Liver Disease in ADPKD

Transcription

1 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.

2 Liver Disease in ADPKD Saturday, June 23rd Marie Hogan MD PhD Division of Nephrology & Hypertension Mayo Clinic College of Medicine

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

4 Polycystic Liver Disease Disease Gene Chromosome Protein Function ADPKD Blank PKD1 Template 16p13.3 Polycystin 1 Membrane receptor PKD2 4q21-23 Polycystin 2 Calcium channel ADPLD PLD1 19 p13.2 Glucosidase II ER protein processing PLD2 6 SEC63 ER protein processing

5 Cystogenesis in ADPKD/ADPLD 32 Point Times New Roman Header in Bold Normal PLD Blank Use this Template template for slides with photos, graphics, etc. Intralobular ductule Copy should be in 28 point Times New Roman. Interlobular duct Please use black type. Select Duplicate Slides to create a new Area duct one don t Segment duct insert new slide or you ll lose the formatting Right hepatic duct Common hepatic duct Common bile duct CP

6 51yo(59kg) With ADPKD With A 9.1-kg Liver Underwent Liver Transplant Wall WJ. NEJM 2007

7 Prevalence of Liver Cysts in ADPKD General Population ADPKD Scintiscanning (n=158) Ultrasonography (n=483) Computed tomography (n=83) % >80 Age (yr) 0 < >60 Age (yr)

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

9 Coronal T2-weighted MRI from four different patients with variable severity of hepatic and renal cysts 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 ( ml) and renal cysts ( ml). Bae, K. T. et al. Clin J Am Soc Nephrol 2006;1:64-69

10 Relationship Between Liver Cyst Volume And Age In Women And Men Bae, K. T. et al. Clin J Am Soc Nephrol 2006;1:64-69

11 Correlation Coefficients Between Liver Cyst Volume And Kidney Cyst Volumes

12 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

13 Symptomatic Polycystic Liver Disease Complications page Hemorrhage Rupture Infection Rare Associations Bile duct dilatation Congenital hepatic fibrosis Cholangiocarcinoma

14 Risk Factors Recent abdominal surgery Kidney Transplant Chronic dialysis Symptoms Liver Cyst Infection Fever + new onset RUQ pain Leukocytosis ESR ALP Bacteremia Cultures of undrained cyst fluid +ve

15 Liver Cyst Infection 1/07 CT- Anatomic resolution Gas bubbles in cysts Blank Changes Template in cyst walls; nodularity, thickening, indistinct margins, contour enhancement of the cyst wall, calcification dominant cyst showing enlargement on serial exam MRI- most sensitive 111 In PET Scan: 4/07 C. Bleeker-Rovers. 41 (6) AJKD.

16 Symptomatic Polycystic Liver Disease Nonsurgical Treatment Options Avoid estrogens, caffeine H 2 -blocker or H + /K + ATPase inhibitor Long-acting octreotide (?)

17 Symptomatic Polycystic Liver Disease Surgical Treatment Options Percutaneous aspiration/sclerosis Fenestration (laparoscopic or open) Hepatic resection/fenestration Liver transplantation

18 Symptomatic Polycystic Liver Disease

19 Autosomal Dominant Polycystic Liver Disease: Alcohol Sclerosis of Liver Cysts Success rate Primary: 69% Secondary: 23% Failure: 8% Complications: Major: None Minor: Transient pain

20 Autosomal Dominant Polycystic Liver Disease Laparoscopic Fenestration For Polycystic Liver INTRAOPERATIVE COMPLICATIONS Hypothermia Hypercapnia POSTOPERATIVE COMPLICATIONS Transient ascites (46%) SYMPTOMATIC RELIEF 85% RECURRENCE of SYMPTOMS 73% Useful for few large cysts Kabbej Brit J Surgery 83:1697, 1996

21 Massive Polycystic Liver Disease Focal (preserved liver segments in >80% of patients) Parenchymal volume constant Nagorney et al: KI 33:202, 1988 Everson et al: Hepatology 8:1627, 1988

22 Resection-Fenestration for Polycystic Liver Disease Distribution of Segmental Resection % Segments

23 Massive Polycystic Liver Disease Combined Resection-Fenestration Que et al: Gastroenterology 108:487, 1995 Liver volume Preop: 9,357 ml Postop: 3,567 ml % Mortality 3 Complications 60 Transient pleural effusion 37 Transient ascites 23 Hemorrhage 13 Infection 7 Transient biliary leak 7 Sustained relief 90

24 Massive Polycystic Liver Disease Combined Resection-Fenestration

25 -10yrs -3yrs -Pre-op +1 year +3years +10years

26 Liver transplantation for Massive Polycystic Liver Disease

27 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)

28 Symptomatic Polycystic Liver Disease Alternative Treatment Options Hepatic Blank artery Template embolization Endovascular stent Transjugular intrahepatic portosystemic shunt (TIPS) La Veen shunt

29 POLYCYSTIC LIVER DISEASE STENTING for INFERIOR VENA CAVA OBSTRUCTION

30 Severe Polycystic Liver Disease Hepatic artery embolization Ubara. AJKD 43: 733, 2004

31 Severe Polycystic Liver Disease Hepatic artery embolization Pre Post (2 years) Ubara. AJKD 43: 733, 2004

32 Aspiration and alcohol sclerosis Laparoscopic fenestration Hepatic artery Embolozation Before right lobectomy & Cyst Fenestration After right lobectomy & Cyst Fenestration Liver Transplant

33 Hepatic Venous Outflow Tract Obstruction

34 Symptomatic Polycystic Liver Disease Nonsurgical Treatment Options Avoid estrogens, caffeine H2-blocker or H+/K+ ATPase inhibitor Long-acting octreotide (?)

35

36 Long-acting Octreotide Trials Randomized, placebo-controlled, cross-over design, n=12 Ongoing phase III, placebo-controlled clinical trial, n=66 Ruggenenti, Kidney Int, 68:206, 2005

37 camp in Isolated Bile Duct Units Masyuk TV. Gastroenterology

38 Normal PCK OCTREOTIDE In PCK RATS Day 1 Day 3 Day 5 camp (pmol per μg DNA) Normal PCK * * * B OCT B OCT B OCT B OCT "-" FSK "+" FSK "-" FSK "+" FSK * Masyuk TV. Gastroenterology 2007.

39 10 mg/kg b.w 100 mg/kg b.w PCK rats, n = 48 Age - 3 weeks PCK rats, n = 12 Age - 3 weeks Group I Group II Group III Group IV H Duration of treatment 4 wks 8 wks 12 wks 16 wks 4 wks Twice a day, daily, at 12 hours interval, intra-peritoneally Masyuk TV. Gastroenterology

40 Octreotide In PCK Rats: camp Levels Masyuk TV. Gastroenterology

41 Octreotide In PCK Rats: Cyst Volumes Masyuk TV. Gastroenterology

42 Saline Control Octreotide Treated 4 weeks 8 weeks 12 weeks 16 weeks 4 weeks 10 mg 100 mg Masyuk TV. Gastroenterology

43 Saline Control Octreotide Treated 4 weeks 8 weeks 12 weeks 16 weeks 4 weeks 10 μg Masyuk TV. Gastroenterology μg

44 Octreotide in PCK Rats: Fibrosis Masyuk TV. Gastroenterology

45 Pilot Study of Long-Acting Octreotide (Octreotide LAR Depot) in the Treatment of Patients with Severe Polycystic Liver Disease

46 LONG-ACTING OCTREOTIDE TRIAL (Mayo Clinic) Prospective, 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)

47 ErbB Ras B-Raf MEK ERK Src PKA Cl CFTR PDE Ca 2+ FC CAML? PC1 PC2 Ca 2+ PC2 Ca 2+ Reduced in PKD Increased in PKD PC1 ER Ca 2+ Ca 2+ IP 3 SOC TSC2/TSC1 Rheb mtor CyclinD Nucleus Protein translation R camp ATP AC-VI Gi Gs V2R PLCγ G q R Octreotide Vasopressin CP

48 Symptomatic Polycystic Liver Disease Nonsurgical Treatment Options Blank Avoid Template estrogens, caffeine H 2 -blocker or H + /K + ATPase inhibitor Long-acting octreotide (?) mtor inhibitors (?)

49 Acknowledgments: Blank Vicente Template Torres MD PhD Peter Harris PhD Chris Ward MD PhD Tatyana and Anatoly Masyuk, Nick LaRusso MD. Octreotide Study: Study Coordinator: Novartis Mayo Foundation