Long-term Efficacy of Octreotide in Patients with Polycystic Kidney and Liver Disease
Three years of long-acting release octreotide (octreotide LAR) significantly reduced liver volume in patients with polycystic kidney and liver disease, researchers found in a placebo-controlled study. These reductions, reported in the July issue of Clinical Gastroenterology and Hepatology, were maintained for 2 years after treatment ended.
Polycystic liver disease (PLD) is observed in up to 94% of patients with adult polycystic kidney disease (ADPKD). Symptoms of PLD, including early satiety, gastroesophageal reflux, pain, and dyspnea, are caused by massive cyst and liver enlargement. Major complications include hepatic venous outflow obstruction, compression of the inferior vena cava, portal vein compression, or bile duct compression leading to obstructive jaundice.
The only treatments have been cyst aspiration and sclerotherapy or fenestration or partial liver resection, but these invasive procedures do not affect cyst growth or slow disease progression. Liver transplantation is the only option for the most severe cases. The only medical treatment for PLD has been analgesics for relief pain and antimicrobial agents to treat infected cysts or biliary tract.
Octreotide is a somatostatin analogue with high affinity for the somatostatin receptor subtype 2. It has specific cytostatic activity against a variety of tumors and has been reported to prevent cyst growth.Antonio Pisani et al performed a long-term, randomized controlled trial to determine the risks and benefits of long-term somatostatin inhibition in 27 patients with ADPKD and concomitant PLD (estimated glomerular filtration rate, 40 mL/min/1.73m2 or more).
The patients were randomly assigned to groups given 40 g octreotide LAR (n = 14) or placebo (n = 13) each month for 3 years. Absolute and percentage changes in total liver volume (TLV) were measured by magnetic resonance imaging at baseline, after 3 years of treatment, and then 2 years after treatment ended.
Pisani et al found that after 3 years, TLV decreased by 130.2 ± 133.2 mL in patients given octreotide LAR (7.8% ± 7.4%) but increased by 144.3 ± 316.8 mL (6.1% ± 14.1%) in patients given placebo. Change vs baseline differed significantly between groups.
Two years after treatment ended, TLV had decreased 14.4 ± 138.4 mL (0.8% ± 9.7%) from baseline in patients given octreotide LAR but increased by 224.4 ± 331.7 mL (11.0% ± 14.4%) in patients given placebo.
Decreases in TLV were similar for each sex, and the change in TLV was greatest among subjects with larger baseline TLV. No patient withdrew because of side effects. Consistent with evidence that only approximately 1% of patients with octreotide-induced gallstones have symptoms per year of treatment, the authors observed only 1 episode of acute cholecystitis—the participant recovered with medical treatment.
Pisani et al conclude that octreotide LAR therapy achieved a significant and clinically relevant protective effect against progressive liver volume growth and was safe and well-tolerated in patients with ADPKD patients with relatively early liver involvement.
The benefit was sustained over time—3 years of octreotide LAR therapy delayed disease progression by approximately 5 years.
How does octreotide work? Renal tubular and biliary tract cells express somatostatin receptors, in particular subtype 2, so receptor activation by octreotide therapy might also help prevent or limit their uncontrolled proliferation in patients with ADPKD and/or PLD. Proliferation and secretion of renal tubular cells and cholangiocytes are regulated by adenosine 3′, 5′-cyclic monophosphate (cAMP), and fluid secretion via secondary transport of chloride can be reduced by somatostatin. Levels of cAMP are increased in kidneys and livers of rats with polycystic disease, so octreotide might reduce kidney and liver weights and mitotic indexes by reducing cAMP levels through interaction with specific tubular and biliary cells receptors.
The authors propose that the prolonged patient exposure period of their study could account for their ability to detect an effect despite the small sample size. They observed a significant effect even in men, challenging the hypothesis that the effects of somatostatin analogues were restricted to women.
Pisani et al state that the net benefit of octreotide LAR vs placebo was larger in patients with more severe hepatomegaly than in those with smaller livers to start with. They propose that somatostatin inhibition therapy may have a specific indication for men and women with ADPKD and liver volumes exceeding approximately 1500 mL. However, larger studies with longer follow-up are needed to assess the effects in patients with smaller livers, to determine whether early intervention prevents progression to more advanced and symptomatic stages of the disease.
The authors propose that the effects of octreotide are biphasic, with a faster short-term benefit followed by a sustained but to some extent slower effect in the long-term. This could be due to the immediate functional inhibition of cyst fluid secretion that may induce prompt cyst shrinkage and liver volume reduction, followed by a slower, progressive structural effect, related to inhibition of cholangiocyte proliferation and development of new cysts.
In an editorial that accompanies the article, Nicholas F. LaRusso et al write that given that somatostatin analogues for PLD treatment are not approved by the Food and Drug Administration and therapy is expensive ($7000-$11,000 per month for patients with health insurance who must obtain approval, usually on a case-by-case basis) it may be reasonable to consider an on and off therapy regimen.