Maladie h

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Maladie hépatique et mucoviscidosePhysiopathologi
e et approche thérapeutique
5èmes Journéès scientifiques de la Fédèration
Francaise des Centres de Ressources et de
Compétences de la MucoviscidoseParis, 4 et 5
Dècembre, 2008
Carla Colombo CF CenterFondazione IRCCS Ospedale
Maggiore Policlinico University of Milan Italy
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MAJOR HEPATOBILIARY PROBLEMS IN CYSTIC FIBROSIS
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EVOLUTION OF LIVER DISEASE IN CYSTIC FIBROSIS
Pathological changes
Clinical finding
Cholangiocyte abnormalities
None
Mucous plugged bile ductules
Proliferation/inflammation
Liver enlargement Biochemical abnormalities
Focal biliary fibrosis
25-30
Adverse genetic modifiers
Extension to adjacent triads
Palpable hard liver
Multilobular biliary cirrhosis
5-10
Hepatosplenomegaly
Portal hypertension
Hypersplenism GI bleeding Ascites
Liver failure
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C.M. 22yrs. Female OLTx 21.3.97
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Liver disease shows great degree of variability
in terms of severity
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FACTORS INVOLVED IN THE PATHOGENESIS OF LIVER
DISEASE IN CF
Environmental factors
Genetic factors

• Nutritional status
• Antioxidant deficiency
• Compliance to therapy
• Drug hepatotoxicity
• Concomitant events - Viral hepatitis -
  TPN - Abdominal surgery

• Severe CFTR genotype
• Genetic modifiers - PI gene - MDR3 -
  MBL2 - TGF-beta - GSPT1 - other
  susceptibility genes ?

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Accumulation of ?1AP protein in CFLD subjects
expressing the Z allele genotype
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LACK/DYSFUCTION OF CFTR PROTEIN
DEFECTIVE CHOLANGIOCYTE Cl AND HCO³ TRANSPORT
ABNORMAL MUCIN SECRETION
LACK OF REGULATION OF OTHER CHANNELS Na
channels Cl channels ATP permeability GSH
transport Water transport
FOCAL BILE DUCTILE STASIS/OBSTRUCTION
DIRECT CHOLANGIOCYTE INJURY
RETENTION OF TOXIC BILE ACIDIS
STELLATE CELL ACTIVATION COLLAGEN SYNTHESIS
RELASE OF INFLAMMATORY CYTOCHINES
FREE RADICAL DEMAGE
EXTENSION OF LESION HEPATOCYTE INURY
ADVERSE GENETIC MODIFIERS
BILIARY CIRRHOSIS
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Lessons from the toxic bile concept
Trauner et al., 2008
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Lessons from animal models

• Experiments with murine models of CF have
  provided valuable insights and increased our
  understanding of CF pathophysiology
• However, CF mice develop a range of intestinal
  pathology, but pathological changes in other
  CF-affected organs (lung, pancreas, liver) are
  mild or absent
• Using a mouse model carrying DF508, hydrophobic
  bile acid profile and hyperbilirubinbiliawere
  found to be involved in the pathogenesis
• In another mouse model (exon-1 knockout) that
  develops progressive liver disease, DHA resulted
  in reduction of the degree of periportal
  inflammation

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Long-term DHA therapy in a congenic murine model
of Cystic Fibrosis

• To evaluate the therapeutic effects of dietary
  DHA in a cogenic CFTR -/- mouse model that
  develops CF-like pathology in all organs
• DHA had no significant therapeutic or harmful
  effect on the lung, pancreas or ileum of CFTR -/-
  mice or their wild-type littermates.
• In contrast dietary DHA resulted in highly
  significant amelioration of the severity of liver
  disease in the CFTR -/- mice, mainly a reduction
  of the degree of periportal inflammation
• Inhibition of cytokines and/or eicosanoid
  metabolism and release of endogenous inhibitors
  of inflammation by DHA may account for the
  anti-inflammatory effect in the liver
• The potential therapeutic benefits of DHA in
  CF-associated liver disease remain to be explored

Beharri S et al. 2006
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wild-type
untreated Cftr-/-
DHA treated Cftr-/-
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LIVER DISEASE IN CYSTIC FIBROSIS

• UDCA
• TREATMENT

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EFFECT OF URSODEOXYCHOLIC ACID ON SECRETORY
FUNCTIONS IN BILIARY EPITHELIUM

• Ursodeoxycholic acid (UDCA) is a non-toxic
  bile acid used in the therapy of cholestatic
  disorders
• UDCA improves clinical and biochemical
  parameters and prolongs survival free of liver
  transplantation in PBC
• UDCA is up to date the only available
  therapeutic approach for the treatment of
  CF-associated cholangiopathy
• Several potential mechanisms and sites of action
  of UDCA in cholestatic liver disease have been
  proposed

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POTENTIAL MECHANISMS AND SITES OF ACTION OF
URSODEOXYCHOLIC ACID IN CHOLESTATIC LIVER DISEASE
from Beuers U (2006)
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MODULATION OF CHOLANGIOCYTE SECRETION BY
URSODEOXYCHOLIC ACID CONJUGATES AS PROPOSED ON
THE BASIS OF EXPERIMENTAL STUDIES
from Beuers U (2006)
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FL, male, 16 yrs, before UDCA
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FL, male, 16 yrs, after UDCA
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MODEL FOR UDCA STIMULATED SECRETION IN MOUSE
CHOLANGIOCYTES
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UDCA FOR CF-ASSOCIATED LIVER DISEASE
Randomised controlled trial
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RANDOMIZED CONTROLLED TRIALS OF UDCA TREATMENT IN
CYSTIC FIBROSIS
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Long-term UDCA treatment in CF-associated liver
disease

• UDCA is able to slow but not halt progression of
  liver disease associated with Cystic Fibrosis

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BASELINE CHARACTERISTICS OF CF PATIENTS ON
LONG-TERM TREATMENT (gt 10yrs) WITH UDCA
No of patients 36 100
Male 21 58
Meconium ileum 11 30.6
DF508/DF508 16 44.5
DF508/other 17 47.2
Other/other 3 8.3
CF-related diabetes 2 5.5
Age at CF Dg (yrs) 2.6 4.8 Range 0-21.8
With cirrhosis 3 8.3
Age at dg of LD (yrs) 7.9 7.0 Range 0.1-28.0
Age at start of UDCA tr (yrs) 10.6 7 Range 0.5-31.7
Duration of UDCA tx (yrs) 10.1 0.4 Range 10.1-17.9
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MODALITY OF FOLLOW-UP AT THE CF CENTER IN MILANO

• Clinical exam every 3 months - weight, height,
  BMI percentiles
• Liver biochemistry every 6 months
• ASAT U/l
• ALAT U/l
• gGT U/l
• Bilirubin mg/dl
• AP U/l
• Albumin, PT, PTT
• Ultrasound once a year
• Pulmonary function
• FEV1
• FVC

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EFFECTS OF LONG-TERM UDCA (20 mg/Kg/d) IN CF
PATIENTS
paramether 0 y 5 y 10 y P
ASAT (IU/l) 6087 4442 3222 0-10 p0.047 5-10 p0.015
ALAT (IU/l) 68132 4037 2915 5-10 p0.016
YGT (IU/l) 5761 55114 4662 ns
Alkaline Phosph (IU/l) 728.9295 726759 461403 0-10 plt0.001 5-10 p 0.008
Platelets(103/mm3) 30185 25396 238121 0-5 p0.01 0-10 p0.006
sAlbumin (g/dl) 4.40.4 4.30.4 4.20.4 ns
PT (sec) 12.31.3 12.21.3 12.61.5 ns
PTT (sec) 32.77.1 35.95.0 35.53.3 0-5 p0.006
Bilirubin (mg/dl) 0.60.6 0.60.5 0.91.2 ns
FEV1 () (n 10 pts) 8920 - 7031 0-10 p0.018
FVC () (n 10 pts) 8632 - 7922 ns
BMI (perc) 3929 3929 3619 ns
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EFFECT OF UDCA (20 MG/KG B.W./D) IN CFALD SERUM
LIVER ENZYMES (MEAN VALUES)
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EFFECT OF UDCA (20 MG/KG B.W./D) IN CFALD
BILIRUBIN (MEAN VALUES)
Bilirubin (mg/dl)
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EFFECT OF UDCA (20 MG/KG B.W./D) IN CFALD SERUM
ALBUMIN (MEAN VALUES)
Albumine in serum (g/dl)
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EFFECT OF UDCA (20 MG/KG B.W./D) IN CFALD PT
AND PTT (MEAN VALUES)
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EFFECT OF UDCA (20 MG/KG B.W./D) IN CFALD
PLATELETS (MEAN VALUES)
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EFFECT OF UDCA (20 MG/KG B.W./D) IN CFLD
ANTHROPOMETRIC PARAMETHERS(MEAN VALUES)
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EFFECT OF UDCA (20 MG/KG B.W./D) IN CFALD FEV1
AND FVC (MEAN VALUES)
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OCCURRENCE OF CLINICALLY RELEVANT EVENTS DURING
UDCA TREATMENT IN 36 CF PTS (MEDIAN DURATION 10
YRS)
No Pts
DeathLiver-related 2 0 5.6
Transplantation 2 lung 1 liver 5.6 2.8
Diabetes 13 36
Cirrhosis 7 19.4
Portal hypertension 8 22.2
Esophageal varices 7 19.4
GI Bleeding/hypersplenism 2 5.6
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OCCURRENCE OF LIVER-RELATED EVENTS SINCE START OF
UDCA TREATMENT
years
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Long-term UDCA treatment in CF-associated liver
disease Summary

• Absolute safety
• Stable improvement of indexes of cytolysis
• No deterioration in hepatic synthetic function
• Slow but progressive development of portal
  hypertension
• Deterioration of pulmonary function not different
  from predicted
• Occurrence of liver-relevant events

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RANDOMIZED CONTROLLED TRIALS OF UDCA TREATMENT IN
CYSTIC FIBROSIS
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RCT OF UDCA FOR CF-ASSOCIATED LIVER DISEASE
Colombo and The Italian UDCA study group

• Study designmulticenter, double-blind, placebo
  controlled trial, 1 yr duration
• Patients
• 55 CF patients with clinical and biochemical LD
  from 12 CF Centers39 males, median age 13.8 yrs
• Results Significant improvement in liver
  biochemistry in the UDCA group
• Shwachman score worsened only in the placebo
  groupNo side effects
• Conclusions
• UDCA improves clinical and biochemical
  parameters in CF patients with liver disease

Hepatology 1996
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UDCA FOR LIVER DISEASE ASSOCIATED WITH
CFLong-term follow-up

• Aim To establish the long-term effects of UDCA
  in the 55 CF patients with liver disease enrolled
  in the Italian Multicenter UDCA Trial carried out
  in 1990
• Design Collection of data on clinical
  progression of liver disease and CF over 15 yrs
• Comparison of clinical outcome with a subset of
  CF pts without liver disease included in the
  Italian CF Registry
• Patient matching
• date of birth, sex, CF center, followed when
  CFLD pts were enrolled (1990)

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ITALIAN UDCA STUDY GROUP
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RCT of UDCA for CF LIVER DISEASE Subsequent
follow-up
55 CF patients enrolled in 1990
Data available for 54 patients 39 males, 15
females
1 patient lost
4 not treated
50 on long-term UDCA
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UDCA FOR LIVER DISEASE ASSOCIATED WITH
CFLong-term follow-up

• Follow-up data 54 (39 males, 15
  females)
• Alive 39
• Deaths 15 (10 male, 5 female pts)
• 12 for pulmonary complications
• 1 for hepatic complications
  1 for renal complications 1 after
  multiorgan transplantation

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RCT of UDCA for CF LIVER DISEASEHepatic status
and liver related events
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CHARACTERISTICS OF CF PATIENTS
Plt0.001
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OVERALL MORTALITY
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SURVIVAL BY LIVER DISEASE
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SURVIVAL BY GENDER
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CONCLUSIONS

• Liver disease does not condition excess mortality
  at least in patients receiving UDCA as background
  treatment
• UDCA probably slows, but does not halt the
  progression of liver disease
• Effectiveness is better in patients with early
  stage liver disease, before symptoms have become
  evident
• Early diagnosis and identification of CF patients
  who are more liable to develop liver disease
  should be actively pursued