Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease

An International, Multicenter, Randomized Controlled Clinical Trial Assessing the Efficacy of Ursodeoxycholic Acid as a Volume Reducing Treatment in Symptomatic Polycystic Liver Disease

Rationale: Polycystic liver disease (PLD) is a rare disorder characterized by >20 fluid-filled hepatic cysts. Polycystic livers are present in the combination with renal cysts as a manifestation of autosomal dominant polycystic kidney disease (ADPKD), or isolated in the absence of renal cysts as autosomal dominant polycystic liver disease (ADPLD or PCLD). PLD patients are confronted with symptoms caused by the mass effect of their polycystic liver every day for the rest of their life. There is no standard therapeutic option for symptomatic PLD patients. Current options are fairly invasive or their efficacy is only moderate.

Preliminary data in our research lab have shown that ursodeoxycholic acid (UDCA) inhibited the proliferation of polycystic human cholangiocytes in vitro through the normalization of the intracellular calcium levels in cystic cholangiocytes. The investigators also found that daily oral administration of UDCA for 5 months to polycystic kidney disease (PCK) rats, an animal model of ARPKD that spontaneously develops hepato-renal cystogenesis, resulted in inhibition of hepatic cystogenesis.

The investigators hypothesize that UDCA is an effective therapeutic tool in reducing liver volume in PLD.

Objective: First, to demonstrate whether UDCA-therapy is effective in reducing total liver volume in PLD patients. Second, the investigators want to assess if UDCA modifies quality of life. Finally, the investigators want to assess safety and tolerability.

Study design: International, multicenter, randomized, controlled trial Study population: 34 subjects (18 ≤age ≤ 80 years) suffering from symptomatic polycystic liver disease with underlying diagnosis of (PCLD or ADPKD), defined as ≥ 20 liver cysts on CT-scan and liver volume of ≥ 2500. Symptomatic is defined as Eastern Cooperative Oncology Group- Performance Score (ECOG-PS) ≥ 1 and having at least three out of ten PLD symptoms.

Intervention: The patients will be randomized (1:1) into two groups. One group of patients will receive 15-20mg/kg/day UDCA for 24 weeks. The other group will receive standard care.

Main study endpoint: Proportional change of total liver volume in UDCA treated patients versus non treated patients, as assessed by CT at baseline and 6 months.

We investigated whether ursodeoxycholic acid was able to reduce total liver volume in polycystic liver disease.

Inclusion Criteria:

• 18 ≤ age ≤ 80 years
• Polycystic liver disease with underlying diagnosis of (PCLD or ADPKD), defined as ≥ 20 liver cysts
• Total liver volume ≥ 2500 mL
• Symptomatic defined as ECOG-PS ≥ 1 (2), and having at least three out of ten PCLD symptoms:
• Informed consent, patients are willing and able to comply with the study drug regimen and all other study requirements.

Exclusion Criteria:

• Use of oral anticonceptives or estrogen supplementation
• Use of UDCA in 3 months before baseline
• Females who are pregnant or breast-feeding or patients of reproductive potential not employing an effective method of birth control.
• Intervention (aspiration or surgical intervention) within six months before baseline
• Treatment with somatostatin analogues within six months before baseline
• Renal dysfunction (MDRD-Glomerular filtration rate< 30 ml/min/1.73m2)
• Patients with a kidney transplant
• Hypersensitivity reaction to UDCA or patients with galactose-intolerance, lactase deficiency or glucose-galactose malabsorption
• Acute cholecystitis or frequent biliary colic attacks
• Acute stomach or duodenal ulcers
• Inflammation of small intestine or colon
• Use of drugs that can interact with UDCA, such as colestyramine, aluminium hydroxide or cyclosporin
• Enrolment in another clinical trial of an investigational agent while participating in this study
• History or other evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study
• Mental illness that interferes with the patient ability to comply with the protocol