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Abstract

Massive polycystic liver may be the source of severe discomfort, early satiety, pain, dyspnea, and finally denutrition. This is in part due to the increase with age in the number of hepatic cysts, but also because the individual cyst volume grows from 0.25 to 22.8 ml over 20 years. Polycystic liver is found in two inherited disorders—autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (PCLD), an infrequent disorder in which no kidney cysts are detected caused by mutations in PKRCSH or SEC63 genes. Studies in ADPKD have indicated that total liver cyst volume and the prevalence of massive polycystic liver are greater in women than in men. Liver cysts arise from cholangiocytes. Secretin is a potent stimulator of adenylate cyclase and thus of cAMP generation. cAMP acts by two major mechanisms: increased electrolyte and water secretion and stimulation of cholangiocyte proliferation. Conversely, somatostatin inhibits cAMP production and thus fluid secretion and proliferation. Additional experimental and clinical data supported the project of initiating a clinical trial of somatostatin analogues on liver cyst progression. Octreotide, a somatostatin analogue, prevented outgrowth of liver and kidney cysts in polycystic kidney (PCK) rats. In contrast, antagonists of the V2 vasopressin receptor have no effect on liver cysts that do not express this receptor, whereas they prevent or slow the progression of renal cysts in various experimental models. In two patients with polycystic livers, a 3- to 6-month treatment with somatostatin analogues led to impressive reductions in liver volume (1). Finally, a randomized, placebo-controlled trial in ADPKD patients using slow-release octreotide (40 mg) showed that kidney volume increase could be reduced by 60% at 6 months compared with placebo but there was an ongoing increase of kidney volume—2.2% in the octreotide group versus 5.9% in the placebo group (2). Van Keimpema et al. (1) designed a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effects of the long-acting somatostatin analogue, lanreotide autosolution (120 mg), or placebo administered subcutaneously every 28 days for 24 weeks in patients with polycystic liver due to ADPKD (32 patients) or PLCD (22 patients). The high percentage of PLCD is explained by the fact that the initiators of and participants in this trial were gastroenterologists and hepatologists. The primary end point was change in liver volume measured on computed tomography (CT) scan at baseline and after 24 weeks of treatment. Health-related quality of life was a secondary end point. Of 113 consecutive patients assessed during the study period, 54 were included in the trial. Relatively more PCLD patients (68%) than ADPKD patients (38%) received lanreotide. The mean liver volume decreased from 4606 to 4471 ml (i.e., an average reduction of 2.9%) whereas there was an average increase of 1.6% in patients receiving lanreotide and in those in the placebo group, respectively. Eighty-five percent of patients on lanreotide showed a decrease of liver volume, compared with 27% of those receiving placebo. Larger livers had proportionally more volume reduction than smaller livers. In the subgroup of patients with ADPKD, mean kidney volume decreased by 1.5% with lanreotide, whereas it increased in the placebo group (P = 0.02). Current health perception improved in lanreotide-treated patients. The most common adverse effect of lanreotide consisted of loose, pale, and fatty stools (19 patients), which were relieved by pancreatic enzymes. Gamma-glutamyl transferase levels increased in the lanreotide group, possibly reflecting increased cyst epithelium degeneration. In this trial, no correlation was found between lanreotide serum levels and response to treatment. Little is known about the optimal dosage of somatostatin analogues. The authors chose for the highest licensed dose of lanreotide. Lanreotide at 120 mg is equivalent to octreotide at 60 mg. However, somatostatin receptor affinity of octreotide is higher compared with that of lanreotide. The results of this trial are very encouraging. Aspiration and sclerosis, laparoscopic fenestration, or hepatic resection have led to disappointing or limited results in women with massive polycystic liver. Combined liver and kidney transplantation has been mandatory in some of them. Noninvasive effective therapy is eagerly awaited. Another trial with a somatostatin analogue is in progress.