UF PediatricPediatricLiver CenterLiver CenterUF UF PediatricPediatricLiver CenterLiver Center What Is CF? “Anatomy & Physiology 101 of CFTR”Anatomy & Physiology 101 of CFTR”

UF Pediatric Liver CenterUF Pediatric Liver Center

Liver Disease in Cystic Fibrosis Liver Disease in Cystic Fibrosis OverviewOverview

BasicBasic

Clinical AspectsClinical Aspects

ManagementManagement

What Is Cystic FibrosisWhat Is Cystic Fibrosis

bull Autosomal recessive diseasebull W-13000 H-110000 AA-115000

bull Mutations of CFTRhellipdefective Cl- transport

bull CFTRbull Lung pancreas GI sweat bile ducts

What Is CFldquoAnatomy amp Physiology 101 of CFTRrdquo

NBD1NBD1

MSD1MSD1

cAMP-PKA-ATPcAMP-PKA-ATP

NBD2NBD2

MSD2MSD2

RATPATP ATPATP

Secretin

uarrcAMP

Phosphorylation

Channel OPENS

SecretinSecretin

uarruarrcAMPcAMP

Phosphorylation Phosphorylation

Channel Channel OPENSOPENS

What is CFldquoAnatomy amp Physiology 101 of CFrdquo

NBD2NBD2NBD1NBD1

MSD1MSD1 Secretin

uarrcAMP

Phosphorylation

Channel OPENS

SecretinSecretin

uarruarrcAMPcAMP

bull Impaired CFTR RNA synthesisbull Defective folding and maturation

bull ∆F508bull Abnormal regulation of Cl- conductionbull Inhibition of Cl- conductionbull Reduced synthesis of normal protein

What is CFldquoAnatomy amp Physiology 101 of CFTRrdquo

NBD1NBD1

MSD1MSD1

darr FlowhellipuarrViscosity

Focal obstruction

uarrldquoBADrdquo bile acids

Liver cell injury

Stellate cells

Fibrosisdarr Secretion of Mucin

darrdarr FlowFlowhelliphellipuarruarrViscosityViscosity

Focal obstructionFocal obstruction

uarruarrldquoldquoBADBADrdquordquo bile acidsbile acids

Liver cell injuryLiver cell injury

Stellate cellsStellate cells

FibrosisFibrosisdarrdarr Secretion of MucinSecretion of Mucin

Prevalence of Liver Disease in CFRetrospective

Country No studied uarr LFT Cirrhosis GB Sx HSMUS 19064 24 01-17

UK 1100 129 06 42

UK 233 25 25

France 450 30 7 08

Prevalence of Liver Disease in CFProspective

Country No studied uarr LFT HepatomegalyUS 99 38

US 526 46

Australia 153 9 30

Italy 189 17 30

What Is the Clinical PresentationWhat Is the Clinical Presentation

bull Hepatomegaly bull Vertical spanbull Xiphoid

bull Portal HTNbull Cirrhosisbull Stigmata

bull Abnormal ldquoLFTrsquosrdquobull Jaundice late

bull Obstructionbull Reduced synthetic fxn

bull Neonatal cholestasisbull Fatty liverbull Gallbladder

CFTR Pancreatic Gender Meconium Mec ileusGenotype Function (MF) Ileus Equivalent

Can liver disease be ldquopredictedrdquoCan liver disease be ldquopredictedrdquo

Lung diseaseWeightHeight

Wilschanski 1999 n=288 (liver dz 80)

What Is the Natural HistoryWhat Is the Natural HistoryItalian-prospective Follow-upTotal studied 177 143 yr

Liver Disease 48

Cirrhosis 17 85 yrsPortal HTN 13Esophageal varices 4Liver Transplant 1

Colombo et al Hepatology 2002Colombo et al Hepatology 2002

What is Natural HistoryWhat is Natural HistoryNormal Ultrasound

(n=106)Normal Ultrasound

(n=106)

Normal (n=87)Normal (n=87)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Hetero(n=15)Hetero(n=15)

Nodular (n=10)

443355

AgeGender

Meconium ileus-equivLung disease

WeightHeight

AgeGender

WeightHeight

Age 6 yoFU 10 yrs6 scanspt

Lenaerts et al J Peds 2003Lenaerts et al J Peds 2003

Evaluation of Liver Disease in CFEvaluation of Liver Disease in CF

bull Historybull Liver-related issues

bull Toxinsbull Medicationsbull Alcoholbull Herbs and supplements

bull Physical examhellipfocus on liver

bull Viral hepatitisbull HAV HBV HCV

bull Metabolicbull A1AT deficiencybull Wilsonrsquos Dzbull Hemochromatosis

bull Autoimmune

bull Drugsbull Hepatic congestion

bull Heart failurebull Anatomical disorders

bull Choledochal cystsbull Congenital hepatic

fibrosis

lsquoIDArsquo ScanlsquoIDArsquo Scan EndoscopyEndoscopy

ERCPERCP

Specialized TestingSpecialized TestingSpecialized Testing

Liver BxLiver Bx

Management of Liver Disease in CFManagement of Liver Disease in CF

bull Screeningbull Liver sizehellipedgebull Liver biochemistry

bull Medicalbull Fatty liver optimize nutritionbull Hepatic congestionbull Cholestasis-fibrosis-cirrhosis

Management of Liver Disease in CFManagement of Liver Disease in CFCholestasis-fibrosis-cirrhosis

bull Ursodeoxycholic acid

bull Mechanisms of actionbull Promotes HCO3-rich bile flowbull Displaces ldquotoxicrdquo bile acids

bull Significantly retards fibrosis in PBC

bull Colombo 1996bull 28 children

bull 138 yrsbull Liver disease

bull Hepatomegalybull uarr LFTrsquos

bull UDCA 15 mgkgd x 1y

GGT 5nuc AST ALTGGT 5nuc AST ALT

No direct evidence delay or reversal

of progressive fibrosis

UDCACirrhosis

112 to 32

No differencePortal HTNEsophageal varices

UDCACirrhosis

112 to 32

URSODEOXYCHOLIC ACIDURSODEOXYCHOLIC ACID

AUC C max T max

Urso250 Urso250 Ursolvan Actigall

AUC C max T max

ARE THEY ALL ALIKE

lsquoWilliamrsquos ReportrsquolsquoWilliamrsquos Reportrsquo

Management of Liver Disease in CFManagement of Liver Disease in CFPortal hypertensionPortal hypertension

bull Varicesbull Endoscopicbull Beta-blockers

bull Ascitesbull Salt restrictionbull Diuretics

SurgicalPorto-systemic shunt

Liver replacement

Management of Liver Disease in CFManagement of Liver Disease in CFLiver TransplantationLiver Transplantation

Pts Survival1 yr 5 yrs

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

Experimental Therapy for CF∆F508

4-phenyl butyrate44--phenyl butyratephenyl butyrate

Enhanced expression and Cl- secretionRestoration of Cl- transport

Enhanced expression and ClEnhanced expression and Cl-- secretionsecretionRestoration of ClRestoration of Cl-- transporttransport

Liver Disease in Cystic Fibrosis Liver Disease in Cystic Fibrosis ConclusionsConclusions

ImportantImportant

Medical TherapyMedical Therapy

FutureFuture

The Liver in Cystic Fibrosis The Liver in Cystic Fibrosis

Regino P Gonzaacutelez-Peralta MDRegino P Gonzaacutelez-Peralta MD

Pediatric Hepatology and Liver TransplantationUniversity of Florida College of Medicine

Gainesville Florida

AcknowledgementsAcknowledgements

UF-Pediatric PulmonaryUF-Pediatric Pulmonary

Axcan-Scandipharm Pharmaceuticals

Liver Disease in Cystic Fibrosis

What Is Cystic Fibrosis

What Is the Clinical Presentation

Can liver disease be ldquopredictedrdquo

What Is the Natural History

What is Natural History

Evaluation of Liver Disease in CF

Management of Liver Disease in CF

URSODEOXYCHOLIC ACID

Experimental Therapy for CFΔF508

The Liver in Cystic Fibrosis

Acknowledgements

What Is Cystic FibrosisWhat Is Cystic Fibrosis

NBD1NBD1

MSD1MSD1

NBD2NBD2

MSD2MSD2

RATPATP ATPATP

Secretin

uarrcAMP

Phosphorylation

Channel OPENS

SecretinSecretin

uarruarrcAMPcAMP

NBD2NBD2NBD1NBD1

MSD1MSD1 Secretin

uarrcAMP

Phosphorylation

Channel OPENS

SecretinSecretin

uarruarrcAMPcAMP

NBD1NBD1

MSD1MSD1

Focal obstruction

Liver cell injury

Stellate cells

UK 1100 129 06 42

UK 233 25 25

France 450 30 7 08

US 526 46

Australia 153 9 30

Italy 189 17 30

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

NBD1NBD1

MSD1MSD1

NBD2NBD2

MSD2MSD2

RATPATP ATPATP

Secretin

uarrcAMP

Phosphorylation

Channel OPENS

SecretinSecretin

uarruarrcAMPcAMP

NBD2NBD2NBD1NBD1

MSD1MSD1 Secretin

uarrcAMP

Phosphorylation

Channel OPENS

SecretinSecretin

uarruarrcAMPcAMP

NBD1NBD1

MSD1MSD1

Focal obstruction

Liver cell injury

Stellate cells

UK 1100 129 06 42

UK 233 25 25

France 450 30 7 08

US 526 46

Australia 153 9 30

Italy 189 17 30

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

NBD2NBD2NBD1NBD1

MSD1MSD1 Secretin

uarrcAMP

Phosphorylation

Channel OPENS

SecretinSecretin

uarruarrcAMPcAMP

NBD1NBD1

MSD1MSD1

Focal obstruction

Liver cell injury

Stellate cells

UK 1100 129 06 42

UK 233 25 25

France 450 30 7 08

US 526 46

Australia 153 9 30

Italy 189 17 30

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

NBD1NBD1

MSD1MSD1

Focal obstruction

Liver cell injury

Stellate cells

UK 1100 129 06 42

UK 233 25 25

France 450 30 7 08

US 526 46

Australia 153 9 30

Italy 189 17 30

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

NBD1NBD1

MSD1MSD1

Focal obstruction

Liver cell injury

Stellate cells

UK 1100 129 06 42

UK 233 25 25

France 450 30 7 08

US 526 46

Australia 153 9 30

Italy 189 17 30

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

UK 1100 129 06 42

UK 233 25 25

France 450 30 7 08

US 526 46

Australia 153 9 30

Italy 189 17 30

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

US 526 46

Australia 153 9 30

Italy 189 17 30

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

Liver Disease 48

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

(n=106)

Hetero(n=5)

Nodular (n=6)

PHT(n=8)PHT(n=8)

Nodular (n=10)

443355

AgeGender

WeightHeight

AgeGender

WeightHeight

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

bull Autoimmune

fibrosis

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

ERCPERCP

Liver BxLiver Bx

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

UDCACirrhosis

112 to 32

UDCACirrhosis

112 to 32

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

AUC C max T max

ARE THEY ALL ALIKE

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

Liver replacement

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

Favorable lung fxn

Mack 1995 8 75 62 55

Fridell 2003 12 92 75

UF Program 2005 8 100 68

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

ImportantImportant

FutureFuture

Gainesville Florida

Acknowledgements

Gainesville Florida

Acknowledgements

Documents

UF PediatricPediatricLiver CenterLiver CenterUF UF PediatricPediatricLiver CenterLiver Center What Is CF? “Anatomy & Physiology 101 of CFTR”Anatomy & Physiology 101 of CFTR”