Acute biliary pancreatitis Tomasz Marek Department of Gastroenterology & Hepatology Medical University of Silesia in Katowice, Poland Department of Gastroenterology & Hepatology Medical University of Silesia in Katowice, Poland 6th EAGE Postgraduate School in Gastroenterology Prague th EAGE Postgraduate School in Gastroenterology Prague 2010

Acute biliary pancreatitis o Pathogenesis o Diagnosis o Determination of etiology o Prognosis o Endoscopic treatment o Pathogenesis o Diagnosis o Determination of etiology o Prognosis o Endoscopic treatment

Opie, Bull John Hopkins Hosp 1901 Pathogenesis of biliary pancreatitis

Acute biliary pancreatitis (ABP) is triggered by obstruction of the ampulla of Vater by migrating or impacted stones Acute biliary pancreatitis (ABP) is triggered by obstruction of the ampulla of Vater by migrating or impacted stones Opie, Bull John Hopkins Hosp 1901 Acosta & Ledesma, NEJM 1974 Pathogenesis of biliary pancreatitis Common channel ? Obstruction !!!

Pathogenesis of biliary pancreatitis

Diagnosis of ABP

o Pain o Elevated enzymes - lipase better than amylase - no specific cut-off, 2-3 x N ? o Imaging studies - usually not necessary - US not perfect (intestinal gas) - CT should not be done within 72h if not for differential diagnosis o Pain o Elevated enzymes - lipase better than amylase - no specific cut-off, 2-3 x N ? o Imaging studies - usually not necessary - US not perfect (intestinal gas) - CT should not be done within 72h if not for differential diagnosis

Determination of biliary etiology

o Elevated liver function tests (~ 2 x N) o Gallstones or sludge (?) o Dilated CBD (> 8 mm) o ERCP (added value): - small CBD stones in non-dilated CBD - endoscopic signs of stone passage - biliary microlithiasis o Elevated liver function tests (~ 2 x N) o Gallstones or sludge (?) o Dilated CBD (> 8 mm) o ERCP (added value): - small CBD stones in non-dilated CBD - endoscopic signs of stone passage - biliary microlithiasis

CBD imaging in ABP o Abdominal US not sensitive enough o MRCP - small (especially impacted) stones may be missed - air bubbles may give false+ results - fluid collections may obscure CDB in severe cases o EUS - may be not readily available 24/24h (ES delay?) - perfect when ERCP fails o Abdominal US not sensitive enough o MRCP - small (especially impacted) stones may be missed - air bubbles may give false+ results - fluid collections may obscure CDB in severe cases o EUS - may be not readily available 24/24h (ES delay?) - perfect when ERCP fails

Determination of biliary etiology CBD stones326 (39.8%) 1 pt lab criteria negative Gallbladder stones only402 (49.0%) 24 pts lab criteria negative ? Biliary microlithiasis 19 ( 2.3%) Signs of stone passage 31 ( 3.8%) Lab criteria only 42 ( 5.1%) CBD stones326 (39.8%) 1 pt lab criteria negative Gallbladder stones only402 (49.0%) 24 pts lab criteria negative ? Biliary microlithiasis 19 ( 2.3%) Signs of stone passage 31 ( 3.8%) Lab criteria only 42 ( 5.1%)

ABP prognosis

o Small differences o Glasgow Blamey - best of „classic” systems o Bilirubin to be removed from AP III J o CRP cut-off to be set higher 180 mg/l works better than 150 mg/l o ERCP can be used for prognosis when done for treatment o Small differences o Glasgow Blamey - best of „classic” systems o Bilirubin to be removed from AP III J o CRP cut-off to be set higher 180 mg/l works better than 150 mg/l o ERCP can be used for prognosis when done for treatment ABP prognosis

ABP treatment

o Obstruction is the main element of the pathogenesis of ABP o The restoration of normal outflow of bile and pancreatic juice should constitute an effective, cause-directed treatment of acute biliary pancreatitis o Endoscopic sphincterotomy could be the method of choice o Obstruction is the main element of the pathogenesis of ABP o The restoration of normal outflow of bile and pancreatic juice should constitute an effective, cause-directed treatment of acute biliary pancreatitis o Endoscopic sphincterotomy could be the method of choice ABP treatment

ES for ABP – First cases

o It is the greatest pleasure of the endoscopist to remove impacted stone in patient with acute pancreatits ABP treatment

ERCP / ES for ABP Neoptolemos et al., Leicester, UK (Lancet) Fan et al., Hong-Kong, Hong-Kong (NEJM) Fölsch et al., Kiel, Germany (NEJM) (multicenter study) 2006 – Acosta et al., Los Angeles, USA (Ann Surg) Oria et al., Buenos-Aires, Argentina (Ann Surg) Randomized comparisons of endoscopic sphincterotomy (ES) versus conventional management (CM) for acute biliary pancreatitis

CM 12% 61% 34% ERCP 12% 24% 17% CM 0% 18% 8% 0% 18% 8%ERCP 0% 4% 2% 0% 4% 2%ABP Predicted mild Predicted severe Total ComplicationsMortality o 121 patients (62 CM, 59 ERCP) o ERCP / ES > 48 & < 72 h o 121 patients (62 CM, 59 ERCP) o ERCP / ES > 48 & < 72 h o ERCP only after 48 hours (severity stratification) o ES only in patients with CBD stones (33% ERCP) o Trend only observed for mortality o ERCP only after 48 hours (severity stratification) o ES only in patients with CBD stones (33% ERCP) o Trend only observed for mortality Neoptolemos et al., Lancet 1988 ERCP / ES for ABP – Neoptolemos et al.

o 195 patients, 127 ABP (64 CM, 63 ERCP) o ERCP / ES < 24 h o 195 patients, 127 ABP (64 CM, 63 ERCP) o ERCP / ES < 24 h o ES only in patients with CBD stones (38% ERCP) o Significant reduction of biliary sepsis in ES group o Trend only observed for mortality o ES only in patients with CBD stones (38% ERCP) o Significant reduction of biliary sepsis in ES group o Trend only observed for mortality CM 17% 54% 33% ERCP 18% 13% 16% CM 0% 18% 8% 0% 18% 8%ERCP 0% 3% 2% 0% 3% 2%ABP Predicted mild Predicted severe Total ComplicationsMortality Fan et al., NEJM 1993 ERCP / ES for ABP – Fan et al.

o 238 patients, (112 CM, 126 ERCP) o ERCP / ES < 72 h o 238 patients, (112 CM, 126 ERCP) o ERCP / ES < 72 h o Exclusion of patients with jaundice (Bil > 5.0 mg/dL) o ES only in CBD stones (46% ERCP / 12% CM group) o Few cases/center; ERCP mortality 5x  vs. UK / HK o Exclusion of patients with jaundice (Bil > 5.0 mg/dL) o ES only in CBD stones (46% ERCP / 12% CM group) o Few cases/center; ERCP mortality 5x  vs. UK / HK Folsch et al., NEJM 1995 CM 51% 11% ERCP 46% 1% CM 4% 4% ERCP 8% 8% ABPTotal ComplicationsMortality New onset jaundice ERCP / ES for ABP – Fölsch et al.

o 61 patients (31 CM, 30 ERCP) o ERCP / ES > 24 h & < 48 h of onset o 61 patients (31 CM, 30 ERCP) o ERCP / ES > 24 h & < 48 h of onset o Complicated design o Patiens with obstruction (Bil ↓ checked every 6h) o ERCP for patients with no spontaneous disobstruction o ES – ERCP 43% 48 h o Complicated design o Patiens with obstruction (Bil ↓ checked every 6h) o ERCP for patients with no spontaneous disobstruction o ES – ERCP 43% 48 h Acosta et al., Ann Surg 2006 CM29%ERCP7%CM 0% 0% ERCP ABPTotal ComplicationsMortality ERCP / ES for ABP – Acosta et al.

o 238 patients, 102 randomized (51 CM, 51 ERCP) o ERCP / ES > 24 h of onset o 238 patients, 102 randomized (51 CM, 51 ERCP) o ERCP / ES > 24 h of onset o Bil >=1.2 mg/dL + CBD >= 8mm on US o Acute cholangitis (temp >= 38.4 C) excluded o ES 76% ERCP group (CBDS) o No difference in organ failure score o Bil >=1.2 mg/dL + CBD >= 8mm on US o Acute cholangitis (temp >= 38.4 C) excluded o ES 76% ERCP group (CBDS) o No difference in organ failure score Oria et al., Ann Surg 2007 CM18%ERCP21%CM 2% 2% ERCP 4% 4% ABPTotal ComplicationsMortality ERCP / ES for ABP – Oria et al.

AOC Jaundice Sev AP Old/unfit o Atlanta ’94 X X o BSG ’98 X X X o SSAT ’98 X o Santorini ’99 X X X o SNFGE ’01 X X o WCG ’02 X X X X o JSAEM ’02 X X X o IAP ’03 X X o BSG ’05 X X X X o ACG ’06 X X X?X o AGA ’07 X X X?X AOC Jaundice Sev AP Old/unfit o Atlanta ’94 X X o BSG ’98 X X X o SSAT ’98 X o Santorini ’99 X X X o SNFGE ’01 X X o WCG ’02 X X X X o JSAEM ’02 X X X o IAP ’03 X X o BSG ’05 X X X X o ACG ’06 X X X?X o AGA ’07 X X X?X ERCP / ES for ABP – Guidelines

o All guidelines recommend the use of ERCP/ES in settings with high suspicion of CBD stones, jaundice and cholangitis o Majority of guidelines recommend ERCP/ES as an emergency procedure (as soon as possible) o No guidelines recommend the use of ERCP/ES in predicted mild pancreatitis (OK if the prognosis system is perfect and it can provide the prognosis on admission) o All guidelines recommend the use of ERCP/ES in settings with high suspicion of CBD stones, jaundice and cholangitis o Majority of guidelines recommend ERCP/ES as an emergency procedure (as soon as possible) o No guidelines recommend the use of ERCP/ES in predicted mild pancreatitis (OK if the prognosis system is perfect and it can provide the prognosis on admission) ERCP / ES for ABP – Guidelines

n (793) % Time P-E (h) Bilirubin (mg/dL) ALT (U) ALP (U) GGT (U) Amylase (U) Lipase (U) CBD Ø (mm) n (793) % Time P-E (h) Bilirubin (mg/dL) ALT (U) ALP (U) GGT (U) Amylase (U) Lipase (U) CBD Ø (mm) IMPS % IMPS % CBDS % CBDS % no CBDS % no CBDS % p p Prediction of CBD stones

n (792) Bilirubin mg/dL mg/dL mg/dL > 5 mg/dL n (792) Bilirubin mg/dL mg/dL mg/dL > 5 mg/dL IMPS 7 ( 6%) 32 (10%) 39 (24%) 53 (29%) IMPS 7 ( 6%) 32 (10%) 39 (24%) 53 (29%) CBDS 33 (25%) 84 (26%) 38 (24%) 51 (28%) CBDS 33 (25%) 84 (26%) 38 (24%) 51 (28%) no CBDS 90 (69%) 204 (64%) 85 (53%) 76 (42%) no CBDS 90 (69%) 204 (64%) 85 (53%) 76 (42%) Prediction of CBD stones – Bilirubin

n (740) CBD diameter mm mm mm > 12 mm n (740) CBD diameter mm mm mm > 12 mm IMPS 1 ( 3%) 20 ( 7%) 44 (15%) 45 (33%) IMPS 1 ( 3%) 20 ( 7%) 44 (15%) 45 (33%) CBDS 4 (11%) 50 (19%) 84 (28%) 54 (39%) CBDS 4 (11%) 50 (19%) 84 (28%) 54 (39%) no CBDS 32 (87%) 199 (74%) 169 (57%) 38 (28%) no CBDS 32 (87%) 199 (74%) 169 (57%) 38 (28%) Prediction of CBD stones – CBD diameter

n (759) Time: Pain – ERCP 0 – 6 h 6 – 12 h 12 – 18 h > 18 h n (759) Time: Pain – ERCP 0 – 6 h 6 – 12 h 12 – 18 h > 18 h IMPS 2 (40%) 15 (30%) 20 (24%) 101 (16%) IMPS 2 (40%) 15 (30%) 20 (24%) 101 (16%) No IMPS 3 (60%) 35 (70%) 65 (76%) 518 (84%) No IMPS 3 (60%) 35 (70%) 65 (76%) 518 (84%) Prediction of impacted stone – ES timing

n (759) Time: Adm – ERCP 0 – 2 h 2 – 4 h 4 – 6 h > 6 h n (759) Time: Adm – ERCP 0 – 2 h 2 – 4 h 4 – 6 h > 6 h IMPS 24 (32%) 49 (21%) 18 (13%) 47 (15%) IMPS 24 (32%) 49 (21%) 18 (13%) 47 (15%) No IMPS 52 (68%) 185 (79%) 121 (87%) 263 (85%) No IMPS 52 (68%) 185 (79%) 121 (87%) 263 (85%) Prediction of impacted stone – ES timing

n (789) % Temp (C) Bilirubin (mg/dL) ALT (U) ALP (U) GGT (U) WBC (G/L) CRP (mg/L) CBD Ø (mm) n (789) % Temp (C) Bilirubin (mg/dL) ALT (U) ALP (U) GGT (U) WBC (G/L) CRP (mg/L) CBD Ø (mm) no AOC % no AOC % AOC % AOC % p p Prediction of acute cholangitis

o CBD stones are difficult to be predicted o ES in patients with no CBD stones ? o ES causes decompression of pancreatic and bile ducts (papillary edema may develop after stone passage) o ES prevents the repeated obstruction of the papilla triggering the next episode of ABP o ES can lead to removal of possible ERC-invisible CBD stones (very rare ~ 3%) o CBD stones are difficult to be predicted o ES in patients with no CBD stones ? o ES causes decompression of pancreatic and bile ducts (papillary edema may develop after stone passage) o ES prevents the repeated obstruction of the papilla triggering the next episode of ABP o ES can lead to removal of possible ERC-invisible CBD stones (very rare ~ 3%) ERCP / ES for ABP – ES for all patients?

o 280 patients, 205 randomized (102 CM, 103 ERCP) o ERCP / ES < 24 h o 280 patients, 205 randomized (102 CM, 103 ERCP) o ERCP / ES < 24 h o ES in 75 patients with impacted stone w/o random o ES in 100% of ES group (irrespective of CBD stones) o ES useful in both predicted mild and severe cases o ES in 75 patients with impacted stone w/o random o ES in 100% of ES group (irrespective of CBD stones) o ES useful in both predicted mild and severe cases CM 25% 74% 38% ES 10% 39% 17% CM 5% 33% 13% 5% 33% 13% ES 0% 4% 2% 0% 4% 2%ABP Predicted mild Predicted severe Total ComplicationsMortality Nowak et al., Gastroenterology 1995 (abstract) ERCP / ES for ABP – Nowak et al.

o 976 patients, 253 randomized (126 CM, 127 ERCP) o ERCP / ES < 12 h (median 5 h) o 976 patients, 253 randomized (126 CM, 127 ERCP) o ERCP / ES < 12 h (median 5 h) o ES w/o random in jaundice, AOC, CBD stones, etc. o ERCP for all, randomization after negative ERC o Stratification for gallbladder stones o ES 100% ES group o ES w/o random in jaundice, AOC, CBD stones, etc. o ERCP for all, randomization after negative ERC o Stratification for gallbladder stones o ES 100% ES group CM48% ES 25%CM5% 1% 1%ABPTotal ComplicationsMortality Nowakowska et al., Gut 2010 (abstract) ERCP / ES for ABP – Nowakowska et al.

o 78 patients with cholestasis (26 CM, 52 ERCP) o ERCP / ES < 72 h from onset o 78 patients with cholestasis (26 CM, 52 ERCP) o ERCP / ES < 72 h from onset o Patients with severe ABP from PROPATRIA study o Prospective study, no randomization o Cholestasis (Bil > 2.3, CBD > 8 (10) mm) o ES 87% ERCP o Patients with severe ABP from PROPATRIA study o Prospective study, no randomization o Cholestasis (Bil > 2.3, CBD > 8 (10) mm) o ES 87% ERCP CM54% ES 25%CM15% 6% 6%ABPTotal ComplicationsMortality Van Santvoort et al., Ann Surg 2009 ERCP / ES for ABP – van Santvoort et al.

7 RCTs, 1107 patients, (547 CM, 560 ERCP) CM 34 % 33 % 51 % 29% 18 % 38 % 48 % 40 % ERCP 17 % 16 % 46 % 7% 7% 22 % 17 % 25 % CM 8.2 % 8.2 % 7.9 % 7.9 % 3.6 % 3.6 % 0.0% 0.0% 2.0 % 2.0 % 12.7 % 4.8 % 4.8 % 6.2 % 6.2 %ERCP 1.7 % 1.6 % 7.9 % 0.0% 3.9 % 2.2 % 0.8 % 2.9 % NeoptolemosFanFölsch Acosta Oria NowakNowakowskaTotal ComplicationsMortality ERCP / ES for ABP – Pooled analysis

o Designs totally different o Different entry criteria o Different treatment regimens o Different outcome criteria o Designs totally different o Different entry criteria o Different treatment regimens o Different outcome criteria ERCP / ES for ABP – Pooled analysis

o May be difficult o Pre-cut necessary up to 35% o Failure rate: 69/820 (8.5%) o Safe – complications: 12 / 820 (1.5%) o Consumes extensive resources Team on call: 3-5 doctors and nurses o May be difficult o Pre-cut necessary up to 35% o Failure rate: 69/820 (8.5%) o Safe – complications: 12 / 820 (1.5%) o Consumes extensive resources Team on call: 3-5 doctors and nurses ERCP / ES for ABP

YearQ1Q2Q3Q4 Tot P/Wk P/Wk Weekly max:15 cases (Mar 27 - Apr 2, 04) Daily max: 5 cases (Nov 16, 01) (8 additional days - 4 cases/d) YearQ1Q2Q3Q4 Tot P/Wk P/Wk Weekly max:15 cases (Mar 27 - Apr 2, 04) Daily max: 5 cases (Nov 16, 01) (8 additional days - 4 cases/d) ERCP / ES for ABP in Katowice

o ABP is triggered by obstruction of major duodenal papilla by biliary stones o Rapid identification of biliary etiology is of great importance o Urgent ERCP / ES decreases complications and mortality rates o As the CBD stones identification is not perfect and there is no time for severity assessment urgent ES should be done in all patients with ABP o ABP is triggered by obstruction of major duodenal papilla by biliary stones o Rapid identification of biliary etiology is of great importance o Urgent ERCP / ES decreases complications and mortality rates o As the CBD stones identification is not perfect and there is no time for severity assessment urgent ES should be done in all patients with ABP Acute biliary pancreatitis - Summary

ERCP for ABP prognosis

No swelling Minor swelling, limited to peripapillary area Severe swelling with extensive involvement of D2, bluish discoloration Moderate swelling with extensive involvement of D2 DGE MUSK DGE MUSK ERCP for ABP prognosis

DGE MUSK Duodenal swelling

DGE MUSK Normal duodenum Deformed duodenal loop D2 deformed and narrowed Deformed duodenal loop D2 deformed and narrowed Duodenal swelling

DGE & DPAT MUSK DGE & DPAT MUSK Mucosal hyperemia Edema of submucosal layer Duodenal swelling

Normal duodenum Marked thickening of D2 wall DGE & DRAD MUSK, Helimed mm Duodenal swelling

DGE & DRAD MUSK, Helimed D2 swelling limited to peripapillary area D2 swelling limited to peripapillary area D2 swelling limited to antero-medial wall D2 swelling limited to antero-medial wall Duodenal swelling

DGE & DRAD MUSK, Helimed Severe swelling with circular D2 involvement; lumen barely visible in the most severe cases Severe swelling with circular D2 involvement; lumen barely visible in the most severe cases Duodenal swelling

n (851) % % severe % surgery % mortality SGS-10 n (851) % % severe % surgery % mortality SGS-10 N % N % MLD 40 5% MLD 40 5% MOD 88 10% MOD 88 10% SEV 33 4% SEV 33 4% p p Duodenopathy grade Marek et al., Gut 2005 (abstract) Duodenal swelling

o Gastric stasis (I 9%; S 73%; RR=2.1) o Erosive gastropathy (I 9%; S 55%; RR=1.5) o Unident. / v. small papilla (I 5%; S 55%; RR=1.8) o Unident. / tight orifice(I 17%; S 54%; RR=1.5) o Failed initial CBD access (I 9%; S 61%; RR=1.7) o Small CBD Ø ≤ 4 mm (I 5%; S 62%; RR=1.8) o Erosive duodenopathy !!! (I 5%; S 31%; RR=0.7) o Gastric stasis (I 9%; S 73%; RR=2.1) o Erosive gastropathy (I 9%; S 55%; RR=1.5) o Unident. / v. small papilla (I 5%; S 55%; RR=1.8) o Unident. / tight orifice(I 17%; S 54%; RR=1.5) o Failed initial CBD access (I 9%; S 61%; RR=1.7) o Small CBD Ø ≤ 4 mm (I 5%; S 62%; RR=1.8) o Erosive duodenopathy !!! (I 5%; S 31%; RR=0.7) I = incidence S = severe AP I = incidence S = severe AP ERCP for ABP prognosis

Easy Normal Difficult Failed initial p Easy Normal Difficult Failed initial p Severe % Severe % Surgery % Surgery % Mortality % Mortality % n n Marek et al., UEGW 2006 ERCP for ABP prognosis – Ease of CBD cannulation

mm 0 ÷ 4 5 ÷ 8 9 ÷ p mm 0 ÷ 4 5 ÷ 8 9 ÷ p Severe % Severe % Surgery % Surgery % Mortality % Mortality % n n Marek et al., UEGW 2006 ERCP for ABP prognosis – CBD diameter

ERCP should not be done purely for prognostic assessment ERCP should not replace current prognostic systems When urgent ERCP is done for treatment of acute episode of ABP, it may be of value to record findings carrying possible prognostic information ERCP should not be done purely for prognostic assessment ERCP should not replace current prognostic systems When urgent ERCP is done for treatment of acute episode of ABP, it may be of value to record findings carrying possible prognostic information ERCP for ABP prognosis

Prognosis of ABP Major duodenal papilla Unident. to small Normal Large / v. large W impacted stone p Unident. to small Normal Large / v. large W impacted stone p Severe % Severe % Surgery % Surgery % Mortality % Mortality % n n Marek et al., UEGW 2006

Pancreatic duodenopathy n (851) n CT (162) Duodenum Wall thick. (mm) Diameter (mm) Lumen (mm) L/D (%) n (851) n CT (162) Duodenum Wall thick. (mm) Diameter (mm) Lumen (mm) L/D (%) N N MLD MLD MOD MOD SEV SEV p p Duodenopathy grade Marek et al., Gut 2005 (abstract)

n (851) % Age (y) Sex (% F) BMI (kg/m2) SE failure (%) n (851) % Age (y) Sex (% F) BMI (kg/m2) SE failure (%) N % N % MLD 40 5% MLD 40 5% MOD 88 10% MOD 88 10% SEV 33 4% SEV 33 4% p p Duodenopathy grade Marek et al., Gut 2005 (abstract)

n (851) % CRP max48 mg/L IL-6 max48 pg/mL WBC max48 G/L AP-O cum48 (score) CTSI 72h (score) n (851) % CRP max48 mg/L IL-6 max48 pg/mL WBC max48 G/L AP-O cum48 (score) CTSI 72h (score) N % N % MLD 40 5% MLD 40 5% MOD 88 10% MOD 88 10% SEV 33 4% SEV 33 4% p p Marek et al., Gut 2005 (abstract) Duodenopathy grade

Patients flow No ERCP Urgent ERCP 77 Failed ERC Successful ERC Non-biliary AP, late phase ABP Early phase of ABP (within 48 h of pain) 1024 Acute pancreatitis 8% / 958 CM Stratification for gallbladder stones RANDOMIZATION ES CBD stones 43% / 881 No CBD stone(s) Indications for ES w/o CBDS (jaundice, AOC, pregnancy, children, etc.) 92% / % / Impacted stone 18% / % / % / No other indications for ES 29% / GBS + 25 GBS GBS + 26 GBS - 4 CBD mini-stones 127 ES ITT PP