Questionnaire PLD-complaint-specific assessment identifies need for therapy in polycystic liver disease: A multi-centric prospective study.

BACKGROUND AND AIMS: Polycystic liver disease (PLD) can lead to extensive hepatomegaly. Symptom relief is the primary goal of the treatment. The role of the recently developed disease-specific questionnaires for identification of the thresholds and the assessment of therapy needs further investigation. METHODS: A five-year prospective multi-centric observational study in 21 hospitals in Belgium gathered a study population of 198 symptomatic PLD-patients of whom the disease-specific symptom questionnaire PLD-complaint-specific assessment (POLCA) scores were calculated. The thresholds of the POLCA score for the need for volume reduction therapy were analyzed. RESULTS: The study group consisted of mostly (82.8%) women with baseline mean age of 54.4 years ±11.2, median liver volume expressed as height-adjusted total liver volume(htLV) of 1994 mL (interquartile range [IQR] 1275; 3150) and median growth of the liver of +74 mL/year (IQR +3; +230). Volume reduction therapy was needed in 71 patients (35.9%). A POLCA severity score (SPI) ≥ 14 predicted the need for therapy both in the derivation (n = 63) and the validation cohort (n = 126). The thresholds to start somatostatin analogues (n = 55) or to consider liver transplantation (n = 18) were SPI scores of ≥14 and ≥ 18 and the corresponding mean htLVs were 2902 mL (IQR 1908; 3964) and 3607 mL (IQR 2901; 4337), respectively. Somatostatin analogues treatment resulted in a decrease in the SPI score -6.0 versus + 4.5 in patients without somatostatin analogues (p < 0.01). Changes in the SPI score were significantly different between the liver transplantation group and no liver transplantation group, +4.3 ± 7.1 versus -1.6 ± 4.9, respectively, (p < 0.01). CONCLUSION: A polycystic liver disease-specific questionnaire can be used as a guide on when to start a volume reduction therapy and to assess the effect of treatment.

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.

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.

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 Cronbach's 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.

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

BACKGROUND: 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 METHODS: All 70 consecutive patients (>16 years) who underwent a percutaneous ASD closure between November 2003 and December 2005 in one of the two participating centers were included in the study. On the basis of standardized headache questionnaire, two independent neurologists diagnosed migraine with or without aura (MA+ and MA-, respectively) according to the International Headache Society criteria, before, 6 and 12 months after closure. RESULTS: Sixty-eight patients (97%; mean age 47.3 + or - 16.4 years; 22% men) agreed to participate in the study and completed the questionnaire. Before ASD closure, the overall prevalence of migraine was 34%, MA+ 22% and MA- 12%. At 6 months follow-up, the headache questionnaire was completed by 63 patients (93%) and the prevalence of overall migraine decreased to 19%, MA+ to 8% and MA- to 11% (Mc Nemar test, P = 0.08, P = 0.07, and P = 1.0, respectively). At 12 months, the prevalence of migraine decreased further to 12%, MA+ to 5% and MA- to 7% (McNemar test, P = 0.003, P = 0.04, and P = 0.29 versus at inclusion, respectively) based on a completed headache questionnaire of 57 patients (84%). CONCLUSION: We found a high prevalence of migraine in patients with an ASD, and observed prospectively a reduction in the occurrence of migraine, especially migraine with aura, 1 year after percutaneous closure.

Closure of a patent foramen ovale is associated with a decrease in prevalence of migraine: a prospective observational study.

BACKGROUND: A causal relationship between migraine and a right-to-left shunt, due to a patent foramen ovale (PFO), has been suggested. In mainly retrospective studies, percutaneous closure of a PFO has been associated with a decrease in the prevalence of migraine. OBJECTIVE: In this prospective observational study we evaluated whether percutaneous closure of a PFO is associated with a decrease in the prevalence of migraine. METHODS: Between November 2003 and August 2005, we included 92 patients (age >16 years) who underwent a percutaneous closure of a symptomatic PFO, which was considered to be related to a paradoxical embolism.They received a headache questionnaire before and six months after closure.Two neurologists diagnosed migraine, according to the International Headache Criteria. RESULTS: Eighty-nine of 92 patients (97%, mean age 51.6 +/- 12.3 years, 63 men) completed the questionnaire immediately before PFO closure.The overall prevalence of migraine was 27.0%, for migraine without aura (MA-) 15.7%, and for migraine with aura (MA+) 11.2%. After more than six months of follow-up 84 of 89 patients (94%, mean age 52.1 +/- 12.0 years, 60 men) returned the questionnaire. The overall prevalence of migraine in this group decreased from 28.6% to 10.7% (P = 0.001), for MA-from 16.7% to 8.3% (P = 0.07), and for MA+ from 11.9% to 2.4% (P = 0.02). CONCLUSIONS: Percutaneous PFO closure is related to a decrease in the prevalence of migraine in this prospective observational study. However, randomized placebo controlled trials have to confirm these findings.