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Liver Disease in ADPKD

The information contained in this presentation is the property of the PKD Foundation and to be used for

individual informational purposes only. No part of this presentation is to be reused, reprinted, or broadcast (via

any media including the internet) without the written permission of the PKD Foundation.

Liver Disease in ADPKD

Marie Hogan MD PhD Division of Nephrology & Hypertension

Mayo Clinic College of Medicine

Saturday, June 23rd

Blank TemplateBlank Template page

Outline• Historical• Natural History• How do you get liver cysts• Symptoms• Medical management• Surgical management• New treatments

Blank TemplateBlank Template pageDisease Gene Chromosome Protein FunctionADPKD PKD1 16p13.3 Polycystin 1 Membrane

receptorPKD2 4q21-23 Polycystin 2 Calcium

channel

ADPLD PLD1 19 p13.2 Glucosidase II ER proteinprocessing

PLD2 6 SEC63 ER proteinprocessing

Polycystic Liver Disease

Blank TemplateBlank Template page• Use this template for slides with photos, graphics, etc.• Copy should be in 28 point Times New Roman.• Please use black type.• Select “Duplicate Slides” to create a new one – don’t

insert new slide or you’ll lose the formatting

32 Point Times New Roman Header in Bold Cystogenesis in ADPKD/ADPLD

NormalNormal

CP1047707-3

PLDPLD

Intralobular ductuleIntralobular ductuleIntralobular ductule

Interlobular ductInterlobular ductInterlobular duct

Area ductArea ductArea duct

Segment ductSegment ductSegment duct

Right hepatic ductRight hepatic ductRight hepatic duct

Common hepatic ductCommon hepatic ductCommon hepatic duct

Common bile ductCommon bile ductCommon bile duct


Wall WJ. NEJM 2007

51yo(59kg) With ADPKD With A 9.1-kg Liver Underwent Liver Transplant


Prevalence of Liver Cysts in ADPKD

100

80

60

40

20

020 40 60 80 >80

Age (yr)Age (yr)

General PopulationGeneral Population

%%

<20 20-29 30-39 40-49 50-59 >60

Age (yr)Age (yr)

ADPKDADPKDScintiscanning (n=158)Ultrasonography (n=483)Computed tomography (n=83)

Scintiscanning (n=158)Ultrasonography (n=483)Computed tomography (n=83)

100

80

60

40

20

0


Clin. J. Am. Soc. Nephrol., Jan 2006;1:64-69.

• Prevalence of liver cysts in early ADPKD• Is liver cyst volume related to kidney cyst and kidney volume?• Compared liver and kidney cyst volumes (compared with age, gender)

• Quantitative MRI scans: 3mm slices


Coronal T2-weighted MRI from four different patients with variable severity of hepatic and renal cysts

Bae, K. T. et al. Clin J Am Soc Nephrol 2006;1:64-69

24yo man liver cysts 6.3ml renal cysts (15.4 ml).

46yo man mild hepatic cyst 9.3 ml severe renal cysts 1940 ml.

44yo man hepatic cysts(318.7 ml) but mild renal cyst burden (37.6 ml).

30yo woman hepatic cysts (2368.8 ml) and renal cysts (1084.5 ml).


Bae, K. T. et al. Clin J Am Soc Nephrol 2006;1:64-69

Relationship Between Liver Cyst Volume And Age In Women And Men


Correlation Coefficients Between Liver Cyst Volume And Kidney Cyst Volumes


Symptomatic Polycystic Liver Disease (1)

Mass Effect (by dominant cyst or massive PLD)

• Abdominal distension/pain• Early satiety, heartburn, emesis • Malnutrition, loss of muscle/fat• Dyspnea, orthopnea• Change in bowel pattern, hemorrhoids• Back pain• Hernias, uterine prolapse, rib fractures• Venous obstruction (hepatic, IVC, porta)• Bile duct obstruction


Symptomatic Polycystic Liver Disease

Complications– Hemorrhage– Rupture– InfectionRare Associations– Bile duct dilatation– Congenital hepatic fibrosis– Cholangiocarcinoma


Liver Cyst Infection• Risk Factors

– Recent abdominal surgery– Kidney Transplant– Chronic dialysis

• Symptoms– Fever + new onset RUQ pain– Leukocytosis ↑ESR– ↑ ALP– Bacteremia– Cultures of undrained cyst fluid +ve


CT- Anatomic resolution– Gas bubbles in cysts– Changes in cyst walls; nodularity,

thickening, indistinct margins, contour enhancement of the cyst wall,

– calcification – dominant cyst showing enlargement on

serial examMRI- most sensitive111InPET Scan:

Liver Cyst Infection 1/07

4/07

C. Bleeker-Rovers. 41 (6).2003. AJKD.


Symptomatic Polycystic Liver DiseaseNonsurgical Treatment Options

• Avoid estrogens, caffeine

• H2-blocker or H+/K+ ATPase inhibitor

• Long-acting octreotide (?)


Symptomatic Polycystic Liver DiseaseSurgical Treatment Options

• Percutaneous aspiration/sclerosis

• Fenestration (laparoscopic or open)

• Hepatic resection/fenestration

• Liver transplantation


Symptomatic Polycystic Liver Disease


Autosomal Dominant Polycystic Liver Disease: Alcohol Sclerosis of Liver Cysts

Success ratePrimary: 69%Secondary: 23%Failure: 8%

Complications: Major: NoneMinor: Transient pain


Autosomal Dominant Polycystic Liver Disease Laparoscopic Fenestration For Polycystic Liver

INTRAOPERATIVE COMPLICATIONSHypothermiaHypercapnia

POSTOPERATIVE COMPLICATIONSTransient ascites (46%)

SYMPTOMATIC RELIEF85%

RECURRENCE of SYMPTOMS73%Useful for few large cysts

Kabbej Brit J Surgery 83:1697, 1996


Massive Polycystic Liver Disease

• Focal (preserved liver segments in >80% of patients) • Parenchymal volume constantNagorneyNagorney et al: KI 33:202, 1988et al: KI 33:202, 1988Everson et al: Hepatology 8:1627, 1988Everson et al: Hepatology 8:1627, 1988


SegmentsSegments

Resection-Fenestration for Polycystic Liver DiseaseDistribution of Segmental Resection

Resection-Fenestration for Polycystic Liver DiseaseDistribution of Segmental Resection

%%

0

20

40

60

80

100

1 2 3 4 5 6 7 8

SegmentsSegments

1

2

3

456

7

8


Massive Polycystic Liver DiseaseCombined Resection-FenestrationMassive Polycystic Liver DiseaseCombined Resection-Fenestration

Que et al: Gastroenterology 108:487, 1995Que et al: Gastroenterology 108:487, 1995

•• Liver volumeLiver volumePreop: 9,357 mLPreop: 9,357 mLPostop: 3,567 mLPostop: 3,567 mL

%%•• MortalityMortality 33•• ComplicationsComplications 6060

Transient pleural effusionTransient pleural effusion 3737Transient Transient ascitesascites 2323HemorrhageHemorrhage 1313InfectionInfection 77Transient biliary leakTransient biliary leak 77

•• Sustained reliefSustained relief 9090


Massive Polycystic Liver DiseaseCombined Resection-Fenestration

+10years-Pre-op +1 year +3years-3yrs-10yrs


Liver transplantation for Massive Polycystic Liver Disease


Model for End-Stage Liver Disease (MELD)

Numerical system that ranks (from 6 to 40) patients waiting for a liver based on three lab test results:

• Bilirubin (how effectively the liver excretes bile)• INR (prothrombin time, ability to clot blood)• Creatinine (kidney function)


Symptomatic Polycystic Liver DiseaseAlternative Treatment Options

•Hepatic artery embolization•Endovascular stent•Transjugular intrahepatic portosystemic shunt (TIPS)•La Veen shunt


POLYCYSTIC LIVER DISEASESTENTING for INFERIOR VENA CAVA OBSTRUCTION


Ubara. AJKD 43: 733, 2004

Severe Polycystic Liver DiseaseHepatic artery embolization


Post (2 years)

Pre

Severe Polycystic Liver DiseaseHepatic artery embolization

Ubara. AJKD 43: 733, 2004


Aspiration and alcohol sclerosis Laparoscopic fenestration Hepatic artery Embolozation

Before right lobectomy & Cyst Fenestration

After right lobectomy & Cyst Fenestration

Liver Transplant


Hepatic Venous Outflow Tract Obstruction



• Avoid estrogens, caffeine• H2-blocker or H+/K+ ATPase inhibitor• Long-acting octreotide (?)


Ruggenenti, Kidney Int, 68:206, 2005

Long-acting Octreotide TrialsRandomized, placebo-controlled, cross-over design, n=12

Ongoing phase III, placebo-controlled clinical trial, n=66


cAMP in Isolated Bile Duct Units

Masyuk TV. Gastroenterology. 2007.Masyuk TV. Gastroenterology. 2007.


cAM

P (p

mol

per

μg

DN

A)

Normal

Day

1D

ay3

Day

5

PCK

Masyuk TV. Gastroenterology 2007.Masyuk TV. Gastroenterology 2007.

OCTREOTIDE In PCK RATS

0

5

10

15

20

25

*

*

*

B OCT B OCT B OCT B OCT

"-" FSK "+" FSK

Normal PCK

"-" FSK "+" FSK

*


Twice a day, daily, at 12 hours interval, intra-peritoneally

Duration of treatment

H

4 wks

Group I

4 wks

Group IV

16 wks

Group III

12 wks

Group II

8 wks

PCK rats, n = 12Age - 3 weeks

PCK rats, n = 48Age - 3 weeks

10 mg/kg b.w 100 mg/kg b.w



Octreotide In PCK Rats: cAMP Levels




Octreotide In PCK Rats: Cyst Volumes


4 weeks 8 weeks 12 weeks 16 weeks 4 weeks10 mg 100 mg

Saline Control

Octreotide Treated



Saline Control

Octreotide Treated


4 weeks 8 weeks 12 weeks 16 weeks 4 weeks

10 μg 100 μg


Octreotide in PCK Rats: Fibrosis


Blank TemplateBlank Template pagePilot Study of Long-Acting Octreotide (Octreotide LAR®Depot) in the Treatment of Patients with Severe Polycystic

Liver Disease

Blank TemplateBlank Template pageProspective, double blind, placebo controlled (2:1), 42 patients

Octreotide LAR 40 mg IM every 4 weeks

Primary endpoint: % change in liver volume at 12 months (MRI)

Secondary endpoints: % change in kidney and liver/renal cyst volumes

Patient Characteristics• Age ≥ 18 years• PLD associated with ADPKD or isolated ADPLD• Liver volume >4000 mL or symptomatic due to mass effects• Not a candidate for or declining surgical intervention• Serum creatinine <3 mg/dL• No exclusion criteria (pregnancy, major illness, uncontrolled DM)

LONG-ACTING OCTREOTIDE TRIAL(Mayo Clinic)


Ca2+

Ca2+

PDE

Ca2+

ErbB

Reduced in PKD

Increased in PKDCl–

CFTR

PKA

Ca2+

PC1

PC2

ER

GqR

IP3

PLCγ

PC2

SrcRas

B-Raf

MEK

TSC2/TSC1

Rheb

mTOR

PC1CAML?

FC

Ca2+

OCSOCOCSOC

Nucleus

ERK

CP1247144-1

CyclinD

GiR V2R

AC-VI

ATP

Octreotide Vasopressin

cAMP

Gs

Proteintranslation

Blank TemplateBlank Template page• Avoid estrogens, caffeine

• H2-blocker or H+/K+ ATPase inhibitor

• Long-acting octreotide (?)

• mTor inhibitors (?)


Blank TemplateBlank Template page• Vicente Torres MD PhD• Peter Harris PhD• Chris Ward MD PhD• Tatyana and Anatoly Masyuk, Nick LaRusso MD. • Octreotide Study:

– Study Coordinator: [email protected]– Novartis– Mayo Foundation

Acknowledgments:

liver disease in adpkd - pkdiet · blank templateblank template page prospective, double blind,...

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