MALATTIE INFIAMMATORIE INTESTINALI E FEGATO NELLADULTO

1
MALATTIE INFIAMMATORIE INTESTINALI E FEGATO
NELLADULTO
Prof. Massimo ZUIN Unita di Epatologia e
Gastroenterologia Medica Polo Universitario S.
Paolo Università degli Studi di Milano
2
ALTERAZIONI DEI TESTS EPATICI NELLE IBD

• 5-15 dei pazienti con IBD ha unalterazione dei
  tests epatici ma 35 di questi non ha evidenza
  istologica di malattia
• Frequenza sovrapponibile in CD ed UC
• La severità, la durata e lestensione dellIBD
  non correla con lentità delle alterazione dei
  tests epatici
• Nelle fasi di acuzie di CD rialzo transitorio dei
  tests epatici
• Diagnosi differenziale
• Steatosi epatica alcolica e non
• Epatotossicità da farmaci (azatioprina,
  metotrexate, infliximab)
• Sepsi

3
HEPATOBILIARY COMPLICATIONS OF INFLAMMATORY BOWEL
DISEASE
(Zakim Boyer 2003 mod.)
4
PRIMARY SCLEROSING CHOLANGITISClassification
(Modified from La Russo, 1999)
5
PRIMARY SCLEROSING CHOLANGITIS Epidemiology

• PSC prevalence in Western countries 8-13/106
  cases/year
• Male to female ratio 1.5 2 1
• Association with IBD
• PSC associated in
• 2.4 - 4 of UC pts
• 5.5 pancolitis
• 0.5 distal colon disease
• 1 - 1.2 of CD pts
• IBD associated in 60 - 80 of PSC pts ( 7 CD)

(Levy, 2006 Shepherd, 1983 Tobias, 1983
Aaland, 1987 Olsson, 1991 Rasmussen, 1992)
6
PRIMARY SCLEROSING CHOLANGITISClinical
presentation
(Modified from Zakim Boyer 2003)
7
CLINICAL, ENDOSCOPIC, HISTOLOGICAL FEATURES OF
IBD ASSOCIATED WITH PSC
Quiescent colitis Substantial preclinical
phase Pancolitis Rectal sparing Backwash
ileitis Pouchitis Colorectal dysplasia/carcinoma
(Loftus et al, 2005 Levy,2006)
8
PRIMARY SCLEROSING CHOLANGITIS ASSESSMENT OF
NATURAL HISTORY
Elusive onset Clinical course highly
variable Exacerbations/remissions Symptom
heterogeneity - specific complications bacterial
cholangitis bile duct lithiasis cholangioca
rcinoma - associated disorders
9
PRIMARY SCLEROSING CHOLANGITISNatural history
5 perspective studies of prognostic
variables Farrant (1991) 126 (Kings College,
London) Dickson (1992) 426 (multicenter, USA
and UK) Schrumpf (1994) 77 (Oslo, Norway) Broome
(1996) 305 (Stockholm, Sweden) Shetty
(1997) 208 (Cleveland, OH) OVERALL 1142 Follow
-up, 3 - 6 yrs
10
NATURAL HISTORY OF PSC
Mean age at diagnosis 32 - 42 yrs Asymptomatic 1
6 - 44 Developing symptoms 22 - 53
Cholangiocarcinoma 6 - 14 Median
survival 12 - 15 yrs
11
NATURAL HISTORY OF SMALL- DUCT PSC
Björnsson, 2002
12
PRIMARY SCLEROSING CHOLANGITIS Neoplastic
potential

• Cholangiocarcinoma (CCA)
• High prevalence at autopsy (30 - 40) and OLT
  (23 - 33)
• Cumulative incidence ranging from 4 to 20 in 5
  to 12 years follow-up
• Unrelated to PSC duration
• Risk factors alcohol, portal hypertension, long
  history of IBD
• Suspicion raised at cholangiography by marked or
  progressive ductal
• dilatation, progressive stricture, polypoid
  mass lesion gt 1 cm ?
• (Chapman, 1980 Broomè, 1995 Farrant, 1991 Abu
  el Magd, 1993 van Laethen, 1995 Chalasani,
  2000 Boberg, 2002 Burak, 2004)
• Hepatocellular carcinoma
• 3 out of 134 pts (2) undergoing OLT, in a
  retrospective evaluation

13
PRIMARY SCLEROSING CHOLANGITIS Neoplastic
potential
Cumulative risk of colorectal cancer
Cumulative risk

40
30
UCPSC
20
UC
10
Duration yrs
10 20 30
(Modified from Broomè, 1995)
14
PRIMARY SCLEROSING CHOLANGITIS Patient management

• Medical treatment
• Management of stenosis
• Role of biliary surgery
• OLT

15
MANAGEMENT OF PSC MEDICAL TREATMENT

• Aimed at
• preventing or reversing symptoms and
• complications related to long-standing
• cholestasis and underlying disease
• - pruritus
• - bone disease
• - metabolic / nutritional problems
• - portal hypertension/ cholangitis
• improving survival

16
TREATMENT OF PRURITUS A Pragmatic Approach

• UDCA for underlying disease
• if persistent pruritus
• Cholestyramine (up to 16 g daily)
• Rifampin (150-300 mg b.i.d.) for up to 6 mo
• Antihistamines (difenhydramine 25 mg bedtime)
• Opiate antagonists (naltrexone, 50 mg daily)
• Serotonin antagonists (ondansetron, 4 mg
  b.i.d.)
• OLT if advanced disease

17
MEDICAL MANAGEMENT OF PSCSupportive treatment
Calcium and Vitamin D Antibiotics if acute
cholangitis
18
PRIMARY SCLEROSING CHOLANGITIS Medical therapy
NO PROVEN BENEFIT OR SERIOUS TOXICITY Antibiotics
Azathioprine Cholestyramine Corticosteroids Cyclo
sporine D-penicillamine Methotrexate Tacrolimus
POSSIBLE BENEFIT Ursodiol Ursodiol baloon
dilatation Ursodiol steroid azathioprine
19
UDCA for PSC Mayo group study

• 105 pts randomised to UDCA (13-15 mg/kg) or
  placebo
• Medium follow-up 2.2 yrs
• Improvement of LFTs (including bilirubin)
• No difference in terms of
• tx failure in all pts (RR 1.01 CI 0.6-1.7)
• in early stage (RR 0.70 CI 0.3-1.8)
• time to OLT (RR 1.5 CI 0.6-3.5)
• (Lindor, 1997)

20
COLON CANCER CHEMOPREVENTIVE EFFECT OF UDCA IN UC
PSC

Pardi, 2003
21
PRIMARY SCLEROSINCHOLANGITISManagement of bile
ducts stenosis (I)
Endoscopic or radiologic intervention Indication
s Obstruction of large bile ducts by a
dominant stricture or stone with clinical
deterioration or recurrent cholangitis Rule out
cholangiocarcinoma or rapidly progressive
disease Choice of the approach - site and
complexity of the stricture(s) - local
expertise Outcome - no clear impact on survival
- improvement of symptoms - repeated
procedures often required - aggressive
dilatation with UDCA reported to improve
survival in an uncontrolled study
22
PRIMARY SCLEROSING CHOLANGITIS Management of
bile ducts stenosis (II)
Biliary surgery Indications dominant
stricture in the CBD or at bifurcation in
patients with early disease (not amenable to
ES or PCT dilatation) Procedure resection with
intraoperative dilatation of more proximal
ducts and long-term trans-hepatic
stenting Outcome prolonged OLT-free survival
compared with pts treated by ES procedures in
a non-randomized study (Ahrendt,
1998) Warning previous biliary surgery may be
associated with higher mortality and morbidity
after OLT
23
PRIMARY SCLEROSING CHOLANGITISLiver
transplantation
Survival 90-97 at 1 year ? 85 at 5
years Timing - Better long-term survival in pts
with less advanced disease
(Mayo score lt 4.4) -
Referrals indicated even in pts
without cirrhosis for poor quality of life,
recurrent cholangitis or jaundice Complications
Higher incidence of ductopenic rejection
and colon cancer in UC Recurrence - PSC can
recur (rate as yet undefined) - Diagnostic
challenge in pts with non anastomotic
biliary stricture - Course of recurrent
disease usually not aggressive
24
PRIMARY SCLEROSING CHOLANGITISTake home messages

• L IBD va sempre ricercata nel paziente con PSC
• Il paziente con IBD e PSC
• - ha caratteristiche di malattia intestinale
  diverse
• da quelle del paziente con sola IBD
• - presenta un ? rischio di colangiocarcinoma e
  di
• adenocarcinoma del colon ? follow up più
  
• rigoroso.

25
MEDICAL MANAGEMENT OF PSCConclusions (Osp. Buzzi
2006)

• NO established medical treatment
• Until there is greater insight into the
• pathogenesis of PSC, it is difficult to
• anticipate major advances in medical
• management
• For patients with advanced PSC, OLT is the
• only therapeutic option
• Mitchell and Chapman, 1997

26
PRIMARY SCLEROSING CHOLANGITISTake home messages
Presence of IBD at diagnosis of PSC
no
yes
Colonscopy with multiple biopsies
IBD
Treatment with UDCA and 5-ASA Annual
colonoscopic surveillance
No IBD
Perform a new colonscopy If diarrea occurs
Dysplasia
No dysplasia
Continue annual Colonosccopic surveillance
Consider colectomy
Broomé and Bergquist, Sem Liver Dis, 2006
27
INDEPENDENT PROGNOSTIC FACTORS FOR PSC
28
CONSEQUENCES OF LONGSTANDING CHOLESTASIS

• Pruritus
• Jaundice
• Hyperlipidemia
• Complications of cirrhosis
• (ascites, g.i. bleeding,
• encephalopathy)
• Osteopenia
• Malabsorption
• Steatorrhea
• Distal tubular acidosis

SYSTEMIC CIRCULATION
Urinary excretion
Colephilic anions/Cu retention
Membranolytic activity Organular
dysfunction Apoptosis, necrosis Fibrosis/cirr
hosis
Fecal excretion
29
(No Transcript)
30
PRIMARY SCLEROSING CHOLANGITISClinical
presentation (3)
UC ulcerative colitis CD crohns disease IC
indeterminate colitis

• Loftus EV, Gut 2005

31
PRIMARY SCLEROSING CHOLANGITISNatural history
(Talwalkar, 2001)
32
PRIMARY SCLEROSING CHOLANGITIS Neoplastic
potential

• Cholangiocarcinoma
• Epidemiology
• Prevalence 6 - 36
• Life time risk 5-15
• Annual incidence 0.5 1
• - Unrelated to PSC duration
  
• 
  Levy, 2006
  Burak 2004
• Risk factors
• Alcohol (Chalasani, 2000)
• Portal Hypertension (Burak, 2004)
• Long history of IBD (Boberg, 2002)