Longitudinal evaluation of individuals with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype).

BACKGROUND AND AIMS: Homozygous Pi*Z mutation in alpha-1 antitrypsin (Pi*ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only one organ, we systematically evaluated an international, multicenter, longitudinal, Pi*ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi*ZZ individuals from 25 different centers without known liver comorbidities that received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least six months. Cohort 2 consisted of 135 Pi*ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least two years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. 41 Pi*ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, i.e., LSM (24 vs. 5 kPa, p<.001) and AST-to-platelet ratio index (APRI, 1.1 vs. 0.3 units, p<.001). Liver-related endpoints within five years were most accurately predicted by LSM (area under the curve [AUC] 0.95) followed by APRI (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within five years (FEV1 AUC 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Non-invasive liver fibrosis surrogates accurately stratify liver-related risks in Pi*ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi*ZZ patients.

Higher need for polycystic liver disease therapy in female patients: Sex-specific association between liver volume and need for therapy.

BACKGROUND AND AIMS: Prognostic tools or biomarkers are urgently needed in polycystic liver disease (PLD) to monitor disease progression and evaluate treatment outcomes. Total liver volume (TLV) is currently used to assess cross-sectional disease severity, and female patients typically have larger livers than males. Therefore, this study explores the sex-specific association between TLV and volume-reducing therapy (VRT). APPROACH AND RESULTS: In this prospective cohort study, we included patients with PLD from European treatment centers. We explored sex-specific differences in the association between baseline TLV and initiation of volume-reducing therapy and determined the cumulative incidence rates of volume-reducing therapy in our cohort.We included 358 patients, of whom 157 (43.9%) received treatment. Treated patients had a higher baseline TLV (median TLV 2.16 vs. 4.34 liter, p < 0.001), were more frequently female (69.7% vs. 89.8%, p < 0.001), and had a higher risk of liver events (HR 4.381, p < 0.001). The cumulative volume-reducing therapy rate at 1 year of follow-up was 21.0% for females compared to 9.1% for males. Baseline TLV was associated with volume-reducing therapy, and there was an interaction with sex (HR females 1.202, p < 0.001; HR males 1.790, p < 0.001; at 1.5 l). CONCLUSION: Baseline TLV is strongly associated with volume-reducing therapy initiation at follow-up in patients with PLD, with sex-specific differences in this association. Disease staging systems should use TLV to predict the need for future volume-reducing therapy in PLD separately for males and females.

An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER: #NCT02900443.

Research gaps and opportunities in autoimmune hepatitis-Results of the international autoimmune hepatitis group research workshop 2022.

Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver-related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor-based treatments, a major unmet clinical need was identified in areas of care delivery and health-related quality of life.

Confidence in treatment is contributing to quality of life in autoimmune liver diseases. The results of ERN RARE-LIVER online survey.

BACKGROUND AND AIMS: Autoimmune liver diseases (AILDs) are associated with impaired health-related quality of life (HrQoL). The aim of this project was to identify potentially modifiable factors related to HrQoL in a large transnational cohort of patients with AILDs. METHODS: A cross-sectional online survey was conducted on patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or primary sclerosing cholangitis from 15 European countries. HrQoL was measured with EQ-5D-5L and EQ visual analogue scale (EQ-VAS) and analysed in relation to demographic, psychosocial, disease- and treatment-related factors. A Patient Health Questionnaire-2 score >3 indicated relevant depression. Multivariable linear regression analyses were used to identify potentially modifiable factors associated with HrQoL and confidence in treatment whilst adjusting for known confounders. RESULTS: A group of 1178 European patients (79% female, mean age 48 ± 14 years) participated in the study. HrQoL was impaired in all three diseases (mean EQ-5D-5L = 0.75, mean EQ VAS = 68.9), most markedly in PBC (mean EQ-5D-5L = 0.73, mean EQ-VAS = 66.2). Relevant depression, which was detected in 17% of patients, was prominently associated with impaired HrQoL. In the regression analysis, treatment confidence was identified as an important modifiable factor positively contributing to HrQoL. This influence was observable even after adjusting for other covariates including depression. Management in a transplant centre, treatment with azathioprine in AIH, and with ursodeoxycholic acid in PBC, was associated with increased treatment confidence. Finally, improved patient-physician relationships contributed to treatment confidence. CONCLUSION: Treatment confidence is a relevant modifiable determinant of HrQoL and should be further investigated to improve the standards of care for patients with AILDs.

Importance of complete response for outcomes of pregnancy in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: While some articles describe outcome of pregnancy in autoimmune hepatitis (AIH), there are less data evaluating influence of AIH control on maternal and perinatal outcomes. This study analysed outcomes of pregnancy and related possible risk factors in AIH. METHOD: A retrospective multicentre cohort study on pregnancy in AIH was performed in 11 hospitals in the Netherlands. Maternal and neonatal outcomes were collected from records and completed by interview. Risk factors-including incomplete response, relapse and cirrhosis-for adverse outcomes were identified using logistic regression analysis. RESULTS: Ninety-seven pregnancies in 50 women resulted in 70 deliveries (72%) with a live birth rate of 98.5%. AIH relapse occurred in 6% during pregnancy, and in 27% of post-partum episodes. Absence of complete biochemical response at conception was identified as risk factor for the occurrence of gestational and post-partum relapses. Relapse of AIH in the year before conception was a risk factor for the occurrence of both gestational relapses and post-partum relapses. No complete biochemical response increased the risk for hypertensive disorders during pregnancy and intrahepatic cholestasis of pregnancy (ICP). Cirrhosis was found to be a risk factor for miscarriages, but not for other outcomes. CONCLUSION: Pregnancy in AIH is related to an increased incidence of maternal and fetal/neonatal complications; in most cases, outcome is good. Incomplete biochemical response at conception or relapse in the year before conception are risk factors for gestational and post-partum relapses, for hypertensive disorders and for ICP. Cirrhosis was a risk factor for miscarriages.

Expanding the clinical application of the polycystic liver disease questionnaire: determination of a clinical threshold to select patients for therapy.

BACKGROUND: Polycystic liver disease (PLD) causes symptoms resulting from cystic volume expansion. The PLD-specific questionnaire (PLD-Q) captures symptom burden. This study aims to develop a threshold to identify patients with symptoms requiring further exploration and possibly intervention. METHODS: We recruited PLD patients with completed PLD-Qs during their patient journey. We evaluated baseline PLD-Q scores in (un)treated PLD patients to determine a threshold of clinical importance. We assessed our threshold's discriminative ability with receiver operator characteristic statistics, Youden Index, sensitivity, specificity, positive and negative predictive value parameters. RESULTS: We included 198 patients with a balanced proportion of treated (n=100) and untreated patients (n=98, PLD-Q scores 49 vs 19, p<0.001; median total liver volume 5827 vs 2185 ml, p<0.001). We established the PLD-Q threshold at 32 points. A score of ≥32 differentiates treated from untreated patients with an area under the ROC of 0.856, Youden Index 0.564, sensitivity of 85.0%, specificity of 71.4%, positive predictive value of 75.2%, and negative predictive value of 82.4%. Similar metrics were observed in predefined subgroups and an external cohort. CONCLUSION: We established the PLD-Q threshold at 32 points with high discriminative ability to identify symptomatic patients. Patients with a score ≥32 should be eligible for treatment or inclusion in trials.

Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment. METHODS: A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. RESULTS: The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as '<50% decrease of serum transaminases within 4 weeks after initiation of treatment'. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for 'any adverse event possibly related to treatment leading to potential drug discontinuation'. CONCLUSIONS: These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints. LAY SUMMARY: Consensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.

Abdominal wall hernia is a frequent complication of polycystic liver disease and associated with hepatomegaly.

BACKGROUND AND AIM: Polycystic liver disease (PLD) is related to hepatomegaly which causes an increased mechanical pressure on the abdominal wall. This may lead to abdominal wall herniation (AWH). We set out to establish the prevalence of AWH in PLD and explore risk factors. METHODS: In this cross-sectional cohort study, we assessed the presence of AWHs from PLD patients with at least 1 abdominal computed tomography or magnetic resonance imaging scan. AWH presence on imaging was independently evaluated by two researchers. Data on potential risk factors were extracted from clinical files. RESULTS: We included 484 patients of which 40.1% (n = 194) had an AWH. We found a clear predominance of umbilical hernias (25.8%, n = 125) while multiple hernias were present in 6.2% (n = 30). Using multivariate analysis, male sex (odds ratio [OR] 2.727 p < .001), abdominal surgery (OR 2.575, p < .001) and disease severity according to the Gigot classification (Type 3 OR 2.853, p < .001) were identified as risk factors. Height-adjusted total liver volume was an independent PLD-specific risk factor in the subgroup of patients with known total liver volume (OR 1.363, p = .001). Patients with multiple hernias were older (62.1 vs. 55.1, p = .001) and more frequently male (22.0% vs. 50.0%, p = .001). CONCLUSION: AWHs occur frequently in PLD with a predominance of umbilical hernias. Hepatomegaly is a clear disease-specific risk factor.

Treatment of Polycystic Liver Disease: Impact on Patient-reported Symptom Severity and Health-related Quality of Life.

Polycystic liver disease (PLD) is a genetic disorder in which patients suffer from progressive development of multiple (>10) hepatic cysts. Most patients remain asymptomatic during the course of their disease. However, a minority of PLD patients suffer from symptoms caused by hepatomegaly leading to serious limitations in daily life. Untreated symptomatic PLD patients score significantly worse on health-related quality of life (HRQoL) compared to age and gender-matched populations. Currently, liver transplantation is the only curative treatment for PLD. The main goal of other available therapies is to strive for symptomatic relief and improvement of HRQoL by suppressing disease progression. In this review, we summarize the effect of PLD treatment on patient-reported outcome measures with a distinction between HRQoL and symptom severity. At present there is heterogeneity in application of questionnaires and no questionnaire is available that measures both HRQoL and PLD symptom severity. Therefore, we recommend the combination of a validated PLD-specific symptom severity questionnaire and a general HRQoL questionnaire to evaluate treatment success as a minimal core set. However, the specific choice of questionnaires depends on treatment choice and/or research question. These questionnaires may serve as a biomarker of treatment response, failure, and adverse events.

Rapid Response to Treatment of Autoimmune Hepatitis Associated With Remission at 6 and 12 Months.

BACKGROUND & AIMS: Changes in serum levels of transaminases immediately after initiation of treatment for autoimmune hepatitis (AIH) might be associated with biochemical markers of remission and liver-related events. We assessed the outcomes of patients with vs without rapid response to treatment of AIH in a large international cohort. METHODS: We performed a retrospective cohort study, collecting data from 2 independent cohorts of adults with AIH from 12 centers in 7 countries in Europe. We collected information on patient demographics; serologic, histologic, and biochemical analyses; and treatment. We used a receiver operating characteristic curve and Youden index to calculate the optimal percentage decrease in level of aspartate aminotransferase (AST) after 8 weeks of treatment that associated with normalization of transaminase levels after 26 weeks of treatment with predniso(lo)ne (primary outcome) in the first (discovery) cohort (n = 370). We evaluated the results in the second (validation) cohort (n = 370). Secondary outcomes were liver-related death or transplantation. We performed univariate and multivariable logistic and Cox regression with correction for confounders. RESULTS: A significant decrease in level of AST after 8 weeks of treatment was significantly associated with normalization of transaminase levels at 26 and 52 weeks (P < .001); a decrease of more than 80% in level of AST was associated with optimal normalization. In both cohorts, rapid responders (≥80% decrease in level of AST after 8 weeks) were more likely to achieve normalization of transaminases at 26 and 52 weeks when compared to non-rapid responders. Rapid responders in the discovery cohort had lower risk of liver-related death or transplantation (adjusted hazard ratio 0.18; 95% CI 0.05-0.63; P = .007), although this was not confirmed in the validation cohort. Results from measurement of alanine aminotransferase did not differ significantly from those of AST for the primary outcome. Slow responders (without normalization of transaminases after 1 year) had the highest risk of liver transplantation or liver-related death. CONCLUSIONS: In a retrospective study of patients with AIH, we found that a rapid response to treatment, based on level of AST after 8 weeks, associates with normalization of transaminase levels in the following year. Patients with a rapid response also have a lower risk of liver-related death or transplantation than patients without this rapid response.

Lanreotide Reduces Liver Growth In Patients With Autosomal Dominant Polycystic Liver and Kidney Disease.

BACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD. METHODS: We performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume ≥2000 mL. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary endpoint was percent change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV. RESULTS: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI], -4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56-6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI, -9.18 to -2.63; P < .001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI, -7.55 to -0.18; P = .04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI, -10.25 to -4.12; P < .001). CONCLUSIONS: In this subanalysis of a randomized trial of patients with polycystic liver disease due to ADPKD, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide. ClinicalTrials.gov, Number: NCT01616927.

High discontinuation rate of azathioprine in autoimmune hepatitis, independent of time of treatment initiation.

BACKGROUND: Guidelines regarding treatment for autoimmune hepatitis (AIH) favour two strategies for azathioprine (AZA) introduction: concurrent with steroids at induction or delayed by 2-4 weeks. The safety and efficacy of both strategies have been unexplored. METHODS: We established a cohort of 900 AIH patients from 12 centres in 7 European countries. There were 631 patients who used AZA as part of the therapeutic regimen. We distinguished two groups: patients with early AZA (<2 weeks) or delayed AZA initiation (≥2 weeks). Primary outcome was discontinuation of AZA in the first year of treatment. Cox regression and propensity score matching was performed to determine difference in outcomes between groups. RESULTS: Patients with early AZA initiation had significantly lower transaminases and bilirubin at baseline. Discontinuation rates of AZA did not differ between early and delayed starters (16.6% vs 14.2%), which did not reach statistical significance (hazard ratio 0.97, 95% confidence interval 0.61-1.55, P = .90). Stratification according to baseline disease activity or propensity score matching did not alter the results. Main reason for AZA discontinuation was intolerance to treatment (14.0% vs 13.2%, P = .78) with nausea and vomiting as main side effects. AIH remission rates were comparable among groups. CONCLUSION: The discontinuation rate of AZA in AIH treatment is ~15% in the first year of treatment. Early or delayed AZA initiation does not differ in remission and discontinuation rates in AIH induction therapy. Our data suggest that either strategy may be used as part of AIH treatment.

Predniso(lo)ne Dosage and Chance of Remission in Patients With Autoimmune Hepatitis.

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) commonly receive induction therapy with predniso(lo)ne followed by maintenance therapy with azathioprine. European Association for Study of the Liver clinical practice guidelines advise a predniso(lo)ne dose range of 0.50-1 mg/kg/day, which leaves room for practice variation. We performed a multicenter study to determine the efficacy of different dose ranges of predniso(lo)ne induction therapy in a large European cohort of patients with AIH. METHODS: We performed a retrospective cohort study using a comparative effectiveness design. We collected data from 451 adults with AIH who began treatment from 1978 through 2017 at 9 centers in 5 European countries. We assigned patients to a high-dose group (initial predniso(lo)ne dose ≥0.50 mg/kg/day; n = 281) or a low-dose group (<0.50 mg/kg/day; n = 170). Logistic regression was performed to determine difference in outcomes between the groups. The primary outcome was normal serum levels of transaminases at 6 months after initiation of therapy. RESULTS: There was no significant difference in rates of normalization of transaminases between the high-dose predniso(lo)ne group and the low-dose group (70.5% vs 64.7%; P = .20). After multivariable logistic regression with correction for confounders, there was no difference in the likelihood of normalization of transaminases between the groups (odds ratio, 1.21; 95% CI, 0.78-1.87; P = .38). Patients given an initial high dose of predniso(lo)ne received more predniso(lo)ne over time than patients started on a lower dose (median doses over 6 months: 3780 mg vs 2573 mg) (P < .01). CONCLUSIONS: In a retrospective study of patients with AIH in Europe, we found that the dose of predniso(lo)ne to induce remission in patients with AIH is less relevant than assumed. An initial predniso(lo)ne dose below 0.50 mg/kg/day substantially decreases unnecessary exposure to predniso(lo)ne in patients with AIH.

Symptom relief and not cyst reduction determines treatment success in aspiration sclerotherapy of hepatic cysts.

OBJECTIVE: To assess whether quantitative assessment of symptom reduction is a better outcome parameter than cyst volume reduction for treatment success in patients treated by aspiration sclerotherapy. METHODS: We included patients with symptomatic, large (> 5 cm), hepatic cysts from a randomized controlled trial (NCT02048319). At baseline and 6 months after treatment, symptoms were assessed with the polycystic liver disease questionnaire (PLD-Q) and we measured cyst volume using ultrasonography. Patient-reported change in health was assessed on a 5-point Likert scale (much worse to much better) after 6 months. We tested whether PLD-Q scores and cyst volumes changed after aspiration sclerotherapy (responsiveness). Changes in PLD-Q scores and cyst volume were compared with change in health as a measure of treatment success (discriminative ability). As secondary analysis, we compared baseline characteristics between responders (improved) and non-responders (not improved). RESULTS: We included 32 patients. Six months after treatment, 23 patients (72%) improved. Both PLD-Q score and cyst volume significantly decreased (median 38 to 18 points, p < 0.001, and 479 to 68 mL, p < 0.001). Larger improvement in PLD-Q score was associated with a positive change in health (p = 0.001), while larger proportional reduction in cyst volume was not significantly associated with health improvement after treatment (p = 0.136). Responders had larger baseline cyst volumes compared to non-responders (median 624 mL [IQR 343-1023] vs. 322 mL [IQR 157-423] p = 0.008). CONCLUSION: Cyst diameter reduction does not reflect treatment success in aspiration sclerotherapy from patients' perspective, while symptoms measured with the PLD-Q can be used as a reliable outcome measure. KEY POINTS: • Cyst diameter reduction poorly reflects treatment success in aspiration sclerotherapy. • Symptoms measured by the polycystic liver disease questionnaire (PLD-Q) is a better outcome measure than cyst volume reduction for treatment success after aspiration sclerotherapy. • Particularly patients with larger cysts (≥ 529 mL) benefit from aspiration sclerotherapy.

Development and Validation of a Patient-Reported Outcome Measurement for Symptom Assessment in Cirrhotic Ascites.

OBJECTIVES: As current treatments of cirrhotic ascites are not associated with survival benefit, symptom relief is the major therapeutic end point. We developed a questionnaire (Ascites-Q; modified polycystic liver disease questionnaire) and assessed validity and responsiveness for symptom assessment in cirrhotic ascites. METHODS: Ascites-Q was compared with Functional Assessment of Chronic Illness Therapy-Ascites Index (FACIT-AI; developed for malignant ascites) and Japanese Ascites Symptom Inventory-7 (ASI-7) in cirrhotics undergoing large-volume paracentesis. Convergent validity was defined as correlation >0.4 between ascites questionnaires and quality of life (QoL) visual analog scale. Responsiveness was assessed by comparing scores at baseline and 7 days after large-volume paracentesis. To test discriminative ability, we compared scores of patients with cirrhotic controls without ascites (n=24) and diuretic-sensitive ascites (n=46). RESULTS: We included 90 patients with refractory cirrhotic ascites (61% male, mean age 59 years, Model of End-Stage Liver Disease (MELD) score 16, median paracentesis volume 4,100 ml). Higher symptoms scores were correlated with lower QoL (Ascites-Q: r=0.479, P<0.001, FACIT-AI: r=0.313, P=0.007; ASI-7: r=0.340, P=0.004), but only Ascites-Q showed convergent validity (r>0.4). Symptoms decreased after paracentesis (Ascites-Q: 57 to 34, FACIT-AI: 44 to 33, and ASI-7: 57 to 25, all P<0.001). Ascites-Q and ASI-7 discriminated between controls without ascites, diuretic-sensitive, and refractory ascites (Ascites-Q: 16 vs. 35 vs. 56 points, ASI-7: 2 vs. 25 vs. 61 points, all P<0.05), whereas FACIT-AI (39 vs. 40 vs. 52 points) could not (P=0.314). Ascites-Q was validated at 3 months in an independent cohort with ascites controlled with a pump. CONCLUSIONS: The Ascites-Q is the best ascites-specific outcome to evaluate symptom relief in cirrhotic ascites.

Regression of hepatocellular adenoma after bariatric surgery in severe obese patients.

BACKGROUND & AIM: Obesity and metabolic syndrome are increasingly recognized as risk factors for hepatocellular adenomas (HCA). There is still sparse evidence whether weight loss or bariatric surgery could induce HCA regression in these patients. In this brief report we describe the effect of weight loss on HCA regression in severe obese patients that had undergone bariatric surgery in our centre. METHODS: We performed an Electronic Patient Database search and included all patients who underwent bariatric surgery in our bariatric referral centre and had an ICD-10 code of benign neoplasm of liver in our centre from (2006-2017). All imaging studies of eligible patients were re-evaluated by the study radiologist. Primary outcome was change in maximal diameter of HCA. RESULTS: Six of 11 eligible patients were excluded because their lesions were classified as probable focal nodular hyperplasia and two were lost to follow-up. Finally, three women with solitary (n = 1) or multiple HCA (n = 2) and a body mass index (BMI) ranging between 39 and 50 kg/m2 were included. In two patients, HCA completely regressed in 1-2 years following bariatric surgery, after BMI reductions of 36%-48%. The third patient showed a reduction of >50% in diameter of the largest HCA in 2.5 years after bariatric surgery (31% BMI reduction), with complete resolution of smaller HCA. CONCLUSIONS: Bariatric induced weight loss results in significant regression of HCA in severe obese women, which emphasizes the role of overweight in HCA pathophysiology.

Pasireotide does not improve efficacy of aspiration sclerotherapy in patients with large hepatic cysts, a randomized controlled trial.

OBJECTIVES: We tested whether complementary use of the somatostatin analogue pasireotide would augment efficacy of aspiration sclerotherapy of hepatic cysts. METHODS: We conducted a double-blind, placebo-controlled trial in patients who underwent aspiration sclerotherapy of a large (>5 cm) symptomatic hepatic cyst. Patients were randomized to either intramuscular injections of pasireotide 60 mg long-acting release (n = 17) or placebo (sodium chloride 0.9 %, n = 17). Injections were administered 2 weeks before and 2 weeks after aspiration sclerotherapy. The primary endpoint was proportional cyst diameter reduction (%) from baseline to 6 weeks. Secondary outcomes included long-term cyst reduction at 26 weeks, patient-reported outcomes including the polycystic liver disease-questionnaire (PLD-Q) and safety. RESULTS: Thirty-four patients (32 females; 53.6 ± 7.8 years) were randomized between pasireotide or placebo. Pasireotide did not improve efficacy of aspiration sclerotherapy at 6 weeks compared to controls (23.6 % [IQR 12.6-30.0] vs. 21.8 % [9.6-31.8]; p = 0.96). Long-term cyst diameter reduction was similar in both groups (49.1 % [27.0-73.6] and 45.6 % [29.6-59.6]; p = 0.90). Mean PLD-Q scores improved significantly in both groups (p < 0.01) without differences between arms (p = 0.92). CONCLUSIONS: In patients with large symptomatic hepatic cysts, complementary pasireotide to aspiration sclerotherapy did not improve cyst reduction or clinical response. KEY POINTS: • Complementary pasireotide treatment does not improve efficacy of aspiration sclerotherapy. • Cyst fluid reaccumulation after aspiration sclerotherapy is a transient phenomenon. • Aspiration sclerotherapy strongly reduces symptoms and normalizes quality of life.