Polycystic liver disease

Transcription

1 Polycystic liver disease Dong Hyun Sinn M.D., Ph.D. Samsung Medical Center Department of Medicine, Seoul, Korea

2 Polycystic liver disease (PCLD) Innumerable (>20 cysts) hepatic cysts Types Isolated PCLD ADPKD (liver & kidney) Drenth et al., Orphanet J Rare Dis 2014

3 Natural course of PCLD Drenth et al., Orphanet J Rare Dis 2014 Hepatomegaly, pain, abdominal discomfort, anorexia, weight loss Cyst hemorrhage, infection, rupture Portal hypertension, ascites Liver failure

4 Factors associated with disease progression Women > Men Risk factors for worse prognosis Multiple pregnancies Who have used oral contraceptive drugs Who have used estrogen replacement therapy Temmerman et al., Aliment Pharmacol Ther 2011

5 Epithelium is sensitive to the proliferative effects of estrogens, FSH ER-a ER-ß FSH FSHR Onori et al., Dig Liver Dis 2010

6 Sherstha et al., Hepatology 1997

7 Review the standard management What is the standard management in PCLD? Is there standard management for PCLD?

8 Case 47/M Referred for second opinion Abdominal distension Palpable liver Family history of adult-onset polycystic kidney disease (ADPKD)

9 Laboratory evaluation CBC: k PT: 1.14 INR Albumin: 4.4 g/dl Total bilirubin: 1.4 mg/dl AST/ALT: 12/13 U/L ALP: 85 U/L BUN/Cr: 16.8/1.04 mg/dl GGT: 162 U/L HBsAg: - HBsAb: + HBcIgG: - Anti-HCV: - HAV IgG: +

10 Imaging study

11 What is your management plan for him? 1. Aspiration/Sclerotherapy 2. Fenestration (laparoscopic or open) 3. Resection 4. Liver transplantation 5. Transarterial embolization 6. Somatostatin analogues 7. mtor inhibitors 8. Observation 9. Others

12 Treatment should be guided by the presence of symptoms. Treatment should be focused on decompressing the liver or reducing the cyst volume as much and as safely as possible. Am J Gastroenterol 2014

13 Temmerman et al., Aliment Pharmacol Ther 2011

14 Cnossen et al., Orphanet J Rare Dis 2014

15 Hepatology Res 2015

16 Symptom-driven management There is no effective treatment option, yet, for asymptomatic patients. Currently available treatment options are not free of cost, significant morbidity and mortality may occur. Symptoms should be severe enough to justify treatmentrelated morbidity or mortality that may occur.

17 Management options What are management options available? What are the risks of the each management option? "Practice two things in your dealings with disease: either help or do not harm the patient" Epidemics, Book I, of the Hippocratic school,

18 Current available options Aspiration and/or sclerotherapy Fenestration Resection Transarterial embolization Liver transplantation Somatostatin analogues mtor inhibitors Others

19 Aspiration Recurrence All patients (13/13 patients) within 2 years Drenth et al., Hepatology 2010; Saini et al., AJR 1983

20 Aspiration and sclerotherapy Sclerosing agent causes destruction of the epithelial lining inhibiting fluid production. Used agents: ethanol, minocycline, tetracycline Drenth et al., Hepatology 2010

21 Aspiration and sclerotherapy Name N o patients Sclerosing agent N o sessions Total regression Partial regression Recurrence Goldstein 1 1 Pantopaque NS Bean 3 6 alcohol Trinkl 4 1 alcohol NS NS NS NS Andersson 5 9 alcohol NS NS Kairaluoma 6 8 alcohol Furuta 7 6 alcohol Hagiwara 8 1 minocycline Morita 9 1 minocycline Simonetti alcohol 1 28 NS 0 Garber 11 1 alcohol 1 NS NS 0 McCullough 12 3 alcohol van Sonnenberg alcohol NS 2 Tanis 14 4 alcohol NS 3 NS 1 Yamada 15 9 minocycline NS 9 0 NS Montorsi alcohol NS Davies 17 1 tetracycline NS Tikkakoski alcohol Larssen alcohol 1 NS NS NS Cellier 20 7 minocycline 1 4 NS NS Lopes 21 7 tetracycline NS Larssen alcohol NS Okano 23 8 alcohol NS Raboei 24 1 alcohol McFarlane 25 2 tetracycline NS NS NS NS Ferris 26 1 alcohol NS Larssen 27 7 alcohol 1 NS NS NS Yoshida 28 9 minocycline 7-8 NS NS NS Blonski 29 1 alcohol NS Erdogan alcohol NS NS NS 13 van Keimpema alcohol NS NS Nakaoka alcohol Fabrizzi 33 1 tetracycline Total 292 (100%) 168 (22%) 24 (19%) 36 (21%) Drenth et al., Hepatology 2010

22 Limitations of aspiration/sclerotherapy Dominant cyst should exists. Procedure-related complications. Recurrence of symptoms due to regrowth or growth of non-treated cysts. Drenth et al., Hepatology 2010

23 Fenestration Drenth et al., Hepatology 2010; Jung DH et al., Korean J Hepatobiliary Pancreat Surg 2015

24 Fenestration Name N o patients Symptom relief Symptom recurrence Cyst recurrence Morbidity Mortality Lin Lin NS Paliard 36 1 NS NS NS 1 0 van Erpecum NS Eggink NS Turnage 39 7 NS NS NS NS 3 Bensa NS NS Morino Tate 42 1 NS NS NS 1 0 Iwase NS Farges Gigot NS 0 Zacherl 46 7 NS NS Kabbej NS Gigot NS Koperna Diez Marks Martin NS NS NS NS 0 De Simone Kakizaki Katkhouda Payatakes NS Gigot Hansman Tocchi NS NS NS 1 0 Ammori 60 1 NS NS Tan Kwon NS Fiamingo 63 6 NS Konstadoulakis Robinson NS 6 NS 2 0 Kornprat 66 8 NS 0 NS 1 0 Hsu Neri NS 3 0 Szabo Garcea 70 6 NS Palanivelu 71 4 NS NS Bai NS van Keimpema NS Liska NS NS 1 NS 0 Capizzi 75 1 NS NS NS 0 0 Total 337 (100%) 156 (92%) 37 (22%) 60 (24%) 62 (23%) 6 (2%) Drenth et al., Hepatology 2010

25 Fenestration Limitations Patients with previous abdominal surgical procedures Deep-seated cysts, segments VII-VIII etc. Complications Ascites, pleural effusion Arterial or venous bleeding Bile leakage Irreversible shock Hepatic abscesses Acute renal failure Drenth et al., Hepatology 2010

26 Resection Can be considered in patients with liver segment with predominantly normal liver parenchyma. Drenth et al., Hepatology 2010

27 Resection Name N o patients Symptom relief Morbidity Mortality Cyst recurrence Reoperation Follow-up (mo) Lanson Armitage Turnage Iwatsuki Eggink Newman Sanchez NS Vauthey Henne-Bruns Madariaga NS Que Soravia Koperna Vons Martin Johnson Szyber Hansman Ammori Petri Andoh Yang Kornprat Li Gamblin Schnelldorfer Total 337 (100%) 290 (86%) 171 (51%) 11 (3%) 115 (34%) 15 (4%) Drenth et al., Hepatology 2010

28 Concern for hepatic resection Carries the risk of hepatic insufficiency if an inadequate hepatic remnant is left. No validated tool that can be used to avoid post-hepatectomy liver failure in PCLD

29 Concern for hepatic resection The normal anatomy of polycystic livers is extremely distorted, as the liver is not only larger, but it is rigid with limited mobility and there is difficult access to vascular supply. Resection and surgical treatment can cause adhesions that may complicate possible future procedures such as liver transplantation.

30 J Am Coll Surg 2014;219:695

31 J Am Coll Surg 2014;219:695

32 Transcatheter arterial embolization (TAE) Park HC et al., JKMS 2009

33 TAE 94.7% 90.8% Hoshino et al., Am J Kidney Dis 2014

34 Hepatology Res 2015

35 Outcomes Hepatology Res 2015

36 Limitations of these approaches Aspiration/sclerotherapy Laparoscopic or laparotomic fenestration Partial liver resection Transarterial chemoeombolization DO NOT CHANGE the natural course of the disease Growth of new cysts or re-growth of treated cysts

37 Liver transplantation Definite treatment option 5-year survival rate = 92.3% (European Liver Transplant Registry study) Keimpema et al., Transplant Int 2011

38 UNOS data for PCLD Duration: ,411 LT performed in the US 357 (0.3%) were for adult PCLD 77% vs 71% Gedaly et al., HPB 2013

39 Limitations of liver transplantation Living donor: limited by genetic inherited disorders DDLT LDLT Deceased donor: Patients with PLD generally have preserved liver function and normal Model for End-Stage Liver Disease (MELD) scores if they do not have renal involvement

40 Current available medical options Aspiration and/or sclerotherapy Fenestration Resection Transarterial embolization Liver transplantation Somatostatin analogues mtor inhibitors

41 Somatostatin Analogs Everson, Gastroenterology 2013

42 Octreotide RCT Inclusion criteria Men or women aged 18 years and older Diagnosis of ADPKD or ADPLD Liver volume >4000 ml or symptomatic disease Not candidates or declining surgical intervention Regimen Octerotide-LAR 40mg IM every 28 days (n = 28) Placebo (n = 14) Primary end point Change in liver volume by MRI Exclusion Serum Cr > 3 mg/dl or dialysis Symptomatic gallstone Uncontrolled hypertension, diabetes Cnacer, major systemic disease Hogan et al., J Am Soc Nephrol 2010

43 Octreotide RCT Hogan et al., J Am Soc Nephrol 2010

44 Octreotide RCT Hogan et al., J Am Soc Nephrol 2010

45 Extension of octreotide RCT Hogan et al., Nephrol Dial Transplant 2012

46 Extension of octreotide RCT Hogan et al., Nephrol Dial Transplant 2012

47 Lanreotide RCT (LOCKCYST) Inclusion criteria Men or women aged 18 years and older More than 20 liver cyst by CT Regimen Lanreotide 120mg SC every 28 days for 24 weeks (n = 27) Placebo (n = 27) Exclusion Use of oral contraceptives or estrogen supplementation Primary end point Change in liver volume by CT Pregnant or breast-feeding Symptomatic gallstones Hemodialysis History of other severe illnesss Keimpema et al., Gastroenterology 2009

48 Lanreotide RCT (LOCKCYST) Keimpema et al., Gastroenterology 2009

49 Lanreotide RCT (LOCKCYST) Keimpema et al., Gastroenterology 2009

50 Extension trial Chrispijn et al., Aliment Pharmacol Ther 2012

51 Rebound increase in liver volume after discontinuation Chrispijn et al., Aliment Pharmacol Ther 2012

52 A pooled analysis of individual patient data Gevers et al., Gastroenterology 2013

53 A pooled analysis of individual patient data Gevers et al., Gastroenterology 2013

54 A pooled analysis of individual patient data Gevers et al., Gastroenterology 2013

55 Somatostain analogues Can be used to halt growth or decrease cyst volume. More effective in young women. Extended use is not associated with further reduction in cyst volume, and re-growth of cyst after discontinuation is a concern. Cost is also a concern (2,000 $ per vial in Korea)

56 mtor inhibitor Retrospective study ADPKD patients with PCLD Received renal transplant Sirolimus-containing or calcineurin inhibitor-based immunosuppression for > 6 months Qian et al., J Am Soc Nephrol 2010

57 Everolimus and long acting octerotide (ELATE trial) Chrispijn et al., Trials 2011;12:246

58 ELATE trial (RCT) Chrispijn et al., J hepatol 2013

59 ELATE trial Chrispijn et al., J hepatol 2013

60 mtor inhibitor May decrease liver cyst volume. Has not been shown to further decrease liver cyst volume when added to somatostatin analogues. Also has side effects

61 The data defining the optimal management choice are limited to small-scale clinical series or case reports. Treatment should be guided by the principle of selecting the least invasive procedure that provides the most effective treatment response and improvement in the quality of life. Am J Gastroenterol 2014

62 Am J Gastroenterol 2014

63 Back to the case

64 After discussion with the patients First, he said he was symptomatic. After discussion of potential management options and their potential risk, he said he is OK, and his symptoms are tolerable.

65 Health-related quality of life in PCLD patients Wijnands eet al., Liver Int 2014

66 Limitations of symptom-driven management A symptom is a departure from normal function or feeling which is noticed by a patient, reflecting the presence of an unusual state, or of a disease. Symptom is subjective, observed by the patient. However, therapeutic decision is also guided by the severity of patient subjective symptom in PCLD management.

67 Temmerman et al., J Hepatology 2014

68 Temmerman et al., J Hepatology 2014

69 POLCA algorithm? Allows tracking the PCLD-related symptoms over time Facilitate the evaluation of treatments effects over time However, whether it can really guide treatment decision need further data Temmerman et al., J Hepatology 2014

70 UDCA? Munoz-Garrido et al., J Hepatology 2015

71 J Hepatology 2016

72 The last question of the patient He has one daughter (17 years) and son (15 years), and was more worried about his children. He asked whether there is any new treatment that can halt cyst progression before cyst become symptomatic (for his children ), as current standard management options for symptomatic PCLD are not good enough.