l'eterogeneità della pancreatite cronica - gastrolearning®

Università di Verona Dipartimento di

Medicina

L’eterogeneitàdella pancreatite

cronica

AOUI di VeronaIstituto del Pancreas

Italo Vantini

Conoscere una malattia - 1

• La conoscenza delle connotazioni di una malattia consente di fornire:– una descrizione utile per l’inquadramento

classificativo (nosologico) (che cosa è)• Etiopatogenetica• Clinica• Anatomopatologica• Fisiopatologica

– un “nome”’per la sua identificazione nosologica (condivisione di come si chiama)

Conoscere una malattia - 2

• Una diagnosi– Matching, illness script, exemplars– Percorsi probabilistici– Criteri, strumenti, percorsi, processi

• La diagnosi non è “tanto” l’inserimento del paziente in una “casella nosologica, ma un giudizio basato su dati e criteri utili per assumere decisioni operative ai fini della:

• Prognosi• Terapia

In principio…

Sarles H, Sarles JC, Camatte R, Muratore R, Gaini M, Guien C, Pastor J, Le Roy

FObservations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis.

Gut 1965; 6: 545-59.

Chronic pancreatitis

Chronic process characterized by inflammatory and fibrotic changes of the pancreas.

Irreversible nature of structural changes and progressive

functional impairment

Fibrosis of the pancreas Damage to the acinar tissue Changes in ductal system• Calcifications

morphologically

Chronic pancreatitis: progressive parenchymal changes

Normal pancreas

Moderate changes more or lessscattered troughout the pancreas

Advanced changes (fibrosis)

Chronic pancreatitis: pancreatic duct

Pancreatic calcification

• Recurrent or persistent pancreatic pain

clinically

Pain in chronic pancreatitis

PATHOPHYSIOLOGY• Acute inflammation

• Ischemia• Increased intraductal and parenchymal pressure

• Mechanical compression (e.g. pseudocyst)Pancreatic neural remodelling and neuropathy

Clinical pictures Type 1pain recurrent with lasting

pain-free intervalsType 2 pain : frequent, persisting,

disabling pain

Chronic pancreatitis• Recurrent or persistent

pancreatic pain Changes in ductal system• Fibrosis of the pancreas• calcification

• Deterioration in pancreatic function

(exocrine and endocrine)

clinically

morphologically

functionally

Frequency of painful relapses/year in 199 patients with chronic pancreatitis

(non-operated upon) followed up to 20 years

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

years since clinical onset

25°50°75°

percentiles

Calcification and dysfunction in time

Scuro LA et al , Am J Gastroenterol 1983; 78: 495-501. Ammann RW et al. Gastroenterology 1984, 86: 820-8..

early advanced late

Prevention andtreatment

of painful relapses and complications

treatment of relapsing

or persisting pain

Treatment ofexocrine failureand secondary

diabetes

alcool

Alcohol and chronic pancreatitis- relative risk -

0-40 41-80 81- 240

grams of alcohol/day

chronicpancreatitiscancer without CP

Durbec J, Sarles H: Digestion 1973Talamini G. et al Dig Dis Sci 1999

function

Chronic Pancreatitis (“old concepts”) - 1

a single and distinct entity

a well defined epidemiological

and clinical pattern

Male/female 4:1; age onset 47 year old

alcoholic in origin (in Western Countries)

Differs from Acute Pancreatitis(etiology, clinical outcome,prognosis)

Acute and chronic pancreatitis are two distinct entities

Pancreatologia

Chronic PancreatitisAlcohol abuse in more recent studies

Italy 2009° India 2008* USA 2008^ China 2009"

f patien

° Frulloni L et al, PanCroInfAISP, Dig Liv Dis 2009; 41: 311-317* Balakrishnan V et al, J Pancreas, 2008; 9: 593-600^ Withcomb DC et al, NAPS2, Pancreatol, 2008; 8: 520-531” Whang LW et al, Chinese CPSG, Pancreas, 2008; 38:248-54.

893 pts 1033 pts 540 pts 2008 pts

Smoking and chronic pancreatitis: a meta-analysis

Andriulli A, Botteri E, Almasio PL, Vantini I, Uomo G, Maisonneuve P: Smoking as a

cofactor for causation of chronic pancreatitis. Pancreas 2010; 39: 1205- 1210

Smoking and pancreatic calcification

Talamini G, Bassi C, Falconi M, Sartori N, Vaona B, Bovo P, Benini L, Cavallini G, Pederzoli P, Vantini I: Smoking cessation at the clinical onset of chronic pancreatitis and risk of pancreatic calcification.

Pancreas 2007; 35: 320-326.

Giving-up smoking within 5years since onset of CP reduces the risk of developing pancreatic

calcifications

Talamini G et al Pancreas. 2007 ;35:320-6.

Pancreatic acinar cell damage in response to cigarette smoke components : sensitization to acinar cell injury, that can be

worsened by alcohol consumption

Alexander M et al Pancreatology; 2011: 11: 469-74

Cytoplasmic swelling

Trypsinogenbut not PSTI

similarto

experimentalacute

pancreatitis

oxidativestress andlipidperossidation

Chronic Pancreatitis (“concepts”) -2

a single and distinct entity

alcohol and smoke interact as risk factors

increased risk of pancreatic cancer

a single clinical pattern, though evolving in time

Epidemiological and clinical features of chronic pancreatitis: the identikit

• Males (80%)• 45 year old at the clinical onset• Alcohol abusers (40-60%)• Smokers in (> 80%)• Pancreatic calcification (20% at onset)• Dilation/changes of pancreatic duct system• Painful relapses• Progressive pancreatic failure (exocrine and

endocrine)

Chronic pancreatisprinciples of therapy-2

• Prevention of relapses– Alcohol withdrawal in an early stage

• Reduction in the risk of pancreatic calcifications and of the progression of the disease– Smoking withdrawal

• Reduction in the risk of pancreatic cancer (?) – Smoking withdrawal

• Treatment of relapses– Treatment of acute flares (starvation, IV fluids, analgesic drugs)

• Treatment of disabling and severe pain and/or of complications– Surgery (drainage or resection) (not “untimed”) associated with

alcohol withdrawal• Treatment of exocrine failure

– Enzyme-containing pancreatic supplements (enteric-coated)

Pancreatologia triumphans

a “new” pancreatitis ?

men heavy alcohol drinkers heavy smokers calcification (90%) dilation of the pancreatic duct (80%) aggressive painful pancreatitis, often

disabling (> 50%) vomiting, jaundice

Cystic Type (75%) Solid Type (25%)

- pathology: cystic and solid types -

Thickened duodenal wall

NormalDuodenal

EUS findings

Cystic dystrophy of the duodenal wallThe “groove” area

D = duodenum P = papilla of Vater BD = common bile duct W = Wirsung’s ductC = cyst

Groove Groove

CYSTIC DYSTROPHY OF DUODENAL WALL

A bud of dorsal pancreas, associated to the Santorini's duct, entrapped within the duodenal wall

during organogenesis

Paraduodenal pancreatitis(cystic or solid duodenal dystrophy)

almost all men

almost all heavy alcohol abusers almost all smokers calcification (90%)

disabling painful relapses vomiting, jaundice (at onset)

Age of onset

M/F Heavy drinkers >80gr/day

Smokers Calcific. Pain Localcomplications

Survival

45-50 3:1 ++ ++ ++ ++ ++ affected

< 20 2:1 - - ++ + + unaffected

40-45 9:1 +++ +++ ++ +++ ++ affected

45-50 2:1 +/- +/- + + + unaffected

50-60 n.d. +/- +/- ++ - +/- unaffected

45-50 2:1 - +/- - +/- +/- unaffected

Main clinical features in different types ofchronic pancreatitis

Alcoholic

Hereditary

Paraduod.

Obstructive

Painless

Alcoholic pancreatitis and paraduodenal pancreatitis (PDP)

• PDP pancreatitis shares the same risk factors and similar epidemiological and clinical pattern of alcoholic pancreatitis

• Morphologically is a distinc form of CP• PDP clinically behaves a severe clinical form of

alcoholic pancreatitis

• Though alcohol withdrawal can induce some clinical improvement, more than 50% of the patients are eligible for surgery because of invalidating pain and/or duodenal obstruction

• It is probable that old series of patients formerly classified as alcoholic pancreatitis were in fact PDP

GrooveZone

Dilation of Wirsung

Head calcifications

D = duodenal lumenW=Wirsung’s duct

cysts of the duodenal wall and chronic pancreatitis

Chronic pancreatitisClassification of Marseille-Rome 1990

• Alcoholic pancreatitis • Obstructive pancreatitis• Hereditary and familial pancreatitis• Idiopathic pancreatitis

– juvenile– senile (may be painless)

• Inflammatory pancreatitis

Sarles H, Scand J Gastroenterol, 1989; 24: 641-2

Obstruction and chronic pancreatitis

• Several experimental data on different animal models show that chronic pancreatitis cannot develop, irrespective of the type of the experimental damage, without an obstruction of the duct system

• Periductal inflammation can lead, together with stellate cells activation, to periductal fibrosis that can induce changes in the pancreatic duct system

Kloeppel G. et al. Pancreas, 1993; 8: 659-670

Necrosis-fibrosis mechanism in chronic pancreatitis

Following an acute pancreatitis

Acute pancreatitis 8 months before

an acute attack ofpancreatitis 6 months before

Chronic pancreatitis can be theconsequence of a necrosis-fibrosis change, leading to

obstruction of pancreatic ductsystem, and then to inflammatory

and fibrotic changes.Acute necrotizing

pancreatitis can lead tochronic pancreatitis

Lankish PG et al., Am J Gastroenterol, 2009; 104: 2796-2805

(19/88=22%)

Acute pancreatitis: frequency of chronicization

Lankish PG et al. Am J Gastroenterol, 2009; 104: 2796-2805

Acute pancreatitis: frequency of relapsesfollowing the first episode

(alcoholic vs. non-alcoholic pancreatitis)

“obstructive” pancreatitis

Factors (different fromslow-growing tumors) hampering

the pancreatic outflow cantrigger a process leading to

obstructive pancreatitis

A “dysfunction” at the Oddi’s sphincter (SOD)can lead to chronic pancreatitis obstructive

Oddi’s sphincter inflammation with altered outflowcan “trigger” chronic pancreatitis

An obstacle to the pancreatic outflow can be associated withrelapsing pancreatitis without evidence of ductal changes

calcificazionecalcificazioneostruenteostruente

dilatazione duttaledilatazione duttaledilatazione duttaledilatazione duttale

Dilatazione duttale e singola calcificazioneostruente

Ricorrenzedolorose

DLD 1999; 41. 311-17

Obstruction is the most frequentassociated factor in women (46%)

Age of onset

M/F Heavy drinkers

Smokers Calcific. Pain Localcomplications

Survival

45-50 3:1 ++ ++ ++ ++ ++ affected

< 20 2:1 - - ++ + + unaffected

40-45 9:1 +++ +++ ++ +++ ++ affected

45-50 2:1 +/- +/- + + + unaffected

50-60 n.d. +/- +/- ++ - +/- unaffected

45-50 2:1 - +/- - +/- +/- unaffected

Main clinical features in different types ofchronic pancreatitis

Alcoholic

Hereditary

Paraduod.

Obstructive

Painless

Pain in chronic pancreatitis

PATHOPHYSIOLOGY OF PAIN IN

“OBSTRUCTIVE PANCREATITIS”

Increased intraductal-parenchymal

pressure caused by decreased drainage of

pancreatic juice into the duodenum•

Clinical pictures Type 1pain recurrent with lasting

pain-free intervalsType 2 pain : frequent, persisting,

disabling pain

The rationale of drainage surgery is a decompression within theductal system and reduction in pain in a substantiaòproprtion of patients

Uncomplicate chronic pancreatitis- Indication for surgery -

ERCP following sphincterotomy,ESW and fragment extraction

Large stone in the duct

Surgery (pancreatojejunostomy) vs. endoscopy (sphincterotomy) in chronic pancreatitis

NEJM 2007; 356: 676-84

Djuna L Cahen et al

but in 6/7 evaluable patientssubmitted to rescue surgery,

it was uneffective

Who are the main clinical and morphological features of the patients with good results of

drainage surgery and poor after endotherapy ?

• Advanced chronic pancreatitis• Distal obstruction• Calcifications (> 90% of the cases)

• Severe, recurrent pain

• Not too enlarged head of the pancreas

In advanced chronic pancreatitiswith symptoms and distal

obstruction, drainage surgeryis superior to endoscopic

therapy

Who are the patients with chronic pancreatitis in which the endoscopic therapy seems to be more effective ?

• single distal obstruction • single distal stone• short duration of the disease• more aggressive, repeated stenting strategy

– Pancreatic sphincterotomy– Stricture dilation– Repeated stenting

– Stone removal Farnbacher et al Gastrointest Endosc 2002; 56: 501-59Costamagna G et al Endoscopy 2006; 38: 254-59Dumonceau JM et al ESGE guidelines- Endoscopy 2012, 44. 784-96

For treating uncomplicated chronic pancreatitis(aimed at relieving pain) ESGE recommends ESW/ERCP at the first-time interval option.The clinical response should be evaluated

at 6-8 weeks. If it is unsatisfactory the case

should be discussed in a multidisciplinaryteam.

Surgical options should be considered,in particular in patients with a predicted poor

outcome after endosopic therapy (RG B)

Candidate parameters for selecting patients for appropriate treatment and timing

(a multidimensional approach)

• Aethiology, natural history• Duration of the disease (stage)• Clinical features (pain type, complications) and QOL scores• Morphological assessment

– Main pancreatic duct and secondary branches changes– Distal stenosis (main duct, Santorini)– “Dominant” duct stricture– Single or multiple obstructions-strictures– Upstream dilation (+/-)– Stone (single, distal, multiple)

– Ductal scars (necrosi/fibrosis)– Complications

• Technical aspects and aggressive strategy

However, paincan persist also following

effective treatment of stricture,or it can subside also

if the stricture is not disappeared

Pain treatment: appropriate patient selection

• A proper patient selection is of vital importance in the indication and in the outcome of treatment, in particular case of endoscopic and surgical therapy

• A more aggressive endoscopic strategy probably will

give better results in properly selected patients

• Surgery should be timed and tailored to the clinical features and risk assessment, morphological pictures, and the best as possibile assessment about the presumptive origin of pain. Combination surgery should be considered

“Small duct”pancreatitis

Chronic pancreatitis: ERCP

Langenbecjs Arch Surg 2003; 388: 132-9

Frequency of painful relapses/year in 199 patients with chronic pancreatitis

(non-operated upon) followed up to 20 years

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

years since clinical onset

25°50°75°

percentiles

Calcification and dysfunction in time

Scuro LA et al , Am J Gastroenterol 1983; 78: 495-501. Ammann RW et al. Gastroenterology 1984, 86: 820-8..

early advanced lateEndotherapy

Medical treatment

Endoscopy-SurgeryMedical treatment

Medicaltreatment

25 years ago…..

• Amman RW et al Gastroenterology 1986– in chronic pancreatiis early surgery is

associated with a poor cinical outcome– the natural history of CP indicates that in

almost 2/3 of the patients pain spontaneously subsides in long-term evolution

– Commentary (Gastronterology 1986)• “The patient patient and the impatient

surgeon”

• Alcoholic pancreatitis • Hereditary and familial pancreatitis• Idiopathic pancreatitis

– juvenile–senile (may be painless)

• Obstructive pancreatitis• Inflammatory pancreatitis

Cationic Trypsinogen – PRSS14,5

R122H, N29I, A16V, R116C, E79K, R112C, D22G, K23R

Pancreatic Secretory Trypsin Inhibitor (PSTI) – SPINK16,7

N34S, P55S, M1T, L14P, -53C>T, IVS3+2T>C

CFTR gene1-3 F508 (nel 50-70% dei casi), altre mutazioni

1 N Engl J Med, 1998: 339; 645-22 N Engl J Med, 1998; 339: 653-8 3 Eur J Hum Genet, 2003; 11: 543-64 Gut, 2002;50:271-2.5 Gut, 2002; 50:687-926 J Med Genet, 2000; 37:67-97 Gut, 2002; 50:675-81

Gene-mutation associated pancreatitis

Hereditary-Familial

one or more relatives of the same familial kindred affected, at different or at the same generation,

No other risk factor of pancreatitis (complete work-up)

Juvenile onset < 10 years (< 20 years)

Recurrent episodes of mild pancreatitis

Progression of pancreatic calcifications

Slow progression toward pancreatic failure

Survival rate comparable to that of the general population

High risk of pancreatic cancer: the first cause of death in hereditary pancreatitis (30 years since the onset)

Gene-mutation associated pancreatitisMain features of Hereditary Pancreatitis

Cumulative risk of cancer in patients with Hereditary Pancreatitis

(smokers vs. non smokers)

smokers

non-smokers

Lowenfels AB et al JAMA 2001; 286:169-70

pancreatite associata a mutazione del CFTR

Pancreatite associata amutazione del gene SPINK 1

SPINK1

SPINK1SPINK1

Chronic pancreatitis associated with gene mutation

Bull-eye signBull-eye sign

Graziani R. et al. Abdominal Radiology, 2010; 115: 885-888

Frulloni L, et al. Pancreas. 2008:371-

non smokers

smokers

• Alcoholic pancreatitis • Hereditary and familial pancreatitis• Idiopathic pancreatitis

– juvenile–senile (may be painless)

• Obstructive pancreatitis• Inflammatory pancreatitis

CFTR Normale86,7%

CFTR Normale95,7%

CFTR 1 Mutazione

Pancreatite Cronica Idiopatica60 pazienti

Controlli600 pazientiRR = 2,52RR = 2,52

SPINK1 Normale77%

SPINK1 Normale99,65%

SPINK1 Mutato

23% SPINK1 1 Mutazione

Pancreatite Cronica Giovanile

96 pazienti

Controlli279 pazienti

Chronic pancreatitis and gene mutations

• Mutation in PRSS1 is present in ¼ of patients with juvenile-type chronic pancreatitis

• Up to 30% of idiopathic pancreatitis have a mutation in the CFTR allele vs. 3-5% in the general population, though a single mutation alone cannot trigger pancreatitis

• 20-30% of Hereditary Pancreatitis do not have PRSS1 mutation

• Mutation in PRSS1 is found in 20% of subjects who do not have any sign of pancreatitis (carriers)

Rebours V et al DLD 2012; 44: 8-15

SI (87%)

Età all’esordio28 ± 14 anni

NO (13%)Età all’esordio

44 ± 18 aa

Esordio clinico = Pancreatite acuta

p = 0.005

Clinica all’esordio: Dolore aspecifico (6) Dispepsia (2) Ittero (1) Altra patologia (2)

CFTR-S = 30 ± 14 anni

CFTR-D = 20 ± 12 anni

SPINK1 = 24 ± 14 anni

p = 0.027

CFTR-S = 30 ± 14 anni

CFTR-D = 20 ± 12 anni

SPINK1 = 24 ± 14 anni

p = 0.027 10 di 11 pazienti

= PC all’esordio

10 di 11 pazienti

= PC all’esordio

Pancreatite associata ad alterazioni geniche

STORIA NATURALE DELLA PANCREATITE ASSOCIATA A MUTAZIONI GENICHE

Giulia De MarchiTesi di Laurea, 2011

Long time ago…. Long time ago….

Ludovico Antonio Scuro1924 – 1989

“Why should the pancreas be the only

human organ not involved by an autoimmune

process?”

Autoimmune pancreatitis• Described by H. Sarles in 1961 yet, • More than 900 papers published (most since

’90s)• Accounts for

– 4-6 % of all the patients with chronic pancreatitis referring to a terziary centre and for

– about 20-40 % of idiopathic chronic pancreatitis

• Its aethiology is still unknown antibodies: CA II, Lactoferrin, SPTI antibodies

(against host antigens); genetics: association with haplotype DRB1 0405 DQB1 0401; Polymorfism of Cytotoxic Lymphocyte-associated antigen-4 49A

No drinker and no smoker patients

Frequent association with other autoimmune diseases

Asymptomatic jaundice at onset (particularly in focal type)

“Atypical” pancreatitis at onset (particularly in diffuse type)

Dramatic, peculiar response to steroids

Autoimmune Pancreatitis Main Clinical Features

AIP Type 2 (15-30%)

IdiopathicDuct-Centric Pancreatitis

(IDCP)

IgG4– (ICH) – GEL+

Inflammatory Bowel Disease

Relapses NOSteroids

AIP Type 1 (70-85%)

Lympho-PlasmacyticSclerosing

Pancreatitis (LPSP)

IgG4+ (ICH) – GEL– IgG4 systemic disease

Relapses YESSteroids

From Zamboni G et al

Autoimmune Pancreatitis is a chronic pancreatitis

LP . periductal inflammationIgG4 positive plasmacells

Duct desctruction and narrowingStoriform fibrosis

Type 1

Granulocytic Epithelial Lesion – GEL –Zamboni G et at, Vierchow Arch, 2004; 445:

552-563

Type 2

Sausage-like Irregular narrowing

swelling Capsule-like rim

Diffuse AIP

mild pancreatitis

Narrowed and irregular duct in autoimmune chronic pancreatitis

Associated witha clinical picture

Autoimmune pancreatitisFocal and mass forming

Early arterial phase

University of Verona: Dpt. of Radiology

jaundice

Mass forming

Mass forming AIP

The problem is not to confirmhistologically AIP, but to exclude cancer

by US or EUS-guided biopsies

University of Verona: Dpt. of Radiology

mandatory

Mass-forming AIP: response to steroid therapy

15 days after initiation of steroidsCT at admission

01-2009

02-2009

Dopo terapiasteroidea

Repertodi base

Pancreatite acuta lieve seguitada precoce ricorrenza lieve e persistenza di moderataelevazione degli enzimi

Shimosegawa T et al, Pancreas, 2011: 40: 352-358

ICDC Autoimmune pancreatitis type 1: cardinal diagnostic criteria and levels of reliability

Shimosegawa T et al, Pancreas, 2011: 40: 352-358

ICDC Autoimmune pancreatitis type 2: cardinal diagnostic criteria and levels of reliability

92 Pazienti

Tipi di pancreatite autoimmunedopo completo work-up (ICDC)

Tsukasa Ikeura et al 2013, submitted

AIP type 1

AIP NOS

AIP type 2

Three types of AIP: overlaps amongdiagnostic features

Gut Online First, published on December 11, 2012 as 10.1136/gutjnl-2012-30361

Phil A Hart et al: Long-term outcomes of autoimmune pancreatitis:a multicentre, international analysis

23 institutions10 countries

1064 patients

ICDCcriteria

Type 1978

Type 286

Relapse rate

Type 131%

Type 29%

(> in IgG4 –related sclerosing cholangitis)

* retreatment with steroids was equally effective

Phil A Hart et al: Long-term outcomes of autoimmune pancreatitis:a multicentre, international analysis

Gut Online First, published on December 11, 2012 as 10.1136/gutjnl-2012-30361

alcoholic

obstructive

paraduodenal

painless

genetic

idiopatic

Eterogeneityand ovelap

Classificazioni della pancreatite cronica• Etiologia, clinica e morfologia (nosografica)

– Marsiglia 1963– Cambridge, 1983 – Marsiglia 1984– Marsiglia-Roma 1988

• Per stadio di malattia (early, late, advanced)– Chari ST, Singer MV Scand J Gastroenterol 1994; 29: 949-60

• Per fattori di rischio– TIGAR-O Etemad B, Whitcomb DC. Gastroenterology. 2001

• Per approccio operativo-terapeutico– Cavallini G, 2000 (“classificazione di Verona”)

• Per probabilità di diagnosi (clinica, imaging, funzione, istologia)– Zurich 1997– JAP 1997

• Per combinazione di clinica, probabilità di diagnosi, stadiazione, severità + score– M-ANNEHEIM (Schneider A, Lohr JM, Singer MV. J Clin

Gastroenterol 2007; 42: 101-119)

Classification by

• EZIOLOGICORisk factors

Probabaility of the diagnosis

Clinical features and stage

Severity

M-ANNHEIM classification of chronic pancreatits

Schneider A, Löhr JM, Singer MV.The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease.J Gastroenterol. 2007; 42:101-19.

- classifications and operative needs -

• Nosographic classification • Diagnostic matching with illness scripts,

exemplars,categories

• Operative classification• Operative diagnosis targeted to decisions

• Complexity/undefined aspets/variation in time• Diagnosis (disease) reliability : defined, probable,

possible, undefined

Evidence Level (EL) of the literature information/source of the

statements

% o f th e s ta te m e n ts

1 2 3 4 5

According to Oxford Centre for Evidence Based Medicine

Recommendation strenght of the statements,and agreement (consensus) rate

% o f th e s ta te m e n ts

A B C D

According to Oxford Centre for Evidence Based Medicine

83% of the statements: agreement rate*> 80% * Agreement rate: “strongly agree or with minor reserve”

In principio…

Sarles H, Sarles JC, Camatte R, Muratore R, Gaini M, Guien C, Pastor J, Le Roy

FObservations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis.

Gut 1965; 6: 545-59.

George Wirsung………Wirsung duct

Padova: giardino dei semplici(botanic garden )

l'eterogeneità della pancreatite cronica - gastrolearning®

Education

le infezioni nel cirrotico: aspetti clinici -...

le infezioni nel cirrotico: aspetti fisiopatologici -...

la terapia del cancro dello stomaco - gastrolearning®

la pancreatite acuta non biliare - gastroenterologi … ·...

pancreatite aguda

pancreatite acute

pdta pancreatite acuta - studiomedicoaimone.it · pdta...

malattie motorie dell'esofago e manometria hr -...

la prevenzione della pancreatite acuta post-ercp: stent o...

pancreatite crÔnica

strategie di screening del cancro colorettale -...

pancreatite acuta

infezione da helicobacter pylori - gastrolearning®

la terapia del cancro del pancreas - gastrolearning®

non-celiac glutensensitivity - gastrolearning®

malattie del pancreas 1 – anomalie / pancreatite ·...

lesioni cistiche pancreatiche: linee guida diagnostiche -...

pancreatite...

sindrome dell'intestino irritabile: diagnosi e terapia -...

pancreatite cronica