Drug holiday in patients with polycystic liver disease treated with somatostatin analogues.
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ABSTRACT: Background
Somatostatin analogues (SAs) reduce liver volume and relief symptoms in polycystic liver disease (PLD). Its effect wears off after continuing therapy suggesting development of SA tolerance in patients on chronic therapy. We postulate that a drug holiday resensitizes the liver to its acute pharmacological effects. Therefore, this study examines the liver volume-reducing effect of SAs after a drug holiday.Methods
Patients were identified from the International PLD Registry and included in our analysis when (1) treated with SAs during two cycles separated by a drug holiday and (2) height-adjusted total liver volume (hTLV) was available at start and end of each cycle. For our primary outcome we compared the effect of SAs (in % per 6 months) on hTLV between the first and second treatment cycle.Results
In 34 patients, initial liver volume-reducing effect was similar to that after rechallenge [-2.6% per 6 months (interquartile range, -3.8-0.8) versus -1.6% per 6 months (interquartile range, -3.1-1.1), p = 0.510]. Cessation of treatment led to a rebound effect, but liver volume remained stable compared with the baseline with intermittent therapy in responders to SA [-0.6% (interquartile range, -7.4-5.7) after 46.5 months].Conclusions
PLD patients treated with SAs benefit from retreatment after a drug holiday. The significant increase of liver volume after cessation of treatment complicates widespread use of a drug holiday as new treatment strategy. Our results contribute to a better understanding of the pharmacological effect of SAs and help to identify patients who might benefit.
SUBMITTER: van Aerts RMM
PROVIDER: S-EPMC6172936 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD.
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Project description: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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Project description:BackgroundA major difference between autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) lies in the pattern of inheritance, and the resultant timing and focality of cyst formation. In both diseases, cysts form in the kidney and liver as a consequence of the cellular recessive genotype of the respective disease gene, but this occurs by germline inheritance in ARPKD and somatic second hit mutations to the one normal allele in ADPKD. The fibrocystic liver phenotype in ARPKD is attributed to abnormal ductal plate formation because of the absence of PKHD1 expression during embryogenesis and organ development. The finding of polycystic liver disease in a subset of adult PKHD1 heterozygous carriers raises the question of whether somatic second hit mutations in PKHD1 in adults may also result in bile duct-derived cyst formation.MethodsWe used an adult-inducible Pkhd1 mouse model to examine whether Pkhd1 has a functional role in maintaining bile duct homeostasis after normal liver development.ResultsInactivation of Pkhd1 beginning at 4 weeks of age resulted in a polycystic liver phenotype with minimal fibrosis at 17 weeks. Increased biliary epithelium, which lines these liver cysts, was most pronounced in female mice. We assessed genetic interaction of this phenotype with either reduced or increased copies of Pkd1, and found no significant effects on the Pkhd1 phenotype in the liver or kidney from altered Pkd1 expression.ConclusionsSomatic adult inactivation of Pkhd1 results in a polycystic liver phenotype. Pkhd1 is a required gene in adulthood for biliary structural homeostasis independent of Pkd1. This suggests that PKHD1 heterozygous carrier patients can develop liver cysts after somatic mutations in their normal copy of PKHD1.
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