= 7.7 +4
7.6-7.69 +3
7.5-7.59 +1
7.33-7.49 0
7.25-7.32 +2
7.15-7.24 +3
< 7.15 +4
serum sodium >= 180 +4
160-179 +3
155-159 +2
150-154 +1
130-149 0
120-129 +2
111-119 +3
<= 110 +4
serum potassium >= 7.0 +4
6.0-6.9 +3
5.5-5.9 +1
3.5-5.4 0
3.0-3.4 +1
2.5-2.9 +2
< 2.5 +4
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serum creatinine >= 3.5 and not acute renal failure +4

in mg/dL
2.0-3.4 and not acute renal failure +3
1.5-1.9 and not acute renal failure +2
0.6-1.4 and not acute renal failure 0
< 0.6 and not acute renal failure +2
>= 3.5 and acute renal failure +8
2.0-3.4 and acute renal failure +6
1.5-1.9 and acute renal failure +4
0.6-1.4 and acute renal failure 0
< 0.6 and acute renal failure +4
hematocrit in >= 60 +4
percent
50-59.9 +2
46-49.9 +1
30-45.9 0
20-29.9 +2
< 20 +4
WBC count in >= 40 +4
thousands
20-39.9 +2
15-19.9 +1
3-14.9 0
1-2.9 +2
<1 +4
Glasgow Coma 15 -
Score (Glasg
ow
Coma
Score)

where:

 The score for serum creatinine is doubled if the patient has acute renal failure.
 mean arterial pressure = ((systolic blood pressure)+ (2 * (diastolic pressure))) / 2

If no blood gas data is available then the serum bicarbonate can be used ( assume in
place of the arterial pH):

Parameter Finding Points -1 1 2 3 4 5

serum bicarbonate in >= 52.0 +4
mmol/L
41.0 – 51.9 +3
32.0 – 40.9 +1
22.0 – 31.9 0
18.0 – 21.9 +2
15.0 – 17.9 +3
< 15.0 +4

Age Points

Age Points
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<= 44 0
45-54 2
55-64 3
65-74 5
>= 75 6

Chronic Health Points

Operative Status Health Status Points

nonoperative patient history of severe organ insufficiency OR 5
immunocompromised
no history of severe organ insufficiency 0
AND immunocompotent
emergency postoperative history of severe organ insufficiency OR 5
patient immunocompromised
no history of severe organ insufficiency 0
AND immunocompotent
elective postoperative history of severe organ insufficiency OR 2
patient immunocompromised
no history of severe organ insufficiency 0
AND immunocompotent

where:

• organ insufficiency or immunocompromised state must have preceded the current

admission
• Immunocompromised if: (1) receiving therapy reducing host defenses
(immunosuppression chemotherapy radiation therapy long term steroid use high
dose steroid therapy) or (2) has a disease severe enough to interfere with immune
function such as malignant lymphoma leukemia or AIDS
• Liver insufficiency if: (1) biopsy proven cirrhosis (2) portal hypertension (3)
episodes of upper GI bleeding due to portal hypertension (4) prior episodes of
hepatic failure coma or encephalopathy
• Cardiovascular insufficiency if: New York Heart Association Class IV
• Respiratory insufficiency if: (1) severe exercise restriction due to chronic
restrictive obstructive or vascular disease (2) documented chronic hypoxia
hypercapnia secondary polycythemia severe pulmonary hypertension (3)
respirator dependency
• Renal insufficiency if: on chronic dialysis

APACHE II score = (acute physiology score) + (age points) + (chronic health points)

Interpretation:

• minimum score: 0
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• maximum score: 71

• An increasing score is associated with an increasing risk of hospital death.

Roumen MN et al in 1992 showed that the sensitivity in prediction of death was best
with APACHE II score greater than 9 (96%) and Ranson score greater than or equal to 3
(95%). APACHE II scoring is concluded to be best for grading the severity of disease on
admission to intensive care, while the MOF score is best for monitoring the degree of
organ dysfunction and the intensity of supportive treatment.
(Scoring systems for predicting outcome in acute hemorrhagic necrotizing pancreatitis.
Roumen RM, Schers TJ, de Boer HH, Goris RJ.: EurJ Surg. 1992 Mar;158(3):167-71)

In 1993 ,following 3 days of group meetings and open discussions, unanimous consensus
on a series of definitions and a clinically based classification system for acute pancreatitis
was achieved by a diverse group of 40 international authorities from six medical
disciplines and 15 countries. This is now known as the Atlanta Criteria of severity of
Acute Pancreatitis. They are as follows:

DEFINITIONS OF SEVERITY (Atlanta Criteria)

(1) Severe Acute pancreatitis
Severe acute pancreatitis is defined by-
- Presence of complication; organ failure/or local complications such as necrosis
& abscess.
- Predicted severe acute pancreatitis as determined by multifactor scoring system
or other predictive test.

(2) Mild Acute pancreatitis

Mild acute pancreatitis is associated with minimal organ dysfunction, and an
uneventful recovery. The predominant pathological feature is interstitial oedema
of the gland.

(3) Acute Fluid collection

 Review of Literature

Acute fluid collection occurs early in the course of Acute pancreatitis, are located
in or near the pancreas and always lack a wall of granulation of fibrous tissue.

(4) Pancreatic necrosis

Pancreatic necrosis is a diffuse or focal area (s) of nonviable pancreatic
parenchyma which is typically associated with peripancreatic fat necrosis. The
onset of infection results in infected necrosis, which is associated with a trebling
of the mortality risk.

(5) Acute pseudocyst:- - It is fluid collection enclosed in a wall of fibrous or

granulation tissue, persisting for more than four weeks, arising from an attack of
acute pancreatitis.

(6) Pancreatic abscess- a pancreatic abscess is circumscribed intra abdominal

collection of pus, usually in proximity to the pancreas, containing little or no
pancreatic necrosis, which arises as a consequence of acute pancreatitis.

(A clinically based classification system for acute pancreatitis. Summary of the

International Symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13,
1992. Bradley EL 3rd.Arch Surg 1993; 128:586-90)

Johnson CD et al in 1994 confirmed that age, obesity and APACHE-II measured in the
first 24 h of hospital admission can predict complications in acute pancreatitis.
Combination of the APACHE-II and obesity scores by simple addition improved
categorical prediction of severity (mild or severe) in patients with acute pancreatitis
(Johnson CD, Toh SK, Campbell MJ.: Combination of APACHE-II score and an obesity
score (APACHE-O) for the prediction of severe acute pancreatitis: Pancreatology.
2004;4(1):1-6. Epub 2004 Feb 24.)

In 2001 R Isenmann et al found that using the Atlanta criteria, a considerable number of patients
with acute pancreatitis is classified as suffering from severe disease despite of having an
underaverage risk of death. So they suggested that a revision of our current classification of acute
pancreatitis seems to be necessary.
 Review of Literature

Failure of the Atlanta Classification to Identify Patients with Poor Prognosis in

Necrotizing Pancreatitis R. Isenmann, B. Rau, H.G. Beger: Pancreatology 2001;1:129–
199

Abu-Eshy SA in 2001 in a study revealed that acute pancreatitis seen in Asir region was
predominantly biliary-associated and was more frequent in females. Although near half
of the attacks were classified as severe pancreatitis, according to Ranson's criteria,
complications occurred in only 22% of the attacks and this may indicate that Ranson's
criteria needs to be modified before application in our setting.

(Abu-Eshy SA. Saudi Med J. 2001 Nov;22(11):1039. : Pattern of acute pancreatitis.)

Blum T et al in 2001 showed that an APACHE II score > or = 6 and a lipase level on
admission > or = 1,000 U/l indicate severe pancreatitis.
(Blum T, Fatal outcome in acute pancreatitis: its occurrence and early prediction.:
Pancreatology. 2001;1(3):237-41.)

Notas et al in 2002 showed that the APACHE III offers little, if any, advantage over the
APACHE II score. Ranson criteria proved to be as powerful a prognostic model as the
more complicated APACHE II and III scoring systems, but with the disadvantage of a
24-hour delay
(Comparison of Ranson, APACHE II and APACHE III Scoring Systems in Acute
Pancreatitis. -Pancreas.25(4):331-335,November,2002--.Chatzicostas, Constantinos;
Roussomoustakaki, Maria; Vlachonikolis, Ioannis G.; Notas, Georgios; Mouzas, Ioannis;
Samonakis, Dimitrios; Kouroumalis, Elias A.)

Lankisch PG et al in 2002 found that the APACHE IIScore had a sensitivity of 36%;
specificity of 72%; the positive predictive value of 24%; and the negative predictive
value of 82%. They concluded that evaluation of sensitivity, specificity, and positive and
negative predictive value for all APACHE II score points showed that there was not a
"golden" cutoff to detect necrotizing pancreatitis and that the score on admission to the
hospital is unreliable to diagnose necrotizing pancreatitis.
(Lankisch PG, Warnecke B, Bruns D, Werner HM, Grossmann F, Struckmann K,
Brinkmann G, Maisonneuve P, Lowenfels AB.: The APACHE II score is unreliable to
 Review of Literature

diagnose necrotizing pancreatitis on admission to hospital:- Pancreas. 2002

Apr;24(3):217-22.)

Venkatesan T et al in 2003 showed that an APACHE II score of >8 exhibited 50%

sensitivity and 69% specificity (positive predictive value, 20%; negative predictive value,
89%). All patients with systemic complications and two of seven patients with only local
complications had an APACHE II score of >8. The APACHE II scoring system exhibited
reasonable sensitivity in predicting systemic complications and/or the need for surgery,
with a low positive predictive value. This most certainly is a function of the low pretest
probability of severe pancreatitis.
(Venkatesan T, Moulton JS, Ulrich CD 2nd, Martin SP.: Prevalence and predictors of
severity as defined by atlanta criteria among patients presenting with acute pancreatitis.:
Pancreas. 2003 Mar;26(2):107-10.)

Halonen KI et al in 2003 proposed a Novel prognostic logistic model with four variables:
age, highest serum creatinine value within 60-72 h from primary admission, need for
mechanical ventilation, and chronic health status for assessing severity of acute
pancreatitis. They found in the study that Ranson and Imrie scores are inaccurate
indicators of the mortality in SAP and that the novel predictive model based on four
variables can reach at least the same predictive performance as the APACHE II system
with 14 variables
(Halonen KI, Leppaniemi AK, Lundin JE, Puolakkainen PA, Kemppainen EA,
Haapiainen RK.: - Predicting fatal outcome in the early phase of severe acute pancreatitis
by using novel prognostic models:- Pancreatology. 2003;3(4):309-15.)

Poves Prim I et al in 2004 showed that APACHE II is not reliable for predicting outcome
within the first 24 hours after admission and should therefore be used together with other
methods. Organ failure mostly develops within the first days after admission, if ever.
They showed that the time of onset of organ failure is the most accurate and reliable
method for predicting death risk in AP
 Review of Literature

(Poves Prim I, Fabregat Pous J, Garcia Borobia FJ, Jorba Marti R, Figueras Felip J,
Jaurrieta Mas E.:- Early onset of organ failure is the best predictor of mortality in acute
pancreatitis:- Rev Esp Enferm Dig. 2004 Oct;96(10):705-9; 709-13.)

Du W et al in 2005 showed that Systemic inflammatory response syndrome (SIRS) is

highly correlated with the severity of acute pancreatitis. Active prevention and treatment
of SIRS may raise the survival rate of severe acute pancreatitis

(Du W, Wang H, Zhang SW, Wang BE. Investigation on the relation between systemic
inflammatory response syndrome and severity of acute pancreatitis:_ Zhongguo Wei
Zhong Bing Ji Jiu Yi Xue. 2005 May;17(5):279-81)

Georgios I et al in 2006 demonstrated that admission APACHE-O score is not more

accurate than APACHE-II. However they suggested that obesity increases the severity of
AP by amplifying the immune response to injury
(Georgios I. Papachristou, Dionysios J. Papachristou, Haritha Avula, Adam Slivka, David
C. Whitcomb:Obesity Increases the Severity of Acute Pancreatitis Performance of
APACHE-O Score and Correlation with the Inflammatory Response: Pancreatology
2006;6:279-285)

Spitzer et al in 2006 proposed the model (BALI), which included BUN >/=25 mg/dL,
Age >/=65 years, LDH >/=300 IU/L, and IL-6 >/=300 pg/mL, measured at admission,
and found that the results were similar to the Ranson, Glasgow, and APACHE II systems
in its ability to identify increased mortality from acute pancreatitis
(Spitzer AL, Barcia AM, Schell MT, Barber A, Norman J, Grendell J, Harris HW.--
Applying Ockham's Razor to Pancreatitis Prognostication: A Four-Variable Predictive
Model.: Ann Surg. 2006 Mar;243(3):380-388.)

BIOCHEMICAL CRITERIA :
a. Markers of Inflammation:
TNF alpha , IL 6 , IL 8 , IL 10, IL 11:
 Review of Literature

J G Norman et al in 1995 demonstrated that early or late blockade of the cytokine

cascade at the level of the IL-1 receptor significantly decreases the mortality of severe
acute pancreatitis. The mechanism by which this is accomplished appears to include
attenuation of systemic inflammatory cytokines and decreased pancreatic destruction.

(Decreased mortality of severe acute pancreatitis after proximal cytokine blockade.: Ann
Surg. 1995 June; 221(6): 625–634. :J G Norman, M G Franz, G S Fink, J Messina, P J
Fabri, W R Gower, and L C Carey

McKay in 1996 reported that systemic complications of acute pancreatitis are associated
with a significant increase in monocyte secretion of TNF-alpha, IL-6 and IL-8 suggesting
that, as in sepsis, these cytokines play a central role in the pathophysiology of the disease.

(McKay CJ, Gallagher G, Brooks B, Imrie CW, Baxter JN. r J Surg 1996; 83:919-23.
Increased monocyte cytokine production in association with systemic complications in
acute pancreatitis)

Pezzilli R ( 1997) found that on the first day of the acute pancreatitis, patients with the
mild disease had serum levels of IL-10 significantly higher than those with severe
disease, whereas in the following days, no statistically significant difference was
observed between the two groups. The elevation of IL-10 on the first day of the illness is
more marked in patients with mild acute pancreatitis than in those with the severe form of
the disease. The finding of low values of serum IL-10 in severe acute pancreatitis
suggests that there may be altered down-regulation of the immune system response in
these patients.

(Pezzilli R, Billi P, Miniero R, Barakat B. Serum interleukin-10 in human acute

pancreatitis: Dig Dis Sci. 1997 Jul;42(7):1469-72

The p60 subtype of soluble receptors of tumour necrosis factor alpha (sTNFR, p60
subtype) is elevated in the plasma of patients with clinically severe acute pancreatitis.
This elevation is positively correlated to abnormalities in physiological parameters,
development of multiorgan failure, and mortality. The association with pancreatic
necrosis suggests that, by mediating the effects of TNF, TNFRp60 reflects inflammatory
tissue damage leading to severe systemic complications. (Kaufmann P 1997)

(Kaufmann P, Tilz GP, Lueger A, Demel U.: Elevated plasma levels of soluble tumor
necrosis factor receptor (sTNFRp60) reflect severity of acute pancreatitis.: Intensive Care
Med. 1997 Aug;23(8):841-8.)
 Review of Literature

During acute severe pancreatitis, the pro- and anti-inflammatory cytokine response
occurred early and persisted in the systemic circulation for several days. Although
associated with the patient's severity at inclusion and outcome, cytokine plasma
concentrations were unable to predict death accurately in individual patients ( Brivet et al
1999)
(Pro- and anti-inflammatory cytokines during acute severe pancreatitis: An early and
sustained response, although unpredictable of death. Critical Care Medicine. 27(4):749-
755, April 1999.Brivet, Francois G. MD; Emilie, Dominique MD; Galanaud, Pierre MD)

C-C Chen in 1999 found that with cut off levels of 30 pg/ml for interleukin
10, 10.5 pg/ml for interleukin 11, and 115 mg/l for C reactive protein, the accuracy rates
for detecting severe pancreatitis were 84%, 64%, and 78% respectively on day one and
82%, 74%, and 84% respectively on day two. They concluded that serum interleukin
10 and interleukin 11 concentrations reflect the severity of acute pancreatitis. Interleukin
10 is a useful variable for early prediction of the prognosis of acute pancreatitis.
(Serum interleukin 10 and interleukin 11 in patients with acute pancreatitis C-C Chen, S-
S Wang, R-H Lu, F-Y Chang, S-D Lee; Gut 1999;45:895-899 ( December ))

Chen C C et al ( 1999) using cutoff levels of 12 pg/ml for tumor necrosis factor-alpha, 1
pg/ml for interleukin-1-beta, 400 pg/ml for interleukin-6, 100 pg/ml for interleukin-8, 12
mg/dl for C-reactive protein, and 10 for the Acute Physiology and Chronic Health
Evaluation (APACHE II) score, the accuracy rates for detecting severe pancreatitis were
72%, 82%, 88%, 74%, 80%, and 72%, respectively, on day 1 and 78%, 74%, 80%, 76%,
80%, and 78%, respectively, on day 2. So he concluded that among the proinflammatory
cytokines, interleukin-6 is the most useful parameter for early prediction of the prognosis
of acute pancreatitis.
(Am J Gastroenterol. 1999 Jan;94(1):213-8. : Chen CC : Proinflammatory cytokines in
early assessment of the prognosis of acute pancreatitis.)

Pooran et al in 2003 demonstrated that IL-6, IL-8, and TNF can be used independently in
differentiating mild acute pancreatitis from early severe acute pancreatitis..
 Review of Literature

(Cytokines (IL-6, IL-8, TNF): Early and Reliable Predictors of Severe Acute Pancreatitis.
Liver, Pancreas, and Biliary Tract: Pooran, Nakechand MD; Indaram, Anant MD; Singh,
Pankaj MD; Bank, Simmy MD :Journal of Clinical Gastroenterology. 37(3):263-266,
September 2003.)

Balog A (2005) studied whether polymorphisms of the tumor necrosis factor alpha (TNF-
alpha), heat shock protein 70-2 (HSP70-2), and CD14 genes correlate with the severity of
acute pancreatitis. They found that there was a moderate increase in the frequency of the
TNF1/2 genotype (P = 0.046) among patients with severe acute pancreatitis as compared
with those with mild disease. A more significant increase was observed in the frequency
of the HSP70-2 G allele between groups of patients with mild or severe pancreatitis
(18.9% vs. 53%; P < 0.001). Conversely, the A/A genotype was markedly more frequent
among the patients with mild pancreatitis (P < 0.0001). There was no significant
correlation between CD14-159 promoter polymorphism and the severity of pancreatitis

(Polymorphism of the TNF-alpha, HSP70-2, and CD14 genes increases susceptibility to

severe acute pancreatitis.:Balog A, Gyulai Z, Boros LG, Farkas G, Takacs T, Lonovics J,
Mandi Y.: Pancreas. 2005 Mar;30(2):e46-50)

C Reactive Protein :

C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the
liver. It is a member of the pentraxin family of proteins. CRP was originally discovered
by Tillett and Francis in 1930 as a substance in the serum of patients with acute
inflammation that reacted with the C polysaccharide of pneumococcus . (1)

The CRP gene is located on the first chromosome (1q21-q23).

Pepys MB in 1981 mentioned that complexed CRP can activate the complement system
and, by virtue of its dramatically increased production in response to tissue injury, it
probably acts primarily as a protective mechanism. However, in some circumstances
CRP may also initiate or exacerbate inflammatory lesions. Clinical measurement of
serum CRP is valuable as a screening test for organic disease and as a sensitive object
 Review of Literature

index of disease activity and response to therapy in some inflammatory, infective, and
ischemic conditions (2)

Gewurz H C et al in 1982 postulated that in addition to serving as a diagnostic aid for the
presence of inflammatory and necrotic processes, elevated levels of CRP may well
provide an important component of the nonspecific host mechanisms, particularly in the
early stages following inflammatory stimuli. Inquiries into the structure and function of
CRP indicated an unexpected relationship of this molecule to an amyloid-related protein
with slight differences. (3)

Mayer AD et al in 1984 showed that the main value of C reactive protein is to provide a
guide to the severity of the inflammation and to increase clinicians' awareness of the
patient's enhanced risk of developing pancreatic collections when the C reactive protein
concentration remains high (greater than 100 mg/l) at the end of the first week of the
illness. In this respect C reactive protein concentrations are superior to white cell count,
erythrocyte sedimentation rate, and temperature and the concentrations of antiproteases.
(4.)

Puolakkainen P in 1987 showed that the increase in CRP was greater in the patients with
severe pancreatitis. One day after admission mean CRP was 280 mg/l in patients with
haemorrhagic and 45 mg/l in those with the mild pancreatitis (p less than 0.001). High
CRP values also correlated with the prognostic signs indicative of severe pancreatitis.
CRP and S-phospholipase A2 determinations are valuable in the early assessment of the
severity of acute pancreatitis, but the CRP assay is much easier to include in hospital
routine(5)

Wilson et al in 1989 monitored serum C-reactive protein (CRP) in patients admitted for
acute pancreatitis . Values indicating complicated pancreatitis were

(1) maximum (peak) CRP on second, third or fourth hospital day >= 210 mg/L

(2) CRP on day 7 >= 120 mg/L

 Review of Literature

During the study they found that CRP peak >= 210 mg/L had a sensitivity of 83%,
specificity of 85%, correctly classified 85% of cases. Also , CRP value on day 7 >=120
mg/L had a sensitivity of 90%, specificity of 85% and correctly classified 87%
cases.The performance was comparable to Glasgow or Ranson scores. ( 6)

Leser HG et al in 1991 showed that C-reactive protein concentrations followed the course
of interleukin-6 concentrations by 1 day. There was a positive correlation between
maximal interleukin 6 concentrations and maximal increases in the serum concentrations
of C-reactive protein. They concluded that elevated serum concentrations of interleukin-6
followed by increased levels of C-reactive protein reflect the severity of acute pancreatitis
{7 }

Chen CC et al in 1992 studied the value of serum C-reactive protein, lactate

dehydrogenase isoenzymes and erythrocyte sedimentation rate in predicting the outcome
of acute pancreatitis. The sensitivity, specificity and accuracy of predicting a severe
attack were 94, 76 and 82% using C-reactive protein greater than or equal to 8 mg/dL on
day 2; 67, 92 and 84% using C-reactive protein greater than or equal to 5 mg/dL on day
7; When compared with Ranson's criteria, lactate dehydrogenase isoenzymes and
erythrocyte sedimentation rate, C-reactive protein is more valuable in the early
assessment of the severity of acute pancreatitis (8)

JA Viedma et al in 1992 demonstrated significant correlations between plasma

concentrations of interleukin-6 and phospholipase A (p = 0.0218) and C-reactive
protein and phospholipase A activity (p < 0.0001) in patients with 'severe' disease.
These findings in a limited number of patients with acute pancreatitis are promising
in that raised interleukin-6 correlated with clinical severity and with two other
established markers, C-reactive protein, and phospholipase A activity (9)
 Review of Literature

DI Heath in 1993 showed that considering a C-reactive protein of > 150 mg/l , it was
able to detect severe attacks of acute pancreatitis with a sensitivity of 90% and specificity
of 79% {10}

JA Viedma et al in 1994 showed that PMN elastase has a dynamic course and it reaches
an early peak value at days 1-2, followed by C reactive protein (days 2-4) phospholipase
A (day 3), and a negative peak for alpha 2-macroglobulin (days 4-5). PMN elastase (day
1) and C reactive protein (day 2) were selected by discriminant analysis as the most useful
variables studied to allow the early accurate prediction of severity (sensitivity 100%,
specificity 95%). These results strongly suggestted a close relation between inflammatory
parameters and clinical course in acute pancreatitis, and discriminant analysis of these
variables provides a useful method to classify severity.(11)

Paajanen H et al in 1995 showed that values for CRP (concentrations greater than 100
mg/l)had a sensitivity and specificity of 84 and 74 per cent respectively in predicting
severe acute pancreatitis . They also compared these values with TNF alpha and found
that, in contrast with CRP, the early determination of peripheral blood TNF concentration
is of no clinical value in assessing the severity of acute pancreatitis{12.}

Buchler M et al in 1996 did serum monitoring of alpha-1-protease inhibitor, alpha-2-

macroglobulin, complement factors C3 + C4, and C-reactive protein (CRP) in patients of
acute pancreatitis and found significant differences between the serum values of all
measured parameters in the two morphologically defined pancreatitis groups. The best
discriminating factors were CRP and alpha-2-macroglobulin, showing 95% and 85%
overall detection rates for pancreatic necrosis, respectively.(13)

Pezzilli R et al in 1997 found no significant difference in serum C-reactive protein levels

was found in the first 2 days in patients with mild pancreatitis compared to those with the
severe form of the disease. Using a cut-off point of 11 mg/dl, the sensitivity of serum C-
reactive protein in assessing the severity of acute pancreatitis during the first two days of
 Review of Literature

the study was 9% and 57%, the specificity, 93% and 81%, and the accuracy 71% and
74%, respectively. So they predicted that serum determination of C-reactive protein in the
first 48 hours of the disease is not a reliable marker of the severity of acute biliary
pancreatitis.{ 14)

Imrie CW in 1997 postulated one practical approach recommended of employing the

Glasgow scoring system plus C-reactive protein levels and also to take into account body
mass index. Any patient with three positive Glasgow factors, or CRP > 150 mg/l or BMI
> 30 kg/m2 has severe acute pancreatitis (15)

M. Armengol-Carrasco et al in 1999 showed that APACHE II score and C-reactive

protein levels were related to the development of secondary pancreatic infection in severe
acute pancreatitis. The best predictive results of the equation (73.7%) were observed at
about day 10. This finding favors the hypothesis that septic complications may be
suspected when an SIRS is maintained beyond 1 week in the evolution of an SAP (16 )

Clyne B et al in 1999 postulated that C reactive protein may be a useful adjunct and may
be elevated with complications or treatment failures in patients with pneumonia,
pancreatitis, pelvic inflammatory disease (PID), and urinary tract infections and in
patients with meningitis, neonatal sepsis, and occult bacteremia . However, CRP has no
role in diagnosing these clinical entities, and a normal CRP level should never delay
antibiotic coverage (17)

Rau B et al in 2000 observed that in comparison to CRP, Serum amyloid A protein

(SAA) was significantly higher in patients who developed complications such as
necrosis, infection of necrosis, or multiple organ dysfunction syndrome or in patients who
died. SAA achieved best results in discriminating between necrotizing pancreatitis and
interstitial edematous pancreatitis. However, CRP provided an earlier differentiation
between both entities and a significantly better overall accuracy. In cases of acute
pancreatitis, however, CRP was still found to be superior to SAA for early and accurate
stratification of patients with a complicated course (18.)
 Review of Literature

Steinbach et al in 2000 postulated that serum amyloid A (SAA) proteins though is an

applicable and readily available variable under clinical routine conditions yet in cases of
acute pancreatitis, CRP is still superior to SAA for early and accurate stratification of
patients with a complicated course.{19}

Del Prete M, et al in 2001 showed that C-reactive protein assay is highly sensitive in
detecting necrotic forms of acute pancreatitis. The authors concluded that C-reactive
protein, together with both serum amylase and serum lipase, often provides a precise
picture of the clinical situation in patients with acute pancreatitis. On this basis the best
therapeutic option can be chosen. (20.}

P. Puolakkainen et al in 2001 found that procalcitonin was more accurate in predicting

severe acute pancreatitis (sensitivity 92 per cent and specificity 84 per cent at 24 h) than
CRP, APACHE II score and Ranson score. Its negative predictive value was high (97 per
cent at 24 h), and it detected each patient who developed subsequent organ failure(21)

Anderson et al in 2001 showed that based on cut-off values of 35 nmol/L for TAP and
150 mg/L for CRP, TAP had a greater sensitivity and NPV than CRP for 24 hours after
symptom onset but was comparable to CRP and APACHE II in distinguishing severe
from mild pancreatitis 24 hours after admission and 48 hours from symptom onset.
(22)

Tsunao Imamura et al in 2002 found that the high sensitivity CRP levels were
significantly increased in the early phase of severe acute pancreatitis, suggesting that hs-
CRP could possibly serve as an early indicator of the progression of acute pancreatitis
into a serious state
(23)

Riche FC et al in 2003 found no difference between non infected and infected pancreatic
necrosis patients when assessed for TNF- alpha and CRP. (24.}
 Review of Literature

Arvanitakis M and others in 2004 used a magnetic resonance severity index based on the
existing Balthazar CTSI and found that magnetic resonance severity index scores
correlated with serum level of C-reactive protein at 48 hours, duration of hospitalization,
and Ranson score, and morbidity from local and systemic complications.
(25.)

In 2005 the UK practice guidelines of Acute Pancreatitis continued unchanged the 2003
recommendations of using the C reactive protein values of greater than 150 mg/dl as a
predictor of severity of acute pancreatitis
(.26)

Other Markers of Inflammation:

Gross V et al in 1990 and Dominguez et al in 1991 have reported that 70 to 80% with
severe acute pancreatitis studied within 48hrs of onset of pain were correctly evaluated
by Granulocyte elastase , which is released by activated neutrophils and is able to damage
cellular membranes and extracellular matrix
(Granulocyte elastase in assessment of severity of acute pancreatitis. Comparison with
acute-phase proteins C-reactive protein, alpha 1-antitrypsin, and protease inhibitor 2-
macroglobulin.-Gross V, Scholmerich J, Leser HG, Salm R, Lausen M, Ruckauer K, et
al.--Dig Dis Sci 1990; 35:97-105)
(Dominguez Munoz JE, Carballo F, Garcia MJ, De Diego JM, Rabago L, Simon MA, de
la Morena J. Clinical usefulness of polymorphonuclear elastase in predicting the severity
of acute pancreatitis: results of a multicenter study.Br J Surg,1991;78:1230-1234)

Amyloid A (SAA) and procalcitonin (PCT) have been reported as useful indicators of
inflammation. the sensitivity of SAA is significantly higher than that of PCT and CRP in
assessing the severity of pancreatitis, whereas PCT and CRP had a specificity
significantly higher than SAA. The accuracy and efficiency were similar for SAA and
CRP, and both these markers had an accuracy and efficiency significantly higher than
those of PCT. (Pezzilli R et al 2000)
 Review of Literature

(Pezzilli R, Melzi d'Eril GV, Morselli-Labate AM, Merlini G, Barakat B, Bosoni T.

: Serum amyloid A, procalcitonin, and C-reactive protein in early assessment of severity
of acute pancreatitis.: Dig Dis Sci. 2000 Jun;45(6):1072-8)

Bhasin DK found that procalcitonin cannot be considered a good marker for assessing
the severity of pancreatitis.( 2005)
(Shafiq N, Malhotra S, Bhasin DK, Rana S, Siddhu S, Pandhi P.: Estimating the
diagnostic accuracy of procalcitonin as a marker of the severity of acute pancreatitis: a
meta-analytic approach: JOP. 2005 May 10;6(3):231-7)

Colin D Johnson ( 2006) postulated through his studies that plasma malondialdehyde
greater than 2.75 µmol/L at 12 hours after admission had high overall accuracy for
predicting severe acute pancreatitis. Superoxide dismutase levels were found to decrease
in acute pancreatitis but no substantial significant difference was demonstrated between
severe and mild acute pancreatitis patients.

(JOP. J Pancreas (Online) 2006; 7(2):185-192.Malondialdehyde and Superoxide

Dismutase as Potential Markers of Severity in Acute Pancreatitis Mohammed Abu-Hilal,
Mark JW McPhail, Lucy Marchand, Colin D Johnson)

b. Markers of trypsinogen Activation :

Alpha-1-protease inhibitor complexes. Levels of trypsin-alpha-1-protease inhibitor

complexes in serum correlate to severity in several reports (Borgstrom A 1984 ,
Hedstrom J 1996) Levels of this complex are always mostly elevated very early during
the disease (from less than 24 to 48 hours). However, high levels of this complex have
also been reported in serum from patients with perforated ulcers and other diseases
associated with a damaged gastrointestinal barrier

( Borgström A, Lasson Å. Trypsin-alpha1-protease inhibitor complexes in serum and clinical course in

acute pancreatitis. Scand J Gastroenterol 1984; 19:1119-22. \

 Hedström J, Sainio V, Kemppainen E, Haapiainen R, Kivilaakso E, Schröder T, et al.

Serum complex of trypsin 2 and alpha 1 antitrypsin as diagnostic and prognostic marker
of acute pancreatitis: clinical study in consecutive patients. Br Med J 1996; 313:333-7.
 Review of Literature

Carboxypeptidase B activation peptide ( CAPAP)

Levels of CAPAP in serum and urine in acute pancreatitis correlate with the severity of
the attack. CAPAP is very stable, and urine contains only CAPAP whereas, in serum,
cross reacting procarboxypeptidase B is found together with CAPAP. ( Appelros 1998)

(The activation peptide of carboxypeptidase B in serum and urine in acute

pancreatitis.:Appelros S, Thim L, Borgström A.Gut 1998; 42:97-102)

Petersson U in 2001 found that concentrations of CAPAP in urine and serum and of
anionic trypsinogen in urine correlated with the severity of the pancreatitis. CAPAP
in urine showed the highest accuracy. The overall accuracy was 90 per cent, with a
positive predictive value of 69 per cent and a negative predictive value of 98 per
cent.

(Br J Surg. 2001 Feb;88(2):216-21: Activation peptide of carboxypeptidase B and anionic

trypsinogen as early predictors of the severity of acute pancreatitis.Appelros
S,Petersson U, Toh S, Johnson C, Borgstrom A.)

Elevated levels of the activation peptide on admission correlated with an accuracy of

92% to later development of pancreatic necrosis. Measurement of the proenzyme
can thus be useful for the diagnosis of acute pancreatitis (accuracy 99%) but levels
did not correlate with later development of pancreatic necrosis (accuracy 56%).(
Muller CA 2002)

(Serum levels of procarboxypeptidase B and its activation peptide in patients with acute
pancreatitis and non-pancreatic diseases.: Muller CA, Appelros S, Uhl W, Buchler
MW, Borgstrom A.: Gut. 2002 Aug;51(2):229-35)

c. Markers of leakage of Pancreatic Enzymes:

 Review of Literature

Amylase.

It is generally accepted that the degree of elevation of the amylase levels in serum and
urine shows little correlation with disease severity and prognosis. If anything, amylase
levels may have an inverse relationship with severity in that some patients with severe
disease have normal or only modestly elevated amylase values when first seen

[ Winslet M, Hall C, London NJ, Neoptolemos JP. Relation of diagnostic serum

amylase levels to aetiology and severity of acute pancreatitis. Gut 1992; 33:982-6.

 Clavien PA, Burgan S, Moossa AR. Serum enzymes and other laboratory tests in
acute pancreatitis. Br J Surg 1989; 76;1234-43.)

].

Trypsinogen 2 (anionic trypsinogen) in serum and urine

Sensitivity and specificity for TAP assay were 80% and 90%, for C-reactive protein 53%
and 55%, and for multifactorial scoring at 48 h, 60% and 93%. Urine TAP assay
distinguishes acute pancreatitis without trypsinogen activation from acute pancreatitis
with trypsinogen activation, and helps to identify patients who will progress to the severe
acute disease. ( Wilson C 1990)
(Gudgeon AM, Heath DI, Hurley P, Jehanli A, Patel G, Wilson C et al : Trypsinogen
activation peptides assay in the early prediction of severity of acute pancreatitis.: Lancet.
1990 Jan 6;335(8680):4-8)

Urinary TAP provided accurate severity prediction as early as 24 hours after symptom
onset. Results were comparable to results from CRP, Ranson, Glasgow, and APACHE II
scoring systems in determining prognosis at later points in the clinical course of patients
with acute pancreatitis.( Anderson et al 2001)
(Anderson, Michelle A. MD ; Evidence-Based Gastroenterology: Volume 2(1) February
2001 pp 34-35 SEVERITY ASSESSMENT IN ACUTE PANCREATITIS)

The sensitivity of the rapid urinary test strip (detection limit, 2000 µg/L) for prediction of
severe AP, both on admission and at 24 h, was 62%; specificities were 87% and 85%,
respectively, positive predictive values were 65% and 62%, and negative predictive
 Review of Literature

values were 85% and 85%. On admission the positive-likelihood ratio for the urinary
trypsinogen-2 test strip was 4.8, and at 24 h it was 4.2.The urinary trypsinogen-2 dipstick
is a simple and rapid method for prediction of severe acute pancreatitis. ( Marko et al
2001)

(
Predicting the Severity of Acute Pancreatitis by Rapid Measurement of Trypsinogen-2
in Urine:Marko Lempinen, Marja-Leena Kylänpää-Bäck: Clinical Chemistry.
2001;47:2103-2107.)

Urinary TAP levels were significantly greater in patients with severe pancreatitis than in
those with mild disease during the first 36 h of admission. The highest of three
estimations of TAP in the first 24 h was as effective as APACHE II at 24 h in
predicting severity. At 24 h after admission, urinary TAP was better than C-
reactive protein (CRP) in predicting severity. The combination of TAP and CRP at
24 h allowed identification of high- and low-risk groups. This new definition of
severity excluded patients with transient organ failure (Johnson CD et al 2004)

(Johnson CD, Lempinen M, Imrie CW, Puolakkainen P, Kemppainen E, Carter R,

McKay C.: Urinary trypsinogen activation peptide as a marker of severe acute
pancreatitis.: Br J Surg. 2004 Aug;91(8):1027-33.)

Lipase

It is more pancreas-specific than amylase, and it has therefore been advocated to be a

more specific marker of acute pancreatitis, especially as it stays elevated for a longer time
after the onset of pancreatitis than amylase does. However, the levels bear just as little
relationship to severity as amylase.( Gumaste V 1992)

( Gumaste V, Dave P, Sereny G. Serum lipase: a better test to diagnose acute alcoholic pancreatitis. Am J
Med 1992; 92:239-42)

Frossard et al in 2000 developed an enymatic score. Enzymatic score was 0 if neither

enzyme was predominant in the peritoneal fluid, 1 if amylase or lipase alone were
predominant and 2 if both enzymes were predominant. The frequency of severe
 Review of Literature

acute pancreatitis significantly increased as the enzymatic score increased. An

enzymatic score greater than 0 predicted a severe outcome (sensitivity 94.1%,
specificity 26.3%), whereas an enzymatic score of 2 predicted a severe attack
(sensitivity 76.5%, specificity 57.9%). However , peritoneal dialysis is less
predictive and more cumbersome than a computed tomography scan in the early
prediction of acute pancreatitis

(Frossard JL, Robert J : Early prediction in acute pancreatitis: the contribution of amylase
and lipase levels in peritoneal fluid.: JOP. 2000 Jul;1(2):36-45)

Pitchumoni et al in 2002 postulated that once the diagnosis of AP is established, daily

measurements of enzymes have no value in assessing the clinical progress of the
patient or ultimate prognosis and should be discouraged. At present, serum C-
reactive protein at 48 h is the best available laboratory marker of severity. Urinary
trypsinogen activation peptides within 12-24 h of onset of AP are able to predict
the severity but are not widely available.

(Yadav D, Agarwal N, Pitchumoni CS.: A critical evaluation of laboratory tests in acute

pancreatitis: Am J Gastroenterol. 2002 Jun;97(6):1309-18.)

RADIOLOGICAL CRITERIA: