Published online Aug 14, 2017. doi: 10.3748/wjg.v23.i30.5499
Peer-review started: March 2, 2017
First decision: April 5, 2017
Revised: May 16, 2017
Accepted: June 1, 2017
Article in press: June 1, 2017
Published online: August 14, 2017
Processing time: 167 Days and 10.6 Hours
To develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly.
Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls (n = 14), lanreotide (LAN: 3 mg/kg per 2 wk) (n = 10) or everolimus (EVR: 1 mg/kg per day) (n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene (quantitative RT-PCR) and protein expression (by Western blot) of the PI3K/AkT/mTOR signaling pathway was investigated.
LV determination by MRI correlated excellent with the ex vivo measurements (r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were: (controls) +31.8%; (LAN) +5.1% and (EVR) +8.8%, indicating a significantly halt of LV progression compared with controls (respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis (P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt (Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/AkT/mTOR signaling cascade but acting at different molecular levels.
Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR-inhibition should be further explored in PCLD patients especially those that need immunosuppression.
Core tip: The continuous increase of liver cysts volume in polycystic-liver-disease (PCLD) leads to extensive hepatomegaly and portal hypertension, an indication for liver transplantation. The effect of mTOR-inhibition on liver volume (LV) in PCLD is unclear. We developed an accurate, non-invasive, MRI-based method to determine LV in a PCLD rat model. When treatment is started at the moment of extensive hepatomegaly (as in humans), the mTOR inhibitor everolimus halt disease progression and also of the development of fibrosis in this model. We speculate that everolimus, given after kidney transplantation in patients with PCLD, can prevent the development of symptomatic hepatomegaly.