Polycystic Liver Disease: The Benefits of Targeting cAMP.

Abstract

Polycystic liver disease (PLD), a group of genetic disorders, exists alone as autosomal-dominant PLD (ADPLD) or in association with autosomal-dominant polycystic kidney disease (ADPKD) or autosomal-recessive polycystic kidney disease (ARPKD). PLD is characterized by the presence of fluid-filled liver cysts derived from cholangiocytes as a result of mutations in PLD-related genes. Hepatic cystogenesis worsens over time increasing liver volume by 0.9%–1.6% per year. The continuous progression of PLD can result in hepatomegaly with total liver volumes exceeding 10 L. Patients with severe disease have constant abdominal pain and distention, dyspnea, gasrtroesophageal reflux, back pain, and hepatic and portal vein compression.1Gevers T.J. Drenth J.P. Diagnosis and management of polycystic liver disease.Nat Rev Gastroenterol Hepatol. 2013; 10: 101-108Google Scholar Multiple in-depth preclinical studies showed that many intracellular signaling pathways and cellular functions are dysregulated in PLD. Indeed, hepatic cystogenesis has been associated with (1) enhanced fluid secretion into the cyst lumen; (2) increased rates of cholangiocyte proliferation; (3) structural and functional ciliary abnormalities; (4) abnormal cell-extracellular matrix interactions; (5) impaired cell cycle progression; (6) morphologic centrosomal defects; (7) global changes in mRNA, microRNA, and protein expression; and (8) increased levels of intracellular adenosine 3’,5’-cyclic monophosphate (cAMP).2Masyuk T.V. Masyuk A.I. La Russo N.F. Therapeutic targets in polycystic liver disease.Curr Drug Targets. 2015; ([Epub ahead of print])Google Scholar Experimental evidence suggests that cAMP controls different mechanisms in PLD including cell proliferation and fluid secretion. Indeed, intravenous administration of secretin, a major agonist of cAMP signaling in cholangiocytes via interaction with the basolaterally located secretin receptor, increases fluid secretion in hepatic cysts of patients with ADPKD.3Everson G.T. Emmett M. Brown W.R. et al.Functional similarities of hepatic cystic and biliary epithelium: studies of fluid constituents and in vivo secretion in response to secretin.Hepatology. 1990; 11: 557-565Google Scholar In cultured cystic cholangiocytes isolated from an animal model of ARPKD, the PCK rat, and from patients with ADPKD, elevated cAMP enhances cell proliferation, accelerates fluid secretion, and affects cell cycle progression via its down-stream modulators PKA, EPAC, and ERK1/2/MEK.2Masyuk T.V. Masyuk A.I. La Russo N.F. Therapeutic targets in polycystic liver disease.Curr Drug Targets. 2015; ([Epub ahead of print])Google Scholar, 4Banales J.M. Masyuk T.V. Gradilone S.A. et al.The cAMP effectors Epac and protein kinase a (PKA) are involved in the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD).Hepatology. 2009; 49: 160-174Google Scholar, 5Banales J.M. Masyuk T.V. Bogert P.S. et al.Hepatic cystogenesis is associated with abnormal expression and location of ion transporters and water channels in an animal model of autosomal recessive polycystic kidney disease.Am J Pathol. 2008; 173: 1637-1646Google Scholar Together, these observations suggest an important role for cAMP machinery in PLD implicating elevated cAMP as a potential therapeutic target. Somatostatin and its synthetic analogues (eg, octreotide and pasireotide), by binding to somatostatin receptors (SSTRs), inhibit cAMP production in different cell types including cholangiocytes. Suppression of cAMP is triggered in response to activation of any of 5 known SSTRs, whereas inhibition of cell proliferation occurs predominantly via SSTR2 and SSTR5 and, in some cases, SSTR1 and SSTR3.6Masyuk T.V. Radtke B.N. Stroope A.J. et al.Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases.Hepatology. 2013; 58: 409-421Google Scholar All 5 SSTRs are present in rat and human cholangiocytes and decreased levels of SSTR1 and SSTR2 (but not SSTR3 and SSTR5) has been observed in liver cysts.6Masyuk T.V. Radtke B.N. Stroope A.J. et al.Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases.Hepatology. 2013; 58: 409-421Google Scholar Experimental in vitro models of hepatic cystogenesis have demonstrated that enhanced cholangiocyte proliferation and increased fluid secretion were abolished after treatment with somatostatin analogues.4Banales J.M. Masyuk T.V. Gradilone S.A. et al.The cAMP effectors Epac and protein kinase a (PKA) are involved in the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD).Hepatology. 2009; 49: 160-174Google Scholar, 6Masyuk T.V. Radtke B.N. Stroope A.J. et al.Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases.Hepatology. 2013; 58: 409-421Google Scholar, 7Masyuk T.V. Masyuk A.I. Torres V.E. et al.Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate.Gastroenterology. 2007; 132: 1104-1116Google Scholar Attenuated hepatic cystogenesis and decreased fibrotic scores were also observed in several animal models of PLD in response to cAMP inhibition by octreotide and pasireotide. Importantly, repressed cystogenesis was accompanied by reduced cAMP levels in serum and in freshly isolated cholangiocytes from octreotide-treated PCK rats.6Masyuk T.V. Radtke B.N. Stroope A.J. et al.Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases.Hepatology. 2013; 58: 409-421Google Scholar, 7Masyuk T.V. Masyuk A.I. Torres V.E. et al.Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate.Gastroenterology. 2007; 132: 1104-1116Google Scholar In line with these preclinical studies, several case reports supported the use of somatostatin analogue therapy in PLD. Total liver volume was reduced after 3 and 6 months of treatment with octreotide by 14.9% and 38.3% in 2 patients with PLD, respectively.8van Keimpema L. de Man R.A. Drenth J.P. Somatostatin analogues reduce liver volume in polycystic liver disease.Gut. 2008; 57: 1338-1339Google Scholar In a patient with ADPKD who received lanreotide for 6 months, total liver volume was decreased by 10%.9Gevers T.J. Drenth J.P. Somatostatin analogues for treatment of polycystic liver disease.Curr Opin Gastroenterol. 2011; 27: 294-300Google Scholar Another case report documented 6.3% reduction in total liver volume after 12 months of octreotide therapy.10Peces R. Cuesta-Lopez E. Peces C. et al.Octreotide reduces hepatic, renal and breast cystic volume in autosomal-dominant polycystic kidney disease.Int Urol Nephrol. 2011; 43: 565-569Google Scholar Finally, in a larger case series (8 patients treated with short-acting octreotide for 135 days), a 3% decrease in liver volume was described.11van Keimpema L. Drenth J.P. Effect of octreotide on polycystic liver volume.Liver Int. 2010; 30: 633-634Google Scholar Together, the preclinical findings and several case reports set the stage for several randomized clinical trials to examine the efficacy of long-acting release somatostatin analogues (octreotideLAR and lanreotide) in patients with PLD. In the current issue of Clinical Gastroenterology and Hepatology, Pisani et al12Pisani A. Sabbatini M. Imbriaco M. et al.Long-term effects of octreotide on liver volume in patients with polycystic kidney and liver disease..Clin Gastroenterol Hepatol. 2016; 14: 1022-1030Abstract Full Text Full Text PDF Scopus (35) Google Scholar evaluated the effects of octreotideLAR therapy on total liver volume in patients with relatively mild PLD in a 3-year prospective, randomized, placebo-controlled trial followed by a 2-year recovery period. Patients were divided into octreotideLAR-treated (n = 14) and placebo-treated (n = 13) groups. In the octreotideLAR group, total liver volume was decreased by 130.2 ± 133.2 mL (ie, 7.8 ± 7.4%; P = .003) over the 3-year treatment period, whereas in the placebo group an increase of 144.3 ± 316.8 mL (ie, 6.1 ± 14.1%; P = .0002) was observed. At the end of treatment, total liver volume was 357.7 ± 619.9 mL smaller in patients receiving octreotideLAR compared with control subjects. During the 2-year recovery, total liver volume increased in octreotideLAR group by 115.8 ± 127.4 mL (9.7 ± 0.2 %) and by 80.1 ± 90.0 mL (4.9 ± 7.2%) in patients originally randomized to placebo. Despite the liver regrowth during off treatment, over the 5 years of observation total liver volume in octreotideLAR patients was decreased by 14.4 ± 138.4 mL (0.8 ± 9.7%) but increased by 224.4 ± 331.7 mL (11.0 ± 14.4%) in those on placebo. Overall, by the end of 5-year period, total liver volume was 322.1 ± 604.9 mL smaller in patients originally randomized to octreotideLAR than in control subjects. Interestingly, the reduction in total liver volume during treatment and recovery to baseline values after treatment did not correlate with mean baseline liver volume (ie, below or above the median) in octreotideLAR group. In contrast, in the control arm, liver growth was faster in patients with larger total liver volume than in those with smaller livers. Besides the study described here, several other clinical trials have tested the effects of somatostatin analogues in PLD (Table 1). Van Kiempema et al13van Keimpema L. Nevens F. Vanslembrouck R. et al.Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2009; 137 (e1661–1662): 1661-1668Google Scholar reported that 27 patients treated with lanreotide for 6 months experienced a reduction of 2.9% in total liver volume, whereas in subjects randomized to placebo (n = 27) a 1.6% increase was documented. In the 12 months of open-label study, an overall 4% decrease in total liver volumes was further observed in 41 participants.14Chrispijn M. Nevens F. Gevers T.J. et al.The long-term outcome of patients with polycystic liver disease treated with lanreotide.Aliment Pharmacol Ther. 2012; 35: 266-274Google Scholar Caroli et al15Caroli A. Antiga L. Cafaro M. et al.Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide.Clin J Am Soc Nephrol. 2010; 5: 783-789Google Scholar described a 71 ± 57 mL reduction in total liver volume in response to octreotideLAR in 12 patients with ADPKD after 6 months of treatment. Hogan et al16Hogan M.C. Masyuk T.V. Page L.J. et al.Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.J Am Soc Nephrol. 2010; 21: 1052-1061Google Scholar randomly allocated 42 patients to octreotideLAR (n = 28) or placebo (n = 14) treatment for 12 months. As a result, liver growth was decreased by 4.95% in the octreotideLAR group compared with 0.9% increase in placebo group. A total of 41 patients participated in open-label extension study for an additional 12 months.17Hogan M.C. Masyuk T.V. Page L. et al.Somatostatin analog therapy for severe polycystic liver disease: results after 2 years.Nephrol Dial Transplant. 2012; 27: 3532-3539Google Scholar In subjects initially randomized to placebo, liver volume decreased by 7.66% but was sustained in patients initially treated with octreotide. In pooled analysis, after 12 months of octreotide treatment total liver volume declined an average of 6.08%. This study was extended again for an additional 24 months after 8.3 months off therapy during which liver growth was increased toward the baseline.18Hogan M.C. Masyuk T. Bergstralh E. et al.Efficacy of 4 years of octreotide long-acting release therapy in patients with severe polycystic liver disease.Mayo Clin Proc. 2015; 90: 1030-1037Google Scholar Twenty-four patients that underwent 2 additional years of treatment experienced a reduction of 4.7% per year in total liver volume. Therefore, after 4 years of octreotideLAR therapy, liver growth declined by 11.8%.18Hogan M.C. Masyuk T. Bergstralh E. et al.Efficacy of 4 years of octreotide long-acting release therapy in patients with severe polycystic liver disease.Mayo Clin Proc. 2015; 90: 1030-1037Google Scholar In addition, 2 other nonplacebo controlled clinical trials showed beneficial effects of somatostatin analogues in PLD.19Temmerman F. Ho T.A. Vanslembrouck R. et al.Lanreotide reduces liver volume, but might not improve muscle wasting or weight loss, in patients with symptomatic polycystic liver disease.Clin Gastroenterol Hepatol. 2015; 13 (e2351): 2353-2359Abstract Full Text Full Text PDF Scopus (24) Google Scholar, 20Chrispijn M. Gevers T.J. Hol J.C. et al.Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial.J Hepatol. 2013; 59: 153-159Google Scholar Thus, based on these studies, it is reasonable to conclude that (1) treatment with somatostatin analogues for 6–12 months decreases total liver volume; (2) reduction in liver volume is sustained beyond 12 months of therapy; (3) response to treatment varies among patients with some (∼15%) nonresponders; (4) once therapy is stopped, liver volume starts to increase toward baseline suggesting that long-term continuous or intermittent treatment is required; (5) somatostatin analogues are well tolerated and improve quality of life; and (6) similar changes in liver volume in response to treatment occurs in patients with ADPKD-associated PLD or isolated autosomal-dominant PLD.Table 1Studies Evaluating Somatostatin Analogues in PLDDrugTreatment durationPatientsTLV (mL)Placebo groupTLV (mL)Treatment groupRefBaselineAfter treatment% ChangeBaselineAfter treatment% ChangeLanreotide (120 mg)6 months54468948951.646064471-2.913van Keimpema L. Nevens F. Vanslembrouck R. et al.Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2009; 137 (e1661–1662): 1661-1668Google Scholar12 months (OLE)41—49744711-4.014Chrispijn M. Nevens F. Gevers T.J. et al.The long-term outcome of patients with polycystic liver disease treated with lanreotide.Aliment Pharmacol Ther. 2012; 35: 266-274Google ScholarNOTE. After 6 month off treatment, TLV increases by 4% toward baseline.Octreotide (40 mg)6 months12158015940.915951524-4.515Caroli A. Antiga L. Cafaro M. et al.Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide.Clin J Am Soc Nephrol. 2010; 5: 783-789Google ScholarOctreotide (40 mg)6 months42537453610.9259075628-5.016Hogan M.C. Masyuk T.V. Page L.J. et al.Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.J Am Soc Nephrol. 2010; 21: 1052-1061Google Scholar, 17Hogan M.C. Masyuk T.V. Page L. et al.Somatostatin analog therapy for severe polycystic liver disease: results after 2 years.Nephrol Dial Transplant. 2012; 27: 3532-3539Google Scholar, 18Hogan M.C. Masyuk T. Bergstralh E. et al.Efficacy of 4 years of octreotide long-acting release therapy in patients with severe polycystic liver disease.Mayo Clin Proc. 2015; 90: 1030-1037Google Scholar12 months (OLE)41Patients received octreotide after 12 months of placebo5649-0.7753604952-7.7NOTE. Pooled data in patients who received octreotide (for 12 or 24 months) show 6.8% overall reduction in TLV.24 months(OLE)28—58635617aReduction in TLV after 12 months of treatment.-4.75304bReduction in TLV after 24 months of treatment.NOTE. After 8.3 months off treatment, TLV increased by 4% toward baseline.Over 4-year period of treatment, TLV was reduced by 11.8%.Octreotide (40 mg)48 weeks23No placebo group64765751-3.5%20Chrispijn M. Gevers T.J. Hol J.C. et al.Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial.J Hepatol. 2013; 59: 153-159Google ScholarNOTE. In this trial combinational effect of octreotide and everolimus was assessed. Result of monotherapy (ie, octreotide only) was included in this table.Lanreotide (90 mg)6 months53No placebo group5244512119Temmerman F. Ho T.A. Vanslembrouck R. et al.Lanreotide reduces liver volume, but might not improve muscle wasting or weight loss, in patients with symptomatic polycystic liver disease.Clin Gastroenterol Hepatol. 2015; 13 (e2351): 2353-2359Abstract Full Text Full Text PDF Scopus (24) Google Scholar12 monthsNOTE. After 6 months of treatment lanreotide dose was increased to 120 mg in nonresponders for additional 12 months of treatment.OLE, open-label extension; TLV, total liver volume.a Reduction in TLV after 12 months of treatment.b Reduction in TLV after 24 months of treatment. Open table in a new tab OLE, open-label extension; TLV, total liver volume. Two somatostatin analogues, octreotide and lanreotide, have been used in clinical trials. A dose of 120 mg of lanreotide is equivalent to 60 mg of octreotide.16Hogan M.C. Masyuk T.V. Page L.J. et al.Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.J Am Soc Nephrol. 2010; 21: 1052-1061Google Scholar Current somatostatin analogues target mainly SSTR2, the expression of which seems to be decreased in hepatic cysts.6Masyuk T.V. Radtke B.N. Stroope A.J. et al.Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases.Hepatology. 2013; 58: 409-421Google Scholar Another somatostatin analogue, pasireotide, has high affinity to 4 SSTRs, with IC50 of 9.3 nM (SSTR1), 1.0 nM (SSTR2), 1.5 nM (SSTR3), and 0.16 nM (SSTR5). Pasireotide is more stable (ie, 12-hour half-life) than octreotide (ie, 70–113 minutes). Therefore, pasireotide might be promising therapy for patients that did not respond to octreotide treatment. A comparative preclinical study demonstrated that pasireotide suppresses hepatic and renal cystogenesis more efficiently than octreotide.6Masyuk T.V. Radtke B.N. Stroope A.J. et al.Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases.Hepatology. 2013; 58: 409-421Google Scholar A clinical trial assessing the efficacy of pasireotide is now underway at Mayo Clinic. The clinical trial published in the current issue of Clinical Gastroenterology and Hepatology12Pisani A. Sabbatini M. Imbriaco M. et al.Long-term effects of octreotide on liver volume in patients with polycystic kidney and liver disease..Clin Gastroenterol Hepatol. 2016; 14: 1022-1030Abstract Full Text Full Text PDF Scopus (35) Google Scholar is one more in the line of several others that described the efficacy of somatostatin analogues in PLD. How does this study differ from previously reported? As shown in Table 1, all13van Keimpema L. Nevens F. Vanslembrouck R. et al.Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2009; 137 (e1661–1662): 1661-1668Google Scholar, 14Chrispijn M. Nevens F. Gevers T.J. et al.The long-term outcome of patients with polycystic liver disease treated with lanreotide.Aliment Pharmacol Ther. 2012; 35: 266-274Google Scholar, 16Hogan M.C. Masyuk T.V. Page L.J. et al.Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.J Am Soc Nephrol. 2010; 21: 1052-1061Google Scholar, 17Hogan M.C. Masyuk T.V. Page L. et al.Somatostatin analog therapy for severe polycystic liver disease: results after 2 years.Nephrol Dial Transplant. 2012; 27: 3532-3539Google Scholar, 18Hogan M.C. Masyuk T. Bergstralh E. et al.Efficacy of 4 years of octreotide long-acting release therapy in patients with severe polycystic liver disease.Mayo Clin Proc. 2015; 90: 1030-1037Google Scholar, 19Temmerman F. Ho T.A. Vanslembrouck R. et al.Lanreotide reduces liver volume, but might not improve muscle wasting or weight loss, in patients with symptomatic polycystic liver disease.Clin Gastroenterol Hepatol. 2015; 13 (e2351): 2353-2359Abstract Full Text Full Text PDF Scopus (24) Google Scholar, 20Chrispijn M. Gevers T.J. Hol J.C. et al.Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial.J Hepatol. 2013; 59: 153-159Google Scholar (but one15Caroli A. Antiga L. Cafaro M. et al.Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide.Clin J Am Soc Nephrol. 2010; 5: 783-789Google Scholar) clinical studies involved patients with severe PLD (median total liver volumes range, 4606–6476 mL). Patients included in the trial conducted by Pisani et al12Pisani A. Sabbatini M. Imbriaco M. et al.Long-term effects of octreotide on liver volume in patients with polycystic kidney and liver disease..Clin Gastroenterol Hepatol. 2016; 14: 1022-1030Abstract Full Text Full Text PDF Scopus (35) Google Scholar had relatively small median liver volumes at baseline (ie, 1477 mL in octreotideLAR group and 1637 mL in placebo group). Despite earlier observations that patients with very enlarged livers respond to treatment more efficiently than those with smaller livers,16Hogan M.C. Masyuk T.V. Page L.J. et al.Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.J Am Soc Nephrol. 2010; 21: 1052-1061Google Scholar a substantial reduction of 7.8% in total liver volumes was detected in response to octreotideLAR therapy in patients with relatively small livers. This observation suggests that although clinical symptoms are the basis for the enrollment in clinical trials, baseline liver volume might also be taken to consideration. Moreover during 2 years off therapy, the liver volumes continued to decrease in octreotideLAR patients as compared with the placebo group suggesting that early intervention might not only halt the growth of liver cysts but even reduce subsequent rate of liver cystogenesis. Finally, given that somatostatin analogues for PLD treatment are not approved by the Food and Drug Administration and therapy is expensive (ie, $7,000-$11,000 per month for patients with health insurance who have to obtain preapproval usually on a case-by-case basis) it may be reasonable to consider an on/off therapy regimen; this is perhaps the major implication of the work by Pisani et al. In conclusion, this study demonstrated that treatment of PLD at early stages might not only stabilize but may consistently reduce total liver volume preventing further suffering. However, an extended study with a larger number of patients to detect the long-term beneficial efficacy and safety profiles of somatostatin analogues, and the utility of an on/off approach, is necessary. Long-term Effects of Octreotide on Liver Volume in Patients With Polycystic Kidney and Liver DiseaseClinical Gastroenterology and HepatologyVol. 14Issue 7PreviewShort-term studies have shown that somatostatin analogues are effective in patients with polycystic kidney and liver disease. We evaluated the long-term effects of long-acting release octreotide (octreotide LAR), a somatostatin inhibitor, vs placebo in these patients. Full-Text PDF