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Dekker SEI, Bierau J, Giera M, Blomberg N, Drenth JPH, Mayboroda OA, de Fijter JW, Soonawala D. Serum bile acids associate with liver volume in polycystic liver disease and decrease upon treatment with lanreotide. Eur J Clin Invest 2024; 54:e14147. [PMID: 38071418 DOI: 10.1111/eci.14147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 03/13/2024]
Abstract
BACKGROUND Polycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a post-hoc exploratory analysis of bile acids in ADPKD patients, who had participated in a trial on the effect of a somatostatin analogue. Our hypothesis was that serum bile acid levels increase in PLD, and that lanreotide, which reduces liver growth, may also reduce bile acid levels. Furthermore, in PLD, urinary excretion of bile acids might contribute to renal disease. METHODS With liquid chromatography-mass spectrometry, 11 bile acids in serum and 6 in urine were quantified in 105 PLD ADPKD patients and 52 age-, sex-, mutation- and eGFR-matched non-PLD ADPKD patients. Sampling was done at baseline and after 120 weeks of either lanreotide or standard care. RESULTS Baseline serum levels of taurine- and glycine-conjugated bile acids were higher in patients with larger livers. In PLD patients, multiple bile acids decreased upon treatment with lanreotide but remained stable in untreated subjects. Changes over time did not correlate with changes in liver volume. Urine bile acid levels did not change and did not correlate with renal disease progression. CONCLUSION In ADPKD patients with PLD, baseline serum bile acids were associated with liver volume. Lanreotide reduced bile acid levels and has previously been shown to reduce liver volume. However, in this study, the decrease in bile acids was not associated with the change in liver volume.
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Affiliation(s)
- Shosha E I Dekker
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Jörgen Bierau
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Niek Blomberg
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Oleg A Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Johan W de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Darius Soonawala
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Internal Medicine, Haga Teaching Hospital, The Hague, the Netherlands
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Smith SR, Matar AJ, Polireddy K, Feltracco HA, Sarmiento JM. Operative Outcomes for Polycystic Liver Disease: Results of a Large Contemporary Series. J Gastrointest Surg 2023; 27:2444-2450. [PMID: 37783909 DOI: 10.1007/s11605-023-05843-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 09/13/2023] [Indexed: 10/04/2023]
Abstract
INTRODUCTION Persistent symptoms of pain, early satiety, dyspnea, and gastrointestinal reflux due to significant liver enlargement are indications for surgical debulking in patients with polycystic liver disease (PCLD) due to the lack of effective medical therapies; however, few data exist on outcomes of surgical intervention for PCLD. METHODS We conducted a retrospective analysis of consecutive patients who underwent operative intervention due to persistent symptoms secondary to PCLD. Preoperative patient characteristics, 30-day postoperative outcomes, and long-term postoperative outcomes, including complications and symptom resolution, were analyzed. RESULTS We identified 50 patients who underwent hepatic resection for symptomatic PCLD. Nine patients (19%) had concomitant polycystic kidney disease, and 14 (28%) had previously undergone interventions for PCLD management. The overall complication rate was 30%, with 8 patients (16%) experiencing Clavien-Dindo Grade III-V complications and no mortalities. The median relative reduction in liver volume was 41%. At a median follow-up of 2 years, 94% has sustained symptom resolution. CONCLUSIONS This is among the largest case series exploring PCLD operative outcomes, revealing that surgical intervention for debulking for advanced PCLD is safe and effective for symptom management. Furthermore, patients with PCLD undergoing hepatectomy tolerate significant liver volume loss without evidence of impaired hepatic function.
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Affiliation(s)
- Savannah R Smith
- Department of Surgery, Emory University, 1364 Clifton Road NE, Suite H-100, Atlanta, GA, 30322, USA
| | - Abraham J Matar
- Department of Surgery, Emory University, 1364 Clifton Road NE, Suite H-100, Atlanta, GA, 30322, USA
| | - Karunesh Polireddy
- Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA, 30322, USA
| | - Haley A Feltracco
- Department of Surgery, Emory University, 1364 Clifton Road NE, Suite H-100, Atlanta, GA, 30322, USA
| | - Juan M Sarmiento
- Department of Surgery, Emory University, 1364 Clifton Road NE, Suite H-100, Atlanta, GA, 30322, USA.
- Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Building A, Floor 4, Atlanta, GA, 30322, USA.
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Liver transplantation in a patient with massive polycystic liver disease: A case report and literature review. INTERNATIONAL JOURNAL OF SURGERY OPEN 2022. [DOI: 10.1016/j.ijso.2022.100517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Yoo JJ, Jo HI, Jung EA, Lee JS, Kim SG, Kim YS, Kim BK. Evidence of nonsurgical treatment for polycystic liver disease. Ther Adv Chronic Dis 2022; 13:20406223221112563. [PMID: 35898920 PMCID: PMC9310217 DOI: 10.1177/20406223221112563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Polycystic liver disease (PCLD) is the most common extrarenal manifestation of polycystic kidney disease. There is an urgent need to assess the efficacy and safety of nonsurgical modalities to relieve symptoms and decrease the severity of PCLD. Herein, we aimed to evaluate the efficacy of the nonsurgical treatment of PCLD and the quality of life of affected patients. METHODS PubMed, Ovid, MEDLINE, EMBASE, and the Cochrane Library were searched for studies on the nonsurgical modalities, either medications or radiological intervention to manage PCLD. Treatment efficacy, adverse events (AEs), and patient quality of life were evaluated. RESULTS In total, 27 studies involving 1037 patients were selected. After nonsurgical treatment, liver volume decreased by 259 ml/m [mean change (Δ) of 6.22%] and the effect was higher in the radiological intervention group [-1617 ml/m (-15.49%)] than in the medication group [-151 ml/m (-3.78%)]. The AEs and serious AEs rates after overall nonsurgical treatment were 0.50 [95% confidence interval (CI): 0.33-0.67] and 0.04 (95% CI: 0.01-0.07), respectively. The results of the SF-36 questionnaire showed that PCLD treatment improved physical function [physical component summary score of 4.18 (95% CI: 1.54-6.83)] but did not significantly improve mental function [mental component summary score of 0.91 (95% CI: -1.20 to 3.03)]. CONCLUSION Nonsurgical treatment was effective and safe for PCLD, but did not improve the quality of life in terms of mental health. Radiological intervention directly reduces hepatic cysts, and thus they should be considered for immediate symptom relief in patients with severe symptoms, whereas medication might be considered for maintenance treatment. REGISTRATION NUMBER PROSPERO (International Prospective Register of Systematic Reviews) CRD42021279597.
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Affiliation(s)
- Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang
University Bucheon Hospital, College of Medicine, Soonchunhyang University,
Bucheon, Republic of Korea
| | - Hye In Jo
- Department of Internal Medicine, Soonchunhyang
University Bucheon Hospital, College of Medicine, Soonchunhyang University,
Bucheon, Republic of Korea
| | - Eun-Ae Jung
- Medical Library, Soonchunhyang University
Bucheon Hospital, Bucheon, Republic of Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei
University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei
University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Cancer, Severance Hospital, Seoul,
Republic of Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang
University Bucheon Hospital, College of Medicine, Soonchunhyang University,
Bucheon, Republic of Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang
University Bucheon Hospital, College of Medicine, Soonchunhyang University,
Bucheon, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei
University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722,
Republic of Korea
- Institute of Gastroenterology, Yonsei
University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Cancer, Severance Hospital,
Seoul, Republic of Korea
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Garofalo C, Capuano I, Pennino L, De Gregorio I, Riccio E, Provenzano M, Crocetto F, Buonanno P, Pandolfo SD, Andreucci M, Pisani A. The effects of somatostatin analogues on liver volume and quality of life in polycystic liver disease: a meta-analysis of randomized controlled trials. Sci Rep 2021; 11:23500. [PMID: 34873228 PMCID: PMC8648823 DOI: 10.1038/s41598-021-02812-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/22/2021] [Indexed: 01/10/2023] Open
Abstract
A clear evidence on the benefits of somatostatin analogues (SA) on liver outcome in patients affected by polycystic liver disease is still lacking. We performed a meta-analysis of RCTs and a trial sequential analysis (TSA) evaluating the effects of SA in adult patients with polycystic liver disease on change in liver volume. As secondary outcome, we evaluated the effects on quality of life as measured by SF36-questionnaire. Six RCTs were selected with an overall sample size of 332 adult patients with polycystic liver disease (mean age: 46 years). Mean liver volume at baseline was 3289 ml in SA group and 3089 ml in placebo group. Overall, unstandardized mean difference in liver volume was - 176 ml (95%CI, - 406, 54; p < 0.133). Heterogeneity was low (I2:0%, p < 0.992). However, we performed a moderator analysis and we found that a higher eGFR significantly correlates to a more pronounced effect of SA on liver volume reduction (p = 0.036). Cumulative Z-curve in TSA did not reach either significance and futility boundaries or required information size. Three RCTs have evaluated Quality of life parameters measured by SF36-QOL questionnaire for a total of 124 patients; no significant difference was found on the effect of SA on QOL parameters when compared with placebo. The present meta-analysis revealed a potential effect of SA on reduction of liver volume and quality of life parameters, but results did not reach a statistical significance. These data could be explained by the need of further studies, as demonstrated through TSA, to reach an adequate sample size to confirm the beneficial outcomes of SAs treatment.
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Affiliation(s)
- Carlo Garofalo
- Division of Nephrology, Department of Scienze Mediche e Chirurgiche Avanzate, University of Campania "Luigi Vanvitelli", Via M. Longo 50, 80138, Naples, Italy.
| | - Ivana Capuano
- Department of Public Health, Chair of Nephrology, University Federico II of Naples, Naples, Italy
| | - Luigi Pennino
- Division of Nephrology, Department of Scienze Mediche e Chirurgiche Avanzate, University of Campania "Luigi Vanvitelli", Via M. Longo 50, 80138, Naples, Italy
| | - Ilaria De Gregorio
- Division of Nephrology, Department of Scienze Mediche e Chirurgiche Avanzate, University of Campania "Luigi Vanvitelli", Via M. Longo 50, 80138, Naples, Italy
| | - Eleonora Riccio
- Institute for Biomedical Research and Innovation, National Research Council of Italy, Palermo, Italy
| | - Michele Provenzano
- Division of Nephrology at Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Felice Crocetto
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Pasquale Buonanno
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Savio Domenico Pandolfo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Michele Andreucci
- Division of Nephrology at Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Antonio Pisani
- Department of Public Health, Chair of Nephrology, University Federico II of Naples, Naples, Italy
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Aldabbab HY, Hakeem MA, Alanazi FM, Asiri MA, Al Hani MF, Alshareef RI, Alkahtani AR, Alfadhli RF, Alharbi LY, Jan AA, Alraddadi MM, Alshammari M. Isolated Polycystic Liver Disease: A Rare Genetic Disorder. Cureus 2021; 13:e18560. [PMID: 34754699 PMCID: PMC8571733 DOI: 10.7759/cureus.18560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2021] [Indexed: 11/26/2022] Open
Abstract
Polycystic liver disease is a rare clinical condition that causes portal hypertension. It constitutes a group of disorders with liver lesions resulting from abnormal development of the embryological ductal system. Isolated polycystic disease with the absence of polycystic kidney disease is considered a rare condition. We present the case of a 46-year-old man who presented with epigastric pain and episodes of hematemesis. Abdominal examination revealed enlarged liver. He underwent a computed tomography scan that revealed innumerable cystic liver lesions with the presence of ascites. Further investigations confirmed abnormal liver functions and portal hypertension. Physicians need to consider this diagnosis in the appropriate clinical settings. Extensive involvement of the liver may lead to persistent severe symptoms requiring liver transplantation.
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Affiliation(s)
| | | | | | | | | | - Rahaf I Alshareef
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Abeer R Alkahtani
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Rahaf F Alfadhli
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Lama Y Alharbi
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Abdulla A Jan
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | | | - Malak Alshammari
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU
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7
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Alsager M, Neong SF, Gandhi R, Teriaky A, Tang E, Skaro A, Qumosani K, Lilly L, Galvin Z, Selzner N, Bhat MP, Puka K, Brahmania M. Liver transplantation in adult polycystic liver disease: the Ontario experience. BMC Gastroenterol 2021; 21:115. [PMID: 33750299 PMCID: PMC7941890 DOI: 10.1186/s12876-021-01703-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/28/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Liver transplantation (LT) remains the curative treatment for symptomatic Polycystic Liver Disease (PCLD) patients and is associated with excellent survival rates. The aim of the study is to review the Ontario experience in LT for PCLD. METHODS A retrospective study was performed from pre-existing LT databases from the LT Units at Toronto General Hospital and London Health Sciences Center, which are the two LT programs in Ontario, Canada. This database contains demographic, clinical parameters and follow-up of all patients transplanted for PCLD. Data was extracted for patients who underwent LT between January 2000-April 2017 and included follow up until December 31st, 2018. RESULTS A total of 3560 patients underwent LT, of whom 51 (1.4%) had PCLD and met inclusion criteria. 43 (84%) of these patients were female. The median physiologic Model for End Stage Liver Disease (MELD-Na) score at time of referral was 13 (IQR = 7-22), however all patients required MELD-Na exception points to receive LT. The median age of transplant was 62 years (IQR = 59-64) for male vs. 52 (IQR = 45-56) for female patients. 33 (65%) of our cohort had PCLD while 9 (17.5%) had ADPKD and 9 (17.5%) had both diseases. 39 (76%) had LT due to symptoms of mass effect, while 8 (16%) had portal hypertensive complications. After a median follow-up of 6.3 (IQR = 2.9-12.5) years, the probability of survival was 96% (95% CI: 90%, 100%). Log-rank test, comparing survival analysis between males and females did not show a statistically significant difference (p = 0.26). CONCLUSION Most patients underwent LT for PCLD due to symptoms of mass effect with women being more likely than men to undergo LT. LT for PCLD had excellent long-term survival.
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Affiliation(s)
- Mohammed Alsager
- Division of Gastroenterology and Multi-Organ Transplant, Western University, London, ON, Canada
| | - Shuet Fong Neong
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Radhika Gandhi
- Division of Gastroenterology and Multi-Organ Transplant, Western University, London, ON, Canada
| | - Anouar Teriaky
- Division of Gastroenterology and Multi-Organ Transplant, Western University, London, ON, Canada
| | - Ephraim Tang
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Anton Skaro
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Karim Qumosani
- Division of Gastroenterology and Multi-Organ Transplant, Western University, London, ON, Canada
| | - Les Lilly
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Zita Galvin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Nazia Selzner
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | | | - Klajdi Puka
- Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Mayur Brahmania
- Division of Gastroenterology and Multi-Organ Transplant, Western University, London, ON, Canada. .,Room A10-224; London Health Sciences Centre: University Hospital, Western University, London, ON, N6A 5A5, Canada.
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Hogan MC, Chamberlin JA, Vaughan LE, Waits AL, Banks C, Leistikow K, Oftsie T, Madsen C, Edwards M, Glockner J, Kremers WK, Harris PC, LaRusso NF, Torres VE, Masyuk TV. Pansomatostatin Agonist Pasireotide Long-Acting Release for Patients with Autosomal Dominant Polycystic Kidney or Liver Disease with Severe Liver Involvement: A Randomized Clinical Trial. Clin J Am Soc Nephrol 2020; 15:1267-1278. [PMID: 32843370 PMCID: PMC7480539 DOI: 10.2215/cjn.13661119] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 06/30/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVES We assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Individuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life. RESULTS Of 48 subjects randomized, 41 completed total liver volume measurements (n=29 pasireotide long-acting release and n=12 placebo). From baseline, there were -99±189 ml/m absolute and -3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo (P<0.001 for both). Total kidney volumes decreased by -12±34 ml/m and -1%±4% in pasireotide long-acting release compared with 21±21 ml/m and 4%±5% increase in the placebo group (P=0.05 for both). Changes in eGFR were similar between groups. Among the n=48 randomized, adverse events included hyperglycemia (26 of 33 [79%] in pasireotide long-acting release versus four of 15 [27%] in the placebo group; P<0.001), and among the 47 without diabetes at baseline, 19 of 32 (59%) in the pasireotide long-acting release group versus one of 15 (7%) in the placebo group developed diabetes (P=0.001). CONCLUSIONS Another somatostatin analog, pasireotide long-acting release, slowed progressive increase in both total liver volume/total kidney volume growth rates without affecting GFR decline. Participants experienced higher frequency of adverse events (hyperglycemia and diabetes). CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Pasireotide LAR in Severe Polycystic Liver Disease, NCT01670110 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_08_28_CJN13661119.mp3.
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Affiliation(s)
- Marie C. Hogan
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Julie A. Chamberlin
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Lisa E. Vaughan
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Angela L. Waits
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Carly Banks
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Kathleen Leistikow
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Troy Oftsie
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Chuck Madsen
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Marie Edwards
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
- Biomedical Imaging Research Core Facility, PKD Translational Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - James Glockner
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Walter K. Kremers
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Peter C. Harris
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Vicente E. Torres
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Tatyana V. Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
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Zhang ZY, Wang ZM, Huang Y. Polycystic liver disease: Classification, diagnosis, treatment process, and clinical management. World J Hepatol 2020; 12:72-83. [PMID: 32231761 PMCID: PMC7097502 DOI: 10.4254/wjh.v12.i3.72] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/06/2020] [Accepted: 03/01/2020] [Indexed: 02/06/2023] Open
Abstract
Polycystic liver disease (PLD) is a rare hereditary disease that independently exists in isolated PLD, or as an accompanying symptom of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease with complicated mechanisms. PLD currently lacks a unified diagnostic standard. The diagnosis of PLD is usually made when the number of hepatic cysts is more than 20. Gigot classification and Schnelldorfer classification are now commonly used to define severity in PLD. Most PLD patients have no clinical symptoms, and minority with severe complications need treatments. Somatostatin analogues, mammalian target of rapamycin inhibitor, ursodeoxycholic acid and vasopressin-2 receptor antagonist are the potentially effective medical therapies, while cyst aspiration and sclerosis, transcatheter arterial embolization, fenestration, hepatic resection and liver transplantation are the options of invasion therapies. However, the effectiveness of these therapies except liver transplantation are still uncertain. Furthermore, there is no unified strategy to treat PLD between medical centers at present. In order to better understand recent study progresses on PLD for clinical practice and obtain potential directions for future researches, this review mainly focuses on the recent progress in PLD classification, clinical manifestation, diagnosis and treatment. For information, we also provided medical treatment processes of PLD in our medical center.
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Affiliation(s)
- Ze-Yu Zhang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
| | - Zhi-Ming Wang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
| | - Yun Huang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
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Treatment of female rhesus macaques with a somatostatin receptor antagonist that increases oocyte fertilization rates without affecting post-fertilization development outcomes. J Assist Reprod Genet 2018; 36:229-239. [PMID: 30430314 DOI: 10.1007/s10815-018-1369-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 11/05/2018] [Indexed: 10/27/2022] Open
Abstract
PURPOSE To determine the effects of PGL1001, a somatostatin receptor isoform-2 (SSTR-2) antagonist, on ovarian follicle development, oocyte fertilization, and subsequent embryo developmental potential in the rhesus macaque. METHODS Cycling female rhesus macaques (N = 8) received vehicle through one menstrual (control) cycle, followed by daily injections of PGL1001, a SSTR-2 antagonist, for three menstrual (treatment) cycles. Main endpoints include overall animal health and ovarian hormones (e.g., estradiol [E2], progesterone [P4], and anti-Müllerian hormone [AMH]), ovarian circumference, numbers of oocytes and their maturation status following controlled ovarian stimulation (COS), as well as oocyte fertilization and subsequent blastocyst rates that were assessed in control and PGL1001 treatment cycles. Circulating PGL1001 levels were assessed at baseline as well as 6, 60, and 90 days during treatment. RESULTS PGL1001 treatment did not impact overall animal health, menstrual cycle length, or circulating levels of ovarian hormones (E2, P4, and AMH) in comparison to vehicle treatment during natural cycles. PGL1001 treatment increased (p ˂ 0.05) ovarian circumference and the day 8 to day 1 ratio of AMH levels (p ˂ 0.05) during a COS protocol, as well as oocyte fertilization rates compared to the vehicle treatment interval. Blastocyst development rates were not significantly different between vehicle and PGL1001 treatment groups. CONCLUSION Prolonged treatment with PGL1001 appears to be safe and does not affect rhesus macaque general health, menstrual cycle length, or ovarian hormone production. Interestingly, PGL1001 treatment increased the fertilization rate of rhesus macaque oocytes collected following ovarian stimulation.
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Isolated Polycystic Liver Disease: An Unusual Cause of Recurrent Variceal Bleed. Case Rep Gastrointest Med 2018; 2018:2902709. [PMID: 29971171 PMCID: PMC6008945 DOI: 10.1155/2018/2902709] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/23/2018] [Accepted: 05/08/2018] [Indexed: 01/26/2023] Open
Abstract
Isolated polycystic liver disease is a rare disorder. Majority of the patients with isolated polycystic liver disease are asymptomatic with incidental detection of liver cysts on imaging studies done for other purposes. Minority of patients develop symptoms which are mostly secondary to enlarging cysts size and hepatomegaly. Rarely, these patients develop portal hypertension and can present with its clinical manifestations and consequences in the form acute variceal bleeding or recurrent ascites. We present a rare case of 67-year-old female patient with significant history of polycystic liver disease who presented to the hospital with recurrent hematemesis and melena. She underwent esophagogastroduodenoscopy which showed multiple large esophageal varices requiring banding.
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12
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Masyuk TV, Masyuk AI, LaRusso NF. Therapeutic Targets in Polycystic Liver Disease. Curr Drug Targets 2018; 18:950-957. [PMID: 25915482 DOI: 10.2174/1389450116666150427161743] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 02/06/2015] [Accepted: 03/02/2015] [Indexed: 02/06/2023]
Abstract
Polycystic liver diseases (PLD) are a group of genetic disorders initiated by mutations in several PLD-related genes and characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. PLD co-exists with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD as well as occurs alone (i.e., Autosomal Dominant Polycystic Liver Disease [ADPLD]). PLD associated with ADPKD and ARPKD belong to a group of disorders known as cholangiociliopathies since many disease-causative and disease-related proteins are expressed in primary cilia of cholangiocytes. Aberrant expression of these proteins in primary cilia affects their structures and functions promoting cystogenesis. Current medical therapies for PLD include symptomatic management and surgical interventions. To date, the only available drug treatment for PLD patients that halt disease progression and improve quality of life are somatostatin analogs. However, the modest clinical benefits, need for long-term maintenance therapy, and the high cost of treatment justify the necessity for more effective treatment options. Substantial evidence suggests that experimental manipulations with components of the signaling pathways that influence cyst development (e.g., cAMP, intracellular calcium, receptor tyrosine kinase, transient receptor potential cation channel subfamily V member 4 (TRPV4) channel, mechanistic target of rapamycin (mTOR), histone deacetylase (HDAC6), Cdc25A phosphatase, miRNAs and metalloproteinases) attenuate growth of hepatic cysts. Many of these targets have been evaluated in pre-clinical trials suggesting their value as potential new therapies. This review outlines the current clinical and preclinical treatment strategies for PLD.
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Affiliation(s)
- Tatyana V Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Anatoliy I Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street, SW Rochester, Minnesota, MN 55905, United States
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13
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Lorenzo Pisarello M, Masyuk TV, Gradilone SA, Masyuk AI, Ding JF, Lee PY, LaRusso NF. Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:981-994. [PMID: 29366679 DOI: 10.1016/j.ajpath.2017.12.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 12/12/2017] [Accepted: 12/28/2017] [Indexed: 02/08/2023]
Abstract
Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide. We also assessed effects of ACY-1215 and pasireotide alone and in combination on cell proliferation, cAMP production, and expression of acetylated α-tubulin in vitro in cultured cholangiocytes and the length of primary cilia and the frequency of ciliated cholangiocytes in vivo in PCK rats. Panobinostat and all three HDAC6 inhibitors decreased hepatorenal cystogenesis in PCK rats. ACY-1215 was more effective than other HDAC inhibitors and was chosen for combinational treatment. ACY-1215 + pasireotide combination synergistically reduced cyst growth and increased length of primary cilia in PCK rats. In cultured cystic cholangiocytes, ACY-1215 + pasireotide combination concurrently decreased cell proliferation and inhibited cAMP levels. These data suggest that the combination of drugs that inhibit HDAC6 and cAMP may be an effective therapy for PLD.
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Affiliation(s)
| | - Tatyana V Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
| | - Sergio A Gradilone
- The Hormel Institute, University of Minnesota, Austin; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | | | - Jingyi F Ding
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
| | - Pui-Yuen Lee
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
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Wong MY, McCaughan GW, Strasser SI. An update on the pathophysiology and management of polycystic liver disease. Expert Rev Gastroenterol Hepatol 2017; 11:569-581. [PMID: 28317394 DOI: 10.1080/17474124.2017.1309280] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Polycystic liver disease (PLD) is characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. They are classified as an inherited ciliopathy /cholangiopathy as pathology exists at the level of the primary cilia of cholangiocytes. Aberrant expression of the proteins in primary cilia can impair their structures and functions, thereby promoting cystogenesis. Areas covered: This review begins by looking at the epidemiology of PLD and its natural history. It then describes the pathophysiology and corresponding potential treatment strategies for PLD. Expert commentary: Traditionally, therapies for symptomatic PLD have been limited to symptomatic management and surgical interventions. Such techniques are not completely effective, do not alter the natural history of the disease, and are linked with high rate of re-accumulation of cysts. As a result, there has been a push for drugs targeted at abnormal cellular signaling cascades to address deregulated proliferation, cell dedifferentiation, apoptosis and fluid secretion. Currently, the only available drug treatments that halt disease progression and improve quality of life in PLD patients are somatostatin analogues. Numerous preclinical studies suggest that targeting components of the signaling pathways that influence cyst development can ameliorate growth of hepatic cysts.
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Affiliation(s)
- May Yw Wong
- a AW Morrow Gastroenterology and Liver Centre , Royal Prince Alfred Hospital and University of Sydney , Sydney , Australia
| | - Geoffrey W McCaughan
- a AW Morrow Gastroenterology and Liver Centre , Royal Prince Alfred Hospital and University of Sydney , Sydney , Australia
| | - Simone I Strasser
- a AW Morrow Gastroenterology and Liver Centre , Royal Prince Alfred Hospital and University of Sydney , Sydney , Australia
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15
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Vasopressin regulates the growth of the biliary epithelium in polycystic liver disease. J Transl Med 2016; 96:1147-1155. [PMID: 27571215 PMCID: PMC5480400 DOI: 10.1038/labinvest.2016.93] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/19/2016] [Accepted: 07/25/2016] [Indexed: 01/04/2023] Open
Abstract
The neurohypophysial hormone arginine vasopressin (AVP) acts by three distinct receptor subtypes: V1a, V1b, and V2. In the liver, AVP is involved in ureogenesis, glycogenolysis, neoglucogenesis and regeneration. No data exist about the presence of AVP in the biliary epithelium. Cholangiocytes are the target cells in a number of animal models of cholestasis, including bile duct ligation (BDL), and in several human pathologies, such as polycystic liver disease characterized by the presence of cysts that bud from the biliary epithelium. In vivo, liver fragments from normal and BDL mice and rats as well as liver samples from normal and ADPKD patients were collected to evaluate: (i) intrahepatic bile duct mass by immunohistochemistry for cytokeratin-19; and (ii) expression of V1a, V1b and V2 by immunohistochemistry, immunofluorescence and real-time PCR. In vitro, small and large mouse cholangiocytes, H69 (non-malignant human cholangiocytes) and LCDE (human cholangiocytes from the cystic epithelium) were stimulated with vasopressin in the absence/presence of AVP antagonists such as OPC-31260 and Tolvaptan, before assessing cellular growth by MTT assay and cAMP levels. Cholangiocytes express V2 receptor that was upregulated following BDL and in ADPKD liver samples. Administration of AVP increased proliferation and cAMP levels of small cholangiocytes and LCDE cells. We found no effect in the proliferation of large mouse cholangiocytes and H69 cells. Increases were blocked by preincubation with the AVP antagonists. These results showed that AVP and its receptors may be important in the modulation of the proliferation rate of the biliary epithelium.
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Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes. Eur J Hum Genet 2016; 24:1707-1714. [PMID: 27552964 DOI: 10.1038/ejhg.2016.97] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Revised: 06/22/2016] [Accepted: 06/28/2016] [Indexed: 12/27/2022] Open
Abstract
Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.
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Neijenhuis MK, Gevers TJ, Hogan MC, Kamath PS, Wijnands TF, van den Ouweland RC, Edwards ME, Sloan JA, Kievit W, Drenth JP. Development and Validation of a Disease-Specific Questionnaire to Assess Patient-Reported Symptoms in Polycystic Liver Disease. Hepatology 2016; 64:151-160. [PMID: 26970415 PMCID: PMC4917464 DOI: 10.1002/hep.28545] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 03/03/2016] [Indexed: 01/01/2023]
Abstract
UNLABELLED Treatment of polycystic liver disease (PLD) focuses on symptom improvement. Generic questionnaires lack sensitivity to capture PLD-related symptoms, a prerequisite to determine effectiveness of therapy. We developed and validated a disease-specific questionnaire that assesses symptoms in PLD (PLD-Q). We identified 16 PLD-related symptoms (total score 0-100 points) by literature review and interviews with patients and clinicians. The developed PLD-Q was validated in Dutch (n = 200) and United States (US; n = 203) PLD patients. We assessed the correlation of PLD-Q total score with European Organization for Research and Treatment of Cancer (EORTC) symptom scale, global health visual analogue scale (VAS) of EQ-5D, and liver volume. To test discriminative validity, we compared PLD-Q total scores of patients with different PLD severity stages (Gigot classification) and PLD-Q total scores of PLD patients with general controls and polycystic kidney disease patients without PLD. Reproducibility was tested by comparing original test scores with 2-week retest scores. In total, 167 Dutch and 124 US patients returned the questionnaire. Correlation between PLD-Q total score and EORTC symptom scale (The Netherlands [NL], r = 0.788; US, r = 0.811) and global health VAS (NL, r = -0.517; US, r = -0.593) was good. There was no correlation of PLD-Q total score with liver volume (NL, r = 0.138; P = 0.236; US, r = 0.254; P = 0.052). Gigot type III individuals scored numerically higher than type II patients (NL, 46 vs. 40; P = 0.089; US, 48 vs. 36; P = 0.055). PLD patients scored higher on the PLD-Q total score than general controls (NL, 42 vs. 17; US, 40 vs. 13 points) and polycystic kidney disease patients without PLD (22 points). Reproducibility of PLD-Q was excellent (NL, r = 0.94; US, 0.96). CONCLUSION PLD-Q is a valid, reproducible, and sensitive disease-specific questionnaire that can be used to assess PLD-related symptoms in clinical care and future research. (Hepatology 2016;64:151-160).
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Affiliation(s)
- Myrte K. Neijenhuis
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Tom J.G. Gevers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Marie C. Hogan
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester (MN), US
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester (MN), US
| | - Titus F.M. Wijnands
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Ralf C.P.M. van den Ouweland
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Marie E. Edwards
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester (MN), US
| | - Jeff A. Sloan
- Quality of Life Group, Department of Health Sciences Research, Mayo Clinic, Rochester (MN), US
| | - Wietske Kievit
- Radboud Institute for Health Sciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Joost P.H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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18
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Polycystic Liver Disease: The Benefits of Targeting cAMP. Clin Gastroenterol Hepatol 2016; 14:1031-4. [PMID: 26972981 PMCID: PMC4912886 DOI: 10.1016/j.cgh.2016.03.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 03/06/2016] [Indexed: 02/06/2023]
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19
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Gevers TJ, Nevens F, Torres VE, Hogan MC, Drenth JP. Alkaline phosphatase predicts response in polycystic liver disease during somatostatin analogue therapy: a pooled analysis. Liver Int 2016; 36:595-602. [PMID: 26481454 PMCID: PMC5497692 DOI: 10.1111/liv.12986] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/07/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy. METHODS We pooled the individual patient data of four trials that evaluated long-acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6-12 months in polycystic liver disease patients. We performed uni- and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre. RESULTS We included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range -31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (-2.7%, 95% CI -5.1 to -0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (-3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro-intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001). CONCLUSION Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy.
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Affiliation(s)
- Tom J.G. Gevers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Frederik Nevens
- Department of Gastroenterology and Hepatology, Gasthuis Leuven, Leuven, Belgium
| | - Vicente E. Torres
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Marie C. Hogan
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Joost P.H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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Neijenhuis MK, Gevers TJG, Nevens F, Hogan MC, Torres VE, Kievit W, Drenth JPH. Somatostatin analogues improve health-related quality of life in polycystic liver disease: a pooled analysis of two randomised, placebo-controlled trials. Aliment Pharmacol Ther 2015; 42:591-598. [PMID: 26129925 DOI: 10.1111/apt.13301] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 02/23/2015] [Accepted: 06/10/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Polycystic liver disease is associated with impaired health-related quality of life (HRQL). Somatostatin analogues reduce hepatomegaly in polycystic liver disease. AIM To determine whether somatostatin analogues improve HRQL and to identify factors associated with change in HRQL in polycystic liver disease. METHODS We pooled data from two randomized, double-blind, placebo-controlled trials that evaluated HRQL using the Short-Form 36 (SF-36) in 96 polycystic liver disease patients treated 6-12 months with somatostatin analogues or placebo. The SF-36 contains a summarizing physical and mental component score and was administered at baseline and at the end of treatment. We used random effect models to delineate the effect of somatostatin analogues on HRQL. We determined the effect of demographics, height-adjusted liver volume, change in liver volume, somatostatin analogue-associated side effects with change in HRQL. In patients with autosomal dominant polycystic kidney disease, we estimated the effect of height-adjusted kidney volume and change in kidney volume in relation to HRQL. RESULTS Physical component scores improved with somatostatin analogues, but remained unchanged with placebo (3.41 ± 1.29 vs. -0.71 ± 1.54, P = 0.044). Treatment had no impact on the mental component score. Large liver volume was independently associated with larger HRQL decline during follow up (-4.04 ± 2.02 points per logarithm liver volume, P = 0.049). In autosomal dominant polycystic kidney disease, patients with large liver and kidney volumes had larger decline in HRQL (5.36 ± 2.54 points per logarithm liver volume; P = 0.040 and -4.00 ± 1.88 per logarithm kidney volume; P = 0.039). CONCLUSION Somatostatin analogues improve HRQL in symptomatic polycystic liver disease. Halting the progressive nature of polycystic liver disease is necessary to prevent further decline of HRQL in severe hepatomegaly.
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Affiliation(s)
- M K Neijenhuis
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - T J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - F Nevens
- Department of Hepatology, University Hospital Leuven, Leuven, Belgium
| | - M C Hogan
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - V E Torres
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - W Kievit
- Department of Health Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - J P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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21
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Gevers TJG, Hol JC, Monshouwer R, Dekker HM, Wetzels JFM, Drenth JPH. Effect of lanreotide on polycystic liver and kidneys in autosomal dominant polycystic kidney disease: an observational trial. Liver Int 2015; 35:1607-1614. [PMID: 25369108 DOI: 10.1111/liv.12726] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Accepted: 10/28/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIM Several trials have demonstrated that somatostatin analogues decrease liver volume in mixed populations of patients with autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease. Chronic renal dysfunction in ADPKD may affect treatment efficacy of lanreotide and possibly enhances risk for adverse events. The aim of this open-label clinical trial (RESOLVE trial) was to assess the efficacy of 6-month lanreotide treatment, 120 mg, subcutaneously every 4 weeks in ADPKD patients with symptomatic polycystic liver disease. METHODS Primary outcome was change in liver volume after 6 months; secondary outcomes were changes in kidney volume, estimated glomerular filtration rate (eGFR), symptom relief and health-related quality of life (Euro-Qol5D). We excluded patients with an eGFR <30 ml/min/1.73 m(2) . We used the Wilcoxon signed-rank test or paired two-sided t-test to analyze within-group differences. RESULTS We included 43 ADPKD patients with polycystic liver disease (84% female, median age 50 years, mean eGFR 63 ml/min/1.73 m(2) ). Median liver volume decreased from 4859 ml to 4595 ml (-3.1%; P < 0.001), and median kidney volume decreased from 1023 ml to 1012 ml (-1.7%; P = 0.006). eGFR declined 3.5% after the first injection, remained stable up to study end, to decline again after lanreotide withdrawal. Lanreotide significantly relieved post-prandial fullness, shortness of breath and abdominal distension. Three participants had a suspected episode of hepatic or renal cyst infection during this study. CONCLUSION Lanreotide reduced polycystic liver and kidney volumes and decreases symptoms in ADPKD patients. Moreover, eGFR decreased acutely after starting lanreotide, stabilized thereafter and declined again after withdrawal. TRIAL REGISTRATION NUMBER Clinical trials.gov NCT01354405 (REGISTRATION: 13 May 2011).
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Affiliation(s)
- Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, the Netherlands
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22
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Perugorria MJ, Masyuk TV, Marin JJ, Marzioni M, Bujanda L, LaRusso NF, Banales JM. Polycystic liver diseases: advanced insights into the molecular mechanisms. Nat Rev Gastroenterol Hepatol 2014; 11:750-761. [PMID: 25266109 PMCID: PMC4526263 DOI: 10.1038/nrgastro.2014.155] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Polycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated.
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Affiliation(s)
- Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), CIBERehd, IKERBASQUE, Paseo del Doctor Beguiristain, 20014 San Sebastián, Spain
| | - Tatyana V Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
| | - Jose J Marin
- Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), Campus Miguel de Unamuno, University of Salamanca, 37007 Salamanca, Spain
| | - Marco Marzioni
- Department of Gastroenterology, "Università Politecnica delle Marche", Piazza Roma 22, 60121, Ancona, Italy
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), CIBERehd, IKERBASQUE, Paseo del Doctor Beguiristain, 20014 San Sebastián, Spain
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), CIBERehd, IKERBASQUE, Paseo del Doctor Beguiristain, 20014 San Sebastián, Spain
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Ramírez de la Piscina P, Duca I, Estrada S, Calderón R, Ganchegui I, Campos A, Spicakova K, Urtasun L, Salvador M, Delgado E, Bengoa R, García-Campos F. Combined liver and kidney transplant in a patient with budd-Chiari syndrome secondary to autosomal dominant polycystic kidney disease associated with polycystic liver disease: report of a case with a 9-year follow-up. Case Rep Gastrointest Med 2014; 2014:585291. [PMID: 24987537 PMCID: PMC4058590 DOI: 10.1155/2014/585291] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Revised: 05/03/2014] [Accepted: 05/15/2014] [Indexed: 12/31/2022] Open
Abstract
Polycystic liver disease (PLD) is a hereditary disease inherited by autosomal dominant trait that occurs as a frequent extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). We report a case of a 59-year-old woman diagnosed with ADPKD associated with PLD. End-stage chronic renal failure with a secondary Budd-Chiari syndrome developed during the patient's clinical course. She underwent combined liver and kidney transplantation, with a successful response over a 9-year follow-up period.
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Affiliation(s)
- Patricia Ramírez de la Piscina
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Ileana Duca
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Silvia Estrada
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Rosario Calderón
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Idoia Ganchegui
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Amaia Campos
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Katerina Spicakova
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Leire Urtasun
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Marta Salvador
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Elvira Delgado
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Raquel Bengoa
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
| | - Francisco García-Campos
- Department of Gastroenterology, Hospital Txagorritxu, Universidad del País Vasco, C/ José Achotegui s/n, Vitoria-Gasteiz, 01009 Álava, Spain
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Meijer E, Drenth JPH, d'Agnolo H, Casteleijn NF, de Fijter JW, Gevers TJ, Kappert P, Peters DJM, Salih M, Soonawala D, Spithoven EM, Torres VE, Visser FW, Wetzels JFM, Zietse R, Gansevoort RT. Rationale and design of the DIPAK 1 study: a randomized controlled clinical trial assessing the efficacy of lanreotide to Halt disease progression in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2014; 63:446-455. [PMID: 24342522 PMCID: PMC4042404 DOI: 10.1053/j.ajkd.2013.10.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 10/04/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD. STUDY DESIGN The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial. SETTING & PARTICIPANTS We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years. INTERVENTION Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care. OUTCOMES Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life. MEASUREMENTS Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume. RESULTS Assuming an average change in eGFR of 5.2 ± 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided α = 0.05, and 20% protocol violators and/or dropouts. LIMITATIONS The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization. CONCLUSIONS The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD.
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Affiliation(s)
- Esther Meijer
- Department of Nephrology, University Medical Center Groningen, University Hospital Groningen, Groningen, the Netherlands.
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Hedwig d'Agnolo
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Niek F Casteleijn
- Department of Nephrology, University Medical Center Groningen, University Hospital Groningen, Groningen, the Netherlands
| | - Johan W de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Tom J Gevers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Peter Kappert
- Department of Radiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Dorien J M Peters
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Mahdi Salih
- Department of Nephrology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Darius Soonawala
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Edwin M Spithoven
- Department of Nephrology, University Medical Center Groningen, University Hospital Groningen, Groningen, the Netherlands
| | - Vicente E Torres
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Folkert W Visser
- Department of Nephrology, University Medical Center Groningen, University Hospital Groningen, Groningen, the Netherlands
| | - Jack F M Wetzels
- Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Robert Zietse
- Department of Nephrology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ron T Gansevoort
- Department of Nephrology, University Medical Center Groningen, University Hospital Groningen, Groningen, the Netherlands
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Macedo FI. Current management of noninfectious hepatic cystic lesions: A review of the literature. World J Hepatol 2013; 5:462-469. [PMID: 24073297 PMCID: PMC3782683 DOI: 10.4254/wjh.v5.i9.462] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 07/16/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023] Open
Abstract
Nonparasitic hepatic cysts consist of a heterogeneous group of disorders, which differ in etiology, prevalence, and manifestations. With improving diagnostic techniques, hepatic cysts are becoming more common. Recent advancements in minimally invasive technology created a new Era in the management of hepatic cystic disease. Herein, the most current recommendations for management of noninfectious hepatic cysts are described, thereby discussing differential diagnosis, new therapeutic modalities and outcomes.
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Gevers TJG, Inthout J, Caroli A, Ruggenenti P, Hogan MC, Torres VE, Nevens F, Drenth JPH. Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data. Gastroenterology 2013; 145:357-65.e652. [PMID: 23665274 DOI: 10.1053/j.gastro.2013.04.055] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Revised: 04/15/2013] [Accepted: 04/30/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Clinical trials have shown that in patients with polycystic liver disease (PLD), short-term treatment with somatostatin analogues (SAs) reduces liver volumes by 4.5%-5.9%, compared with placebo. However, the effects of SA therapy vary among individuals. We collected data from individual patients with PLD to identify subgroups that benefit most from SA therapy. METHODS We analyzed data from 107 patients with PLD from 3 randomized placebo-controlled trials (67 received SAs, 52 received placebo). We used multiple linear regression analysis to determine the effects of SAs based on patients' age, sex, baseline liver volume, and diagnosis (autosomal dominant polycystic liver or kidney disease). The primary outcome was change in liver volume after 6-12 months of treatment. RESULTS The effects of SA therapy did not differ significantly among patients with different diagnoses or baseline liver volumes; the overall difference in liver volume between groups receiving SAs therapy vs placebo was 5.3% (P < .001). Among subjects given placebo, young women (48 years old or younger) had the greatest increase in polycystic liver volume (4.8%; 95% confidence interval: 2.2%-7.4%), and mean liver volumes did not increase in older women and men. Women 48 years old or younger had a greater response to therapy (a reduction in liver volume of 8.0% compared with placebo; P < .001) than older women (a reduction in liver volume of 4.1% compared with placebo; P = .022). CONCLUSIONS Based on a pooled analysis of data from individual patients with PLD, treatment with somatostatin analogues is equally effective for patients with autosomal dominant polycystic kidney disease or polycystic liver disease; efficacy does not depend on size of the polycystic liver. Young female patients appear to have the greatest benefit from 6-12 months of SA therapy, which might avert the progressive course of the disease in this specific group.
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Affiliation(s)
- Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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Chrispijn M, Gevers TJG, Hol JC, Monshouwer R, Dekker HM, Drenth JPH. Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial. J Hepatol 2013; 59:153-159. [PMID: 23499726 DOI: 10.1016/j.jhep.2013.03.004] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 02/25/2013] [Accepted: 03/05/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Polycystic liver disease (PLD) is associated with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PCLD). The resulting hepatomegaly compromises quality of life. Somatostatin analogues reduce PLD volume by approximately 5% when given for 6-12 months. A pilot trial in 16 ADPKD patients demonstrated that sirolimus, an mTOR inhibitor, reduced PLD volume by 26%. The aim of this study was to assess the PLD volume reducing effect of everolimus and octreotide relative to octreotide monotherapy. METHODS We designed a randomized controlled trial that compared 48 weeks of everolimus 2.5 mg daily, combined with octreotide 40 mg intramuscularly every 4 weeks, to octreotide monotherapy. We included PCLD and ADPKD patients. Exclusion criteria were MDRD-GFR <60 ml/min/1.73 m(2) and liver volume <2500 ml. Primary outcome was change in liver volume measured with CT-volumetry. RESULTS We randomized 44 PLD patients (29 PCLD, 15 ADPKD, 89% female) to treatment with octreotide (n=23) or octreotide-everolimus (n=21). Liver volume decreased by 3.5% (p<0.01) in the monotherapy arm, compared to 3.8% with combination therapy (p<0.01). The difference between treatment arms was not significant (p=0.73). CONCLUSIONS Adding everolimus to octreotide in PLD does not increase the liver volume reducing effect of octreotide.
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Affiliation(s)
- Melissa Chrispijn
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Masyuk TV, Radtke BN, Stroope AJ, Banales JM, Gradilone SA, Huang B, Masyuk AI, Hogan MC, Torres VE, LaRusso NF. Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases. Hepatology 2013; 58:409-21. [PMID: 23172758 PMCID: PMC3616157 DOI: 10.1002/hep.26140] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Accepted: 11/06/2012] [Indexed: 12/21/2022]
Abstract
UNLABELLED In polycystic liver (PLD) and kidney (PKD) diseases, increased cyclic adenosine monophosphate (cAMP) levels trigger hepatorenal cystogenesis. A reduction of the elevated cAMP by targeting somatostatin receptors (SSTRs) with octreotide (OCT; a somatostatin analog that preferentially binds to SSTR2) inhibits cyst growth. Here we compare the effects of OCT to pasireotide (PAS; a more potent somatostatin analog with broader receptor specificity) on: (1) cAMP levels, cell cycle, proliferation, and cyst expansion in vitro using cholangiocytes derived from control and PCK rats (a model of autosomal recessive PKD [ARPKD]), healthy human beings, and patients with autosomal dominant PKD (ADPKD); and (2) hepatorenal cystogenesis in vivo in PCK rats and Pkd2(WS25/-) mice (a model of ADPKD). Expression of SSTRs was assessed in control and cystic cholangiocytes of rodents and human beings. Concentrations of insulin-like growth factor 1 (IGF1) and vascular endothelial growth factor (VEGF) (both involved in indirect action of somatostatin analogs), and expression and localization of SSTRs after treatment were evaluated. We found that PAS was more potent (by 30%-45%) than OCT in reducing cAMP and cell proliferation, affecting cell cycle distribution, decreasing growth of cultured cysts in vitro, and inhibiting hepatorenal cystogenesis in vivo in PCK rats and Pkd2(WS25/-) mice. The levels of IGF1 (but not VEGF) were reduced only in response to PAS. Expression of SSTR1 and SSTR2 (but not SSTR3 and SSTR5) was decreased in cystic cholangiocytes compared to control. Although both OCT and PAS increased the immunoreactivity of SSTR2, only PAS up-regulated SSTR1; neither drug affected cellular localization of SSTRs. CONCLUSION PAS is more effective than OCT in reducing hepatorenal cystogenesis in rodent models; therefore, it might be more beneficial for the treatment of PKD and PLD.
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Affiliation(s)
- Tatyana V Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
| | - Brynn N Radtke
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
| | - Angela J Stroope
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
| | - Jesús M Banales
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA,IKERBASQUE, Basque Foundation of Science, Division of Hepatology, Biodonostia Institute, Donostia Hospital, CIBERehd, University of Basque Country, San Sebastián, Spain
| | - Sergio A Gradilone
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
| | - Bing Huang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
| | - Anatoliy I Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
| | - Marie C Hogan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN USA
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN USA
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
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Friedman SL. Focus. J Hepatol 2013; 59:1-2. [PMID: 23583274 DOI: 10.1016/j.jhep.2013.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 04/10/2013] [Indexed: 12/04/2022]
Affiliation(s)
- Scott L Friedman
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA.
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30
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Lantinga MA, Gevers TJG, Drenth JPH. Evaluation of hepatic cystic lesions. World J Gastroenterol 2013; 19:3543-3554. [PMID: 23801855 PMCID: PMC3691048 DOI: 10.3748/wjg.v19.i23.3543] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Revised: 03/05/2013] [Accepted: 03/22/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatic cysts are increasingly found as a mere coincidence on abdominal imaging techniques, such as ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). These cysts often present a diagnostic challenge. Therefore, we performed a review of the recent literature and developed an evidence-based diagnostic algorithm to guide clinicians in characterising these lesions. Simple cysts are the most common cystic liver disease, and diagnosis is based on typical USG characteristics. Serodiagnostic tests and microbubble contrast-enhanced ultrasound (CEUS) are invaluable in differentiating complicated cysts, echinococcosis and cystadenoma/cystadenocarcinoma when USG, CT and MRI show ambiguous findings. Therefore, serodiagnostic tests and CEUS reduce the need for invasive procedures. Polycystic liver disease (PLD) is arbitrarily defined as the presence of > 20 liver cysts and can present as two distinct genetic disorders: autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (PCLD). Although genetic testing for ADPKD and PCLD is possible, it is rarely performed because it does not affect the therapeutic management of PLD. USG screening of the liver and both kidneys combined with extensive family history taking are the cornerstone of diagnostic decision making in PLD. In conclusion, an amalgamation of these recent advances results in a diagnostic algorithm that facilitates evidence-based clinical decision making.
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Abstract
Polycystic liver disease (PLD) is arbitrarily defined as a liver that contains >20 cysts. The condition is associated with two genetically distinct diseases: as a primary phenotype in isolated polycystic liver disease (PCLD) and as an extrarenal manifestation in autosomal dominant polycystic kidney disease (ADPKD). Processes involved in hepatic cystogenesis include ductal plate malformation with concomitant abnormal fluid secretion, altered cell-matrix interaction and cholangiocyte hyperproliferation. PLD is usually a benign disease, but can cause debilitating abdominal symptoms in some patients. The main risk factors for growth of liver cysts are female sex, exogenous oestrogen use and multiple pregnancies. Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver and to differentiate between ADPKD and PCLD. Current radiological and surgical therapies for symptomatic patients include aspiration-sclerotherapy, fenestration, segmental hepatic resection and liver transplantation. Medical therapies that interact with regulatory mechanisms controlling expansion and growth of liver cysts are under investigation. Somatostatin analogues are promising; several clinical trials have shown that these drugs can reduce the volume of polycystic livers. The purpose of this Review is to provide an update on the diagnosis and management of PLD with a focus on literature published in the past 4 years.
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Affiliation(s)
- Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, P. O. Box 9101, Code 455, 6500 HB Nijmegen, The Netherlands
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Abstract
Polycystic liver disease rarely occurs in isolation as part of autosomal dominant polycystic liver disease, but more commonly, it exists as an extra-renal manifestation of autosomal dominant polycystic kidney disease. The pathogenesis of polycystic liver disease involves defects in the primary cilium of the cholangiocyte, with genetic mutations that impair key proteins integral to the complex functioning of cilia. While most patients are asymptomatic and require no intervention aside from reassurance and genetic counseling, in a minority of patients, polycystic liver disease creates a myriad of symptoms from the compressive effects of enlarged cysts, and can even cause malnutrition and liver decompensation in the severest of cases. In patients with symptomatic disease, a variety of interventional radiology or surgical techniques can be considered, including aspiration with sclerotherapy of a dominant cyst, fenestration, segmental hepatic resection, and even liver transplantation. Although there are no curative medical options for polycystic liver disease, somatostatin analogs hold promise and have shown minimal efficacy in human studies. However, further research is needed to develop more efficacious medical treatments.
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Affiliation(s)
- Natasha Chandok
- Department of Medicine, Multi-Organ Transplant Program, Western University, London, Ontario, Canada.
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Current world literature. Curr Opin Endocrinol Diabetes Obes 2012; 19:328-37. [PMID: 22760515 DOI: 10.1097/med.0b013e3283567080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Gevers TJG, Chrispijn M, Wetzels JFM, Drenth JPH. Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease. BMC Nephrol 2012; 13:17. [PMID: 22475206 PMCID: PMC3368739 DOI: 10.1186/1471-2369-13-17] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 04/04/2012] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial. METHODS/DESIGN This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, α1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed. DISCUSSION We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response. TRIAL REGISTRATION NUMBER Clinical trials.gov NCT01354405.
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Affiliation(s)
- Tom JG Gevers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Melissa Chrispijn
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Jack FM Wetzels
- Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Joost PH Drenth
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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Spirli C, Locatelli L, Fiorotto R, Morell CM, Fabris L, Pozzan T, Strazzabosco M. Altered store operated calcium entry increases cyclic 3',5'-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes. Hepatology 2012; 55:856-68. [PMID: 21987453 PMCID: PMC3272110 DOI: 10.1002/hep.24723] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
UNLABELLED Mutations in polycystins (PC1 or PC2/TRPP2) cause progressive polycystic liver disease (PLD). In PC2-defective mice, cyclic 3',5'-adenosine monophosphate/ protein kinase A (cAMP/PKA)-dependent activation of extracellular signal-regulated kinase/ mammalian target of rapamycin (ERK-mTOR) signaling stimulates cyst growth. We investigated the mechanisms connecting PC2 dysfunction to altered Ca(2+) and cAMP production and inappropriate ERK signaling in PC2-defective cholangiocytes. Cystic cholangiocytes were isolated from PC2 conditional-KO (knockout) mice (Pkd2(flox/-) :pCxCreER™; hence, called Pkd2KO) and compared to cholangiocytes from wild-type mice (WT). Our results showed that, compared to WT cells, in PC2-defective cholangiocytes (Pkd2KO), cytoplasmic and ER-Ca(2+) (measured with Fura-2 and Mag-Fluo4) levels are decreased and store-operated Ca(2+) entry (SOCE) is inhibited, whereas the expression of Ca(2+) -sensor stromal interaction molecule 1 (STIM1) and store-operated Ca(2+) channels (e.g., the Orai1 channel) are unchanged. In Pkd2KO cells, ER-Ca(2+) depletion increases cAMP and PKA-dependent ERK1/2 activation and both are inhibited by STIM1 inhibitors or by silencing of adenylyl cyclase type 6 (AC6). CONCLUSION These data suggest that PC2 plays a key role in SOCE activation and inhibits the STIM-dependent activation of AC6 by ER Ca(2+) depletion. In PC2-defective cells, the interaction of STIM-1 with Orai channels is uncoupled, whereas coupling to AC6 is maximized. The resulting overproduction of cAMP, in turn, potently activates the PKA/ERK pathway. PLD, because of PC2 deficiency, represents the first example of human disease linked to the inappropriate activation of store-operated cAMP production.
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Affiliation(s)
- Carlo Spirli
- Dept. of Internal Medicine; Liver Center and Digestive Diseases Section; Yale University; New Haven; USA
- CeLiveR; Ospedali Riuniti di Bergamo; Bergamo, Italy
| | - Luigi Locatelli
- Dept. of Internal Medicine; Liver Center and Digestive Diseases Section; Yale University; New Haven; USA
- CeLiveR; Ospedali Riuniti di Bergamo; Bergamo, Italy
- Dept. of Clinical Medicine and Prevention University of Milan-Bicocca, Monza, Italy
| | - Romina Fiorotto
- Dept. of Internal Medicine; Liver Center and Digestive Diseases Section; Yale University; New Haven; USA
- CeLiveR; Ospedali Riuniti di Bergamo; Bergamo, Italy
| | - Carola M. Morell
- Dept. of Internal Medicine; Liver Center and Digestive Diseases Section; Yale University; New Haven; USA
- Dept. of Clinical Medicine and Prevention University of Milan-Bicocca, Monza, Italy
| | - Luca Fabris
- CeLiveR; Ospedali Riuniti di Bergamo; Bergamo, Italy
- Department of Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Tullio Pozzan
- Consiglio Nazionale delle Ricerche, Neuroscience Institute, Dept. of Biomedical Sciences, University of Padova and Venetian Institute of Molecular Medicine, Padova, Italy
| | - Mario Strazzabosco
- Dept. of Internal Medicine; Liver Center and Digestive Diseases Section; Yale University; New Haven; USA
- CeLiveR; Ospedali Riuniti di Bergamo; Bergamo, Italy
- Dept. of Clinical Medicine and Prevention University of Milan-Bicocca, Monza, Italy
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36
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van Keimpema L, Nevens F, Adam R, Porte RJ, Fikatas P, Becker T, Kirkegaard P, Metselaar HJ, Drenth JPH. Excellent survival after liver transplantation for isolated polycystic liver disease: an European Liver Transplant Registry study. Transpl Int 2011; 24:1239-45. [PMID: 21955068 DOI: 10.1111/j.1432-2277.2011.01360.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Patients with end-stage isolated polycystic liver disease (PCLD) suffer from incapacitating symptoms because of very large liver volumes. Liver transplantation (LT) is the only curative option. This study assesses the feasibility of LT in PCLD. We used the European Liver Transplant Registry (ELTR) database to extract demographics and outcomes of 58 PCLD patients. We used Kaplan-Meier survival analysis for survival rates. Severe abdominal pain (75%) was the most prominent symptom, while portal hypertension (35%) was the most common complication in PCLD. The explantation of the polycystic liver was extremely difficult in 38% of patients, because of presence of adhesions from prior therapy (17%). Karnofsky score following LT was 90%. The 1- and 5-year graft survival rate was 94.3% and 87.5%, while patient survival rate was 94.8% and 92.3%, respectively. Survival rates after LT for PCLD are good.
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Affiliation(s)
- Loes van Keimpema
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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