Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

BACKGROUND AND HYPOTHESIS: Dysregulated energy metabolism is a recently discovered key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate concentrations are associated with reduced disease progression in patients with ADPKD. METHODS: We analyzed data from 670 patients with ADPKD participating in the DIPAK cohort, a multi-center prospective observational cohort study. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. RESULTS: Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 (IQR 495-1327) ml/m, and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73m2. The median concentration of beta-hydroxybutyrate was 94 (IQR 68-147) µmol/L. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with htTKV. Longitudinally, beta-hydroxybutyrate was positively associated with eGFR slope (B = 0.35 ml/min/1.73m2 (95% CI 0.09 to 0.61), p = 0.007), but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration was associated with an improvement in the annual rate of eGFR by 0.33 ml/min/1.73m2 (95% CI 0.09 to 0.57, p = 0.008). CONCLUSION: These observational analyses support the hypothesis that interventions that raise beta-hydroxybutyrate concentration could reduce the rate of kidney function decline in patients with ADPKD.

Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study.

BACKGROUND: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. METHODS: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). DISCUSSION: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 .

Clinical follow-up on weight loss, glycemic control, and safety aspects of 24 months of duodenal-jejunal bypass liner implantation.

BACKGROUND: The duodenal-jejunal bypass liner (DJBL) is an endoscopic device designed to induce weight loss and improve glycemic control. The liner is licensed for a maximum implant duration of 12 months. It might be hypothesized that extension of the dwelling time results in added value. The goals of our study were to determine weight change, change in glycemic control, and safety in patients with an intended 24 months of DJBL dwelling time. METHODS: Patients were initially selected for a 12-month implantation period. When no physical complaints or adverse events (AEs) occurred, motivated patients who responded well were selected for extension of dwelling time to 24 months. Patients underwent a control endoscopy 12 months after implantation and visited the out-patient clinic every 3 months up to explantation. Patients agreed to remove the DJBL when complaints or AEs occurred that could not be treated conservatively. RESULTS: Implantation was extended in 44 patients, and 24 (55%) patients completed the full 24 months. Twenty patients required early removal due to AEs. During dwelling time, body weight decreased significantly (15.9 kg; TBWL 14.6%). HbA1c decreased non-significantly (4.9 mmol/mol). The number of insulin users and daily dose of insulin both decreased significantly. At 24 months after removal, glycemic control had worsened, while body weight was still significantly lower compared to baseline. In total, 68% of the patients experienced at least one AE. Two patients developed a hepatic abscess. CONCLUSIONS: DJBL treatment results in significant weight loss and improves glycemic control during implantation. The largest beneficial effects occur during the first 9-12 months after implantation. Extension of dwelling time to 24 months results only in stabilization of body weight and glycemic control. After explantation, weight improvements are maintained, but glycemic control worsens. As the cumulative risk of AEs increases with time, a maximal dwelling time of 12 months is advisable.

A Risk Assessment of Factors for the Presence of Angiodysplasias During Endoscopy and Factors Contributing to Symptomatic Bleeding and Rebleeds.

BACKGROUND: Few studies have assessed factors associated with angiodysplasias during endoscopy or factors associated with symptomatic disease. AIMS: To evaluate risk factors for the presence of and contribution to symptomatic disease in patients with angiodysplasias. METHODS: We performed a systematic MEDLINE, EMBASE and Cochrane Library search according to the PRISMA guidelines for studies assessing risk factors involved in angiodysplasias detected during endoscopy and factors that lead to anemia or overt bleeding. Study quality was assessed with the Newcastle-Ottawa scale. A risk assessment was performed by selecting risk factors identified by two independent studies and/or by a large effect size. RESULTS: Twenty-three studies involving 92,634 participants were included. The overall quality of the evidence was moderate. Risk factors for the diagnosis of angiodysplasias during endoscopy confirmed by at least two studies were increasing age (OR 1.09 per year, 95% CI 1.04-1.1), chronic kidney disease (OR 4.5, 95% CI 1.9-10.5) and cardiovascular disease (2.9, 95% CI 1.4-6.2). The risk of rebleeds was higher in the presence of multiple lesions (OR 4.2, 95% CI 1.1-16.2 and 3.8, 95% CI 1.3-11.3 and 8.6, 95% CI 1.4-52.6), liver cirrhosis (OR 4.0, 95% 1.1-15.0) and prothrombin time < 30% (OR 4.2, 95% 1.1-15.4) with a moderate effect size. Multiple comorbidities were associated with an increased in-hospital mortality (OR 2.29, 95% CI 1.2-4.3). CONCLUSIONS: This systematic review identified age, chronic kidney disease and cardiovascular disease as the most important risk factors for the diagnosis of angiodysplasias during endoscopy. Multiple lesions increase the risk of recurrent bleeding.

Genetics and mechanisms of hepatic cystogenesis.

Polycystic liver disease (PLD) is a heterogeneous genetic condition. PKD1 and PKD2 germline mutations are found in patients with autosomal dominant polycystic kidney disease (ADPKD). Autosomal dominant polycystic liver disease (ADPLD) is associated with germline mutations in PRKCSH, SEC63, LRP5, and recently ALG8 and SEC61. GANAB mutations are found in both patient groups. Loss of heterozygosity of PLD-genes in cyst epithelium contributes to the development of hepatic cysts. A genetic interaction network is implied in hepatic cystogenesis that connects the endoplasmic glycoprotein control mechanisms and polycystin expression and localization. Wnt signalling could be the major downstream signalling pathway that results in hepatic cyst growth. PLD in ADPLD and ADPKD probably results from changes in one common final pathway that initiates cyst growth. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

The association between portal system vein diameters and outcomes in acute pancreatitis.

BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) progresses to necrotizing pancreatitis in 15% of cases. An important pathophysiological mechanism in AP is third spacing of fluids, which leads to intravascular volume depletion. This results in a reduced splanchnic circulation and reduced venous return. Non-visualisation of the portal and splenic vein on early computed tomography (CT) scan, which might be the result of smaller vein diameter due to decreased venous flow, is associated with infected necrosis and mortality in AP. This observation led us to hypothesize that smaller diameters of portal system veins (portal, splenic and superior mesenteric) are associated with increased severity of AP. METHODS: We conducted a post-hoc analysis of data from two randomized controlled trials that included patients with predicted severe and mild AP. The primary endpoint was AP-related mortality. The secondary endpoints were (infected) necrotizing pancreatitis and (persistent) organ failure. We performed additional CT measurements of portal system vein diameters and calculated their prognostic value through univariate and multivariate Poisson regression. RESULTS: Multivariate regression showed a significant inverse association between splenic vein diameter and mortality (RR 0.75 (0.59-0.97)). Furthermore, there was a significant inverse association between splenic and superior mesenteric vein diameter and (infected) necrosis. Diameters of all veins were inversely associated with organ failure and persistent organ failure. CONCLUSIONS: We observed an inverse relationship between portal system vein diameter and morbidity and an inverse relationship between splenic vein diameter and mortality in AP. Further research is needed to test whether these results can be implemented in predictive scoring systems.

Biochemical Effects on the Liver of 1 Month of Alcohol Abstinence in Moderate Alcohol Consumers.

SHORT SUMMARY: : In this study in healthy moderate alcohol consumers, we observe that one month of alcohol abstinence results in decreased gamma-glutamyl transferase levels, which return to baseline levels after resumption of alcohol consumption.

Daclatasvir 30 mg/day is the correct dose for patients taking atazanavir/cobicistat.

BACKGROUND: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with atazanavir. OBJECTIVES: To determine whether the fixed-dose combination of atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents atazanavir and ritonavir. METHODS: A prospective, open-label, two-period, randomized, cross-over trial was performed in 16 healthy subjects (NCT02565888). Treatment consisted of 300/100 mg of atazanavir/ritonavir plus 30 mg of daclatasvir once daily (reference) and a second period of 300/150 mg of atazanavir/cobicistat plus 30 mg of daclatasvir once daily (test). A 24 h pharmacokinetic, steady-state curve was recorded for all drugs. Geometric mean ratios (GMRs) with 90% CI were calculated for daclatasvir and atazanavir AUCτ and Cmax to compare the effect of both treatments (test versus reference). Laboratory safety and adverse events were evaluated throughout the trial. RESULTS: All 16 healthy subjects completed the study. Median (range) age and BMI were 48.5 (21-55) years and 24.5 (19.0-29.2) kg/m2, respectively. Pharmacokinetic parameters of ritonavir and cobicistat were comparable to those in the literature. The GMRs (90% CI) of daclatasvir AUCτ and Cmax (test versus reference) were 101% (92%-111%) and 97% (89%-106%), respectively. Atazanavir GMRs (90% CI) of AUCτ and Cmax were 82% (75%-79%) and 74% (68%-81%), respectively. No serious adverse events were reported. CONCLUSIONS: Atazanavir/cobicistat and atazanavir/ritonavir had a similar influence on daclatasvir pharmacokinetics in healthy volunteers. Daclatasvir at 30 mg once daily is the correct dose when combined with atazanavir/cobicistat.

Hepatic cyst penetration of cefazolin in patients receiving aspiration sclerotherapy.

BACKGROUND: Hepatic cyst infection is a potentially severe complication in cystic disease. Treatment demands effective antibiotic concentrations within the infected cyst. OBJECTIVES: The aim of this study was to use elective hepatic cyst drainage as a unique pharmacokinetic model to investigate whether cefazolin, a first-generation cephalosporin, is able to penetrate hepatic cysts. PATIENTS AND METHODS: Patients scheduled to undergo percutaneous aspiration sclerotherapy of a symptomatic non-infected, non-neoplastic hepatic cyst were eligible for this study. All participants received a single perioperative prophylactic dose of cefazolin (1000 mg, intravenously). We collected blood and cyst fluid samples to determine total and unbound cefazolin concentrations using HPLC. The primary outcome was hepatic cyst penetration, expressed as the ratio (%) of unbound concentration of cefazolin in cyst fluid to plasma (both in mg/L). RESULTS: We included eight patients [male = 25%, median age = 60 years (IQR 54-75), median estimated glomerular filtration rate = 97 mL/min/1.73 m(2) (IQR 67-102) and median serum albumin = 40 g/L (IQR 37-40)]. We detected low concentrations of unbound cefazolin in cyst fluid (≤1.0 mg/L). The median plasma unbound cefazolin peak level (immediately after cefazolin administration) was 36.6 mg/L (IQR 23.7-54.1) and the level at the time of cyst fluid aspiration was 16.1 mg/L (IQR 13.0-20.1). In total, the hepatic cyst penetration of free cefazolin was only 2.2% (IQR 0.7-5.2). CONCLUSIONS: We developed a study model to investigate the penetration of antibiotics into hepatic cysts. Cefazolin did not reach adequate intracystic concentrations. Future studies should explore alternatives.

A randomized controlled trial to compare a restrictive strategy to usual care for the effectiveness of cholecystectomy in patients with symptomatic gallstones (SECURE trial protocol).

BACKGROUND: Five to 22 % of the adult Western population has gallstones. Among them, 13 to 22 % become symptomatic during their lifetime. Cholecystectomy is the preferred treatment for symptomatic cholecystolithiasis. Remarkably, cholecystectomy provides symptom relief in only 60-70 % of patients. The objective of this trial is to compare the effectiveness of usual (operative) care with a restrictive strategy using a standardized work-up with stepwise selection for cholecystectomy in patients with gallstones and abdominal complaints. DESIGN AND METHODS: The SECURE-trial is designed as a multicenter, randomized, parallel-arm, non-inferiority trial in patients with abdominal symptoms and ultrasound proven gallstones or sludge. If patients meet the inclusion criteria they will be randomized to either usual care or the restrictive strategy. Patients in the usual care group will be treated according to the physician's knowledge and preference. Patients in the restrictive care group will be treated with interval evaluation and stepwise selection for laparoscopic cholecystectomy. In this stepwise selection, patients strictly meeting the preselected criteria for symptomatic cholecystolithiasis will be offered a cholecystectomy. Patients not meeting these criteria will be assessed for other diagnoses and re-evaluated at 3-monthly intervals. Follow-up consists of web-based questionnaires at 3, 6, 9 and 12 months. The main end point of this trial is defined as the proportion of patients being pain-free at 12 months follow-up. Pain will be assessed with the Izbicki Pain Score and Gallstone Symptom Score. Secondary endpoints will be the proportion of patients with complications due to gallstones or cholecystectomy, the association between the patients' symptoms and treatment and work performance, and ultimately, cost-effectiveness. DISCUSSION: The SECURE trial is the first randomized controlled trial examining the effectiveness of usual care versus restrictive care in patients with symptomatic gallstones. The outcome of this trial will inform clinicians whether a more restrictive strategy can minimize persistent pain in post-operative patients at least as good as usual care does, but at a lower cholecystectomy rate. (The Netherlands National Trial Register NTR4022, 17th December 2012) TRIAL REGISTRATION: The Netherlands National Trial Register NTR4022 http://www.zonmw.nl/nl/projecten/project-detail/scrutinizing-inefficient-use-of-cholecystectomy-a-randomized-trial-concerning-variation-in-practi/samenvatting/.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Antiviral therapy in chronic hepatitis E: a systematic review.

Hepatitis E viral infection can lead to a chronic infection in immunocompromised patients, resulting in progressive liver disease and cirrhosis. Isolated cases have shown that treatment with ribavirin or pegylated interferon-α can result in viral eradication. This systematic review evaluated efficacy and safety of both treatments in chronic hepatitis E. A systematic literature search was performed on PubMed, Web of Science and clinicaltrials.gov for articles and abstracts. The keywords '"Hepatitis E" or HEV' AND 'ribavirin or Rebetol or Copegus' OR 'pegylated interferon OR peginterferon' were combined. The primary outcome was sustained viral response (SVR). Secondary endpoints include rapid viral response (RVR), relapse rates and side effects. Twenty-four studies matched our criteria, representing a total of 105 ribavirin-treated and 8 pegylated interferon-treated patients. The majority of patients had a solid organ transplant. Sixty-four per cent of ribavirin-treated patients achieved a SVR at 6 months after treatment cessation compared to 2/8 peginterferon-treated patients. Ribavirin was relatively well tolerated with the main side effect being anaemia, requiring dose reduction in 28% of patients. Peginterferon leads to acute transplant rejection in 2/8 patients. Ribavirin monotherapy appears to be an effective and safe treatment in all immunocompromised patients with chronic hepatitis E. The use of pegylated interferon in transplant patients may lead to transplant rejection and is not recommended. Therefore, ribavirin should be the antiviral treatment of choice in chronic hepatitis E.

Prospective multicentre cohort study of patient-reported outcomes after cholecystectomy for uncomplicated symptomatic cholecystolithiasis.

BACKGROUND: Up to 33 per cent of patients with uncomplicated symptomatic cholecystolithiasis report persistent pain after cholecystectomy. The aim of this study was to determine characteristics associated with patient-reported absence of abdominal pain after cholecystectomy, improved abdominal symptoms, and patient-reported positive cholecystectomy results in a prospective cohort multicentre study. METHODS: Patients aged 18 years or more with symptomatic cholecystolithiasis who had a cholecystectomy between June 2012 and June 2014 in one of three hospitals were included. Before surgery all patients were sent the Gastrointestinal Quality of Life Index (GIQLI) questionnaire and the McGill Pain Questionnaire (MPQ). At 12 weeks after surgery, patients were invited to complete the GIQLI and Patients' Experience of Surgery Questionnaire (PESQ). Logistic regression analyses were performed to determine associations. RESULTS: Questionnaires were sent to 552 patients and returned by 342 before and after surgery. Postoperative absence of abdominal pain was reported by 60·5 per cent of patients. A high preoperative GIQLI score, episodic pain, and duration of pain of 1 year or less were associated with postoperative absence of pain. These factors showed no association with improved abdominal symptoms (reported by 91·5 per cent of patients) or a positive surgery result (reported by 92·4 per cent). CONCLUSION: Preoperative characteristics determine the odds for relief of abdominal pain after cholecystectomy. However, these factors were not associated with patient-reported improvement of abdominal symptoms or patient-reported positive cholecystectomy results, highlighting the variation of internal standards and expectations of patients before cholecystectomy.

Ribavirin rather than PEG-interferon pharmacodynamics predict nonresponse to antiviral therapy in naive chronic hepatitis C patients.

Twenty to fifty per cent of patients with chronic hepatitis C (CHC) experience nonresponse to current antiviral therapy, which may relate in part to ribavirin or PEG-interferon pharmacodynamics. We evaluated potential relevance of various factors for nonresponse. Two hundred forty-two naive CHC patients who received in a previous trial at least 24 weeks of antiviral therapy, including PEG-interferon alfa-2b and ribavirin, were analysed. Of them, 53% were infected with hepatitis C virus (HCV) genotype 1-4, 71% exhibited high viral load and 32% had severe fibrosis/cirrhosis. After 24 weeks of treatment, 39 patients (16%) were nonresponders. In multivariate analysis, lower serum ribavirin concentrations, HCV genotype 1-4 and higher baseline γ-GT predicted nonresponse. Week-24 ribavirin concentrations (2.2 vs 2.8 mg/L, P < 0.001), average ribavirin doses (14.5 vs 15.2 mg/kg per day, P = 0.03) and week-24 haemoglobin decreases (1.7 vs 2.0 mm, P = 0.02) were lower in nonresponders. Nonresponse rates increased progressively at decreasing ribavirin concentrations: 4%, 11%, 13% and 36% in case of serum ribavirin concentrations ≥4, 3-4, 2-3 and ≤2 mg/L, respectively (P = 0.001). Ribavirin concentrations correlated with both week-24 haemoglobin decreases (r = 0.42, P < 0.001) and ribavirin doses (r = 0.17, P = 0.01). Subgroup analysis in HCV genotype 1-4 patients revealed essentially the same results. Nonresponse was exceptional in HCV genotype 2-3 patients and associated with ribavirin concentrations <2 mg/L. Presumed interferon-related factors (average PEG-interferon doses and decreases in leucocytes, granulocytes, platelets and body weight) did not differ between nonresponders and responders. In conclusion, ribavirin- rather than PEG-interferon-related factors are independent and potentially modifiable predictors of nonresponse in treatment-naive CHC patients.

On-demand anakinra treatment is effective in mevalonate kinase deficiency.

BACKGROUND: Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory syndrome marked by recurrent attacks of fever and inflammation. Severe enzyme deficiency results in mevalonic aciduria (MA) and milder deficiency in hyperimmunoglobulin D syndrome (HIDS). Treatment remains a challenge. OBJECTIVE: To observe the effect of the recombinant interleukin-1 receptor antagonist anakinra in patients with MKD. METHODS: A prospective observational study was undertaken. Two patients with MA started continuous treatment with anakinra (1-2 mg/kg/day) and nine patients with HIDS chose between continuous treatment and on-demand treatment (starting at first symptoms of attack, 100 mg/day or 1 mg/kg/day for 5-7 days). RESULTS: Anakinra induced partial remission in one patient with MA but there was no response in the other patient with MA. In one patient with HIDS continuous treatment induced complete remission for 7 months but was stopped because of side effects. Eight patients with HIDS preferred on-demand treatment from the start. This induced a clinical response (≥50% reduction in duration) in 8 of 12 treated attacks without a change in attack frequency. Anakinra prevented fever attacks due to vaccination without inhibiting antibody induction. No major side effects were seen. CONCLUSIONS: On-demand treatment with anakinra in HIDS decreases the duration and severity of fever attacks. Because of the burden of daily injections and relatively long asymptomatic intervals of HIDS, all patients with HIDS preferred on-demand treatment.

Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency.

Mutations in the signal transducer and activator of transcription 3 (STAT3) were reported to cause hyperimmunoglobulin E syndrome (HIES). The present study investigates T helper type 17 (Th17) responses triggered by the relevant stimuli Staphylococcus aureus and Candidia albicans in five 'classical' HIES patients, and a family with three patients who all had a milder HIES phenotype. We demonstrate that patients with various forms of HIES have different defects in their Th17 response to S. aureus and C. albicans, and this is in line with the clinical features of the disease. Interestingly, a partial deficiency of interleukin (IL)-17 production, even when associated with STAT3 mutations, leads to a milder clinical phenotype. We also observed defective Th17 responses in patients with the 'classical' presentation of the disease but without STAT3 mutations. These data demonstrate that defective IL-17 production in response to specific pathogens can differ between patients with HIES and that the extent of the defective Th17 response determines their clinical phenotype.

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63.

Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation-sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, PolyPhen, and pMut and sift. We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non-sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.

[Safe prescribing in patients with liver cirrhosis; 5 pitfalls]. / Veilig voorschrijven bij levercirrose: 5 misvattingen.

The liver has a major role in the pharmacokinetics and pharmacodynamics of medicines and hepatic impairment could therefore lead to increased plasma levels and adverse drug reactions. Due to the large overcapacity of the liver, medication adjustments are only needed when a chronic liver disease has progressed to cirrhosis. Important pharmacokinetic alterations that could occur in cirrhosis are: (a) a decreased first-pass effect, (b) impaired metabolism by liver enzymes, and (c) in an advanced stage also impairment of renal elimination. Patients with cirrhosis could also be more sensitive to certain adverse drug reactions at normal drug levels, such as renal impairment due to NSAIDs or the sedative effect of morphinomimetics and psychotropic drugs. Prescribing in patients with cirrhosis is complex, which we illustrate by 5 common pitfalls. In practice, healthcare professionals could use a website with guidance for prescribing almost 300 medicines (www.geneesmiddelenbijlevercirrose.nl).

NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders.

Gain-of-function mutations of Na(V)1.7 have been shown to produce two distinct disorders: Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na(V)1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4-S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (-7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na(V)1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na(V)1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.