Assesment of Severity of Acute Pancreatitis

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)


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


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


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


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


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 >


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.


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

• 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.

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 criteria Mortality rate

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

(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

during 1st 48 hours

Points

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 ÂµL 1

<= 15,000 per ÂµL 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.

(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 30-31.9 +3 <= 29.9 +4mean arterial pressure mm Hg

>= 160 +4

130-159 +3 110-129 +2 70-109 0 50-69 +2 <= 49 +4heart rate in beats/minute

>= 180 +4

140-179 +3 110-139 +2 70-109 0 55-69 +2 40-54 +3 <= 39 +4respiratory rate in breaths/min

>=50 +4

35-49 +3 25-34 +1 12-24 0 10-11 +1 6-9 +2 <= 5 +4oxygenation 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 +4arterial 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 +4serum sodium >= 180 +4 160-179 +3 155-159 +2 150-154 +1 130-149 0 120-129 +2 111-119 +3 <= 110 +4serum 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 +4serum creatinine in mg/dL

>= 3.5 and not acute renal failure +4

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 +4hematocrit in percent

>= 60 +4

50-59.9 +2 46-49.9 +1 30-45.9 0 20-29.9 +2 < 20 +4WBC count in thousands

>= 40 +4

20-39.9 +2 15-19.9 +1 3-14.9 0 1-2.9 +2 < 1 +4Glasgow Coma Score

15 - (Glasgow 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 5serum bicarbonate in mmol/L

>= 52.0 +4

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<= 44 045-54 255-64 365-74 5>= 75 6

Chronic Health Points

Operative StatusHealth Status

Points

nonoperative patient history of severe organ insufficiency OR immunocompromised

5

no history of severe organ insufficiency AND immunocompotent

0

emergency postoperative patient

history of severe organ insufficiency OR immunocompromised

5


0

elective postoperative patient

history of severe organ insufficiency OR immunocompromised

2


0

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

• 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

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.

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 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

(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:

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.)

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..

(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

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

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)

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

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.)

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.}

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)

(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.

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:

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

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 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: