Frederik Temmerman

Systematic review: the pathophysiology and management of polycystic liver disease

Aliment Pharmacol Ther 2011; 34: 702–713

Safety and efficacy of different lanreotide doses in the treatment of polycystic liver disease: pooled analysis of individual patient data

Long‐acting lanreotide (LAN) 120 mg every 4 weeks reduces liver volume (LV) in patients with polycystic liver diseases (PCLD). Animal studies demonstrated that the inhibition of hepatic and renal cystogenesis is dose dependent.

Is a predominant left‐to‐right shunt associated with migraine?: A prospective atrial septal defect closure study

A right‐to‐left shunt, as seen in patients with a patent foramen ovale, seems to be associated with migraine. An atrial septal defect (ASD), however, is characterized by a predominant left‐to‐right shunt (LRS). We prospectively evaluated the effect of percutaneous ASD closure on migraine

Development and validation of a polycystic liver disease complaint-specific assessment (POLCA)

BACKGROUND & AIMS Polycystic liver disease (PCLD) may lead to extensive hepatomegaly and invalidating complaints. Therapeutic decisions, including somatostatin-analogues (SAs) and (non)-transplant surgery are besides the existence of hepatomegaly, also guided by the severity of complaints. We developed and validated a self-report instrument to capture the presence and severity of disease specific complaints for PCLD. METHODS The study population consisted of 129 patients. Items for the PCLD-complaint-specific assessment (POLCA) were developed based on the chart review of symptomatic PCLD patients (n=68) and literature, and discussed during expert-consensus-meetings. 61 patients who needed therapy were asked to complete the POLCA and the short form health survey version 2 (SF36V2) at baseline and after 6 months of SA-treatment. CT-scans were used to calculate liver volumes (LV). Factor analysis was conducted to identify subscales and remove suboptimal items. Reliability was assessed by Cronbachs alpha. Convergent, criterion validity and responsiveness were tested using prespecified hypotheses. RESULTS In the validation group (n=61), 47 received lanreotide (LAN) and 14 were offered LAN as bridge to liver transplantation (LTx). Factor analysis identified four subscales, which correlated with the physical component summary (PCS). Baseline POLCA scores were significantly higher in LTx-listed patients. In contrast to SF36V2, POLCA-paired observations in 47 patients demonstrated that 2 subscales were lowered significantly and 2 borderline. LV reduction of ⩾ 120 ml resulted in a numerical, more pronounced relative decrease of all scores. CONCLUSIONS In contrast to SF36V2, the POLCA shows good validity and responsiveness to measure complaint severity in PCLD.

Lanreotide Reduces Liver Volume, But Might Not Improve Muscle Wasting or Weight Loss, in Patients With Symptomatic Polycystic Liver Disease

BACKGROUND & AIMS Polycystic liver disease (PCLD) can induce malnutrition owing to extensive hepatomegaly and patients might require liver transplantation. Six months of treatment with the somatostatin analogue lanreotide (120 mg) reduces liver volume. We investigated the efficacy of a lower dose of lanreotide and its effects on nutritional status. METHODS We performed an 18-month prospective study at 2 tertiary medical centers in Belgium from January 2011 through August 2012. Fifty-nine patients with symptomatic PCLD were given lanreotide (90 mg, every 4 weeks) for 6 months. Patients with reductions in liver volume of more than 100 mL (responders, primary end point) continued to receive lanreotide (90 mg) for an additional year (18 months total). Nonresponders were offered increased doses, up to 120 mg lanreotide, until 18 months. Liver volume and body composition were measured by computed tomography at baseline and at months 6 and 18. Patients also were assessed by the PCLD-specific complaint assessment at these time points. RESULTS Fifty-three patients completed the study; 21 patients (40%) were responders. Nineteen of the responders (90%) continued as responders until 18 months. At this time point, they had a mean reduction in absolute liver volume of 430 ± 92 mL. In nonresponders (n = 32), liver volume increased by a mean volume of 120 ± 42 mL at 6 months. However, no further increase was observed after dose escalation in the 24 patients who continued to the 18-month end point. All subjects had decreased scores on all subscales of the PCLD-specific complaint assessment, including better food intake (P = .04). Subjects did not have a mean change in subcutaneous or visceral fat mass, but did have decreases in mean body weight (2 kg) and total muscle mass (1.06 cm(2)/h(2)). Subjects also had a significant mean reduction in their level of insulin-like growth factor 1, from 19% below the age-adjusted normal range level at baseline to 50% at 18 months (P = .002). CONCLUSIONS In a prospective study, we observed that low doses of lanreotide (90 mg every 4 weeks) reduced liver volumes and symptoms in patients with PCLD. However, patients continued to lose weight and muscle mass. The effects of somatostatin analogues on sarcopenia require investigation. Clinicaltrials.gov: NCT01315795.

Reply to: “Development and validation of a polycystic liver disease complaint-specific assessment (POLCA) – Use of the Delphi technique for content validation”

reliability. The authors ask additional information concerning the applied method for ‘‘content validation’’. In this regard, we want to reply concisely. In brief, patients with polycystic liver disease (PCLD) may develop severe hepatomegaly and this may become very disabling. The interpretation of complaints expressed by these patients in terms of severity and impact on the health related quality of life is subjective but crucial, as decisions on medical treatment and even indication for liver transplantation are partially based on the severity of the reported complaints and, therefore, we developed and psychometrically validated the POLCA. We first organized a general informative session in which the conceptual framework defining the item generation process and psychometric properties. For content validation, we used the Nominal Group technique, in which the professional judgement by experts was guided by: an analysis of medical records from 68 patients including the transcripts of social workers and by a review of the literature. The board consisted of experts with different expertise dealing with these patients: hepatologists, nephrologists and abdominal transplant surgeons. In addition, experts both from a Dutch and French speaking tertiary center participated. Three consensus meetings were needed to downgrade the initial 27 items into 16 items. Based on that list, the POLCA questionnaire was compiled, which was again fine-tuned by phone conferences, and e-mail, to allow for comprehensiveness and clarity. All participants approved the final version. By doing this, we are convinced that we could overcome the limitations of the ‘‘Nominal group technique’’ that in one face-to-face meeting one expert influences the others. As was mentioned in the paper, severe symptomatic PCLD is a rare disease, and such pretesting of the questionnaire in symptomatic PCLD patients was not performed in order not to lose patients for the instrument’s validation. The validation of self-report instruments is a complex, continuous process and there is obviously a need for further studies. Further validation of the POLCA is currently being performed in 20 Belgian hospitals and data are expected within 2 years

Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease

AIM 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. METHODS 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. RESULTS 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. CONCLUSION 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.

O085 : Lanreotide reduces liver volume yet accelerates muscle wasting and weight loss in symptomatic polycystic liver disease

alpha diversity. Most genera separating PSC and HC were similar in PSC and UC. However, PSC patients exhibited a significantly increased abundance (2.8 fold) of the Veillonella genus compared to both HC and UC (p < 0.02). Conclusions: The fecal microbial profile in PSC patients was different from HC and UC patients without PSC, while the profiles in PSC patients with and without IBD were similar. Compared with HC and UC, PSC patients exhibited a marked increase in abundance of the Veillonella genus, which has also been linked to other conditions of fibrosis.