Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons.

Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH.

Detection and alterations of acetylcarnitine (AC) in human liver by 1 H MRS at 3T after supplementation with l-carnitine.

PURPOSE: Acetylcarnitine can be assessed in vivo using proton MRS (1 H-MRS) with long TEs and this has been previously applied successfully in muscle. The aim of this study was to evaluate a 1 H-MRS technique for liver acetylcarnitine quantification in healthy humans before and after l-carnitine supplementation. METHOD: Baseline acetylcarnitine levels were quantified using a STEAM sequence with prolonged TE in 15 healthy adults. Using STEAM with four different TEs was evaluated in phantoms. To assess reproducibility of the measurements, five of the participants had repeated 1 H-MRS without receiving l-carnitine supplementation. To determine if liver acetylcarnitine could be changed after l-carnitine supplementation, acetylcarnitine was quantified 2 h after intravenous l-carnitine supplementation (50 mg/kg body weight) in the other 10 participants. Hepatic lipids were also quantified from the 1 H-MRS spectra. RESULTS: There was good separation between the acetylcarnitine and fat in the phantoms using TE = 100 ms. Hepatic acetylcarnitine levels were reproducible (coefficient of reproducibility = 0.049%) and there was a significant (p < 0.001) increase in the relative abundance after a single supplementation of l-carnitine. Hepatic allylic, methyl, and methylene peaks were not altered by l-carnitine supplementation in healthy volunteers. CONCLUSION: Our results demonstrate that our 1 H-MRS technique could be used to measure acetylcarnitine in the liver and detect changes following intravenous supplementation in healthy adults despite the presence of lipids. Our techniques should be explored further in the study of fatty liver disease, where acetylcarnitine is suggested to be altered due to hepatic inflexibilities.

Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH. METHODS: This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory. RESULTS: A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis. CONCLUSIONS: In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH. CLINICAL TRIAL REGISTRATION NUMBER: NCT03987074. LAY SUMMARY: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.

Liver fibrosis in patients with tetralogy of Fallot, an unrecognised complication?

OBJECTIVES: Improved survival has led to a growing population of adults with congenital heart disease (CHD), followed by numerous reports of late complications. Liver disease is a known complication in some patients, with most studies focusing on Fontan associated liver disease. Whether liver disease also exists in other patients with CHD is not fully investigated. Elevated central venous pressure is considered pivotal in the development of liver disease in Fontan associated liver disease, and other patients with alterations in central venous pressure may also be at risk for developing liver fibrosis. We wanted to see if liver fibrosis is present in patients with tetralogy of Fallot. Many patients with tetralogy of Fallot have severe pulmonary regurgitation, which can lead to elevated central venous pressure. Patients with tetralogy of Fallot may be at risk of developing liver fibrosis. MATERIALS AND METHODS: Ten patients (24-56 years) with tetralogy of Fallot and pulmonary regurgitation were investigated for liver fibrosis. All patients were examined with magnetic resonance elastography of liver, hepatobiliary iminodiacetic acid scan, indocyanine green elimination by pulse spectrophotometry, elastography via FibroScan, abdominal ultrasound including liver elastography, and blood samples including liver markers. RESULTS: Three out of ten patients had findings indicating possible liver fibrosis. Two of these had a liver biopsy performed, which revealed fibrosis stage 1 and 2, respectively. The same three patients had an estimated elevated central venous pressure in previous echocardiograms. CONCLUSIONS: Mild liver fibrosis was present in selected patients with tetralogy of Fallot and may be related to elevated central venous pressure.

A combined effect of anti-HPA-1a and anti-HLA Class I in pregnancy?

BACKGROUND: Maternal anti-human leukocyte antigen (HLA) Class I is commonly detected alongside anti-human platelet antigen (HPA)-1a in fetal and neonatal alloimmune thrombocytopenia (FNAIT). Little is known regarding whether the presence of anti-HLA Class I may exert an additive effect on the risk and severity of FNAIT. METHODS AND MATERIALS: We reanalyzed samples originally collected as part of a large Norwegian screening study on FNAIT during 1995-2004. This study identified and managed 170 pregnancies where the mother was HPA-1a negative and had detectable anti-HPA-1a during pregnancy. Maternal samples from 166 of these pregnancies were rescreened for anti-HLA Class I, revealing 111 (67%) that were antibody positive. Various regression models were used to assess if and how maternal anti-HLA Class I influenced the neonatal platelet count. RESULTS AND CONCLUSIONS: Unadjusted neonatal platelet counts and the frequency of neonatal thrombocytopenia was not significantly affected by the presence of anti-HLA Class I alongside anti-HPA-1a, but results from regression analyses revealed a possible increased risk when the mother was nulliparous. These results warrant further investigation.

Strategies to develop a prophylaxis for the prevention of HPA-1a immunization and fetal and neonatal alloimmune thrombocytopenia.

Anti-HPA-1a-antibodies are the main cause of fetal and neonatal alloimmune thrombocytopenia (FNAIT) which may result in intracranial hemorrhage (ICH) and death among fetuses and newborns. Advances in understanding the pathogenesis of FNAIT and proof of concept for prophylaxis to prevent immunization suggest that development of hyperimmune anti-HPA-1a IgG aimed at preventing immunization against HPA-1a and FNAIT is feasible. Anti-HPA-1a IgG can be obtained either by isolating immunoglobulin from already-immunized women or by development of monoclonal anti-HPA-1a antibodies. Here we discuss recent advances that may lead to the development of a prenatal and postnatal prophylactic treatment for the prevention of HPA-1a-associated FNAIT and life-threatening FNAIT-induced complications.

Environmental pollutants in blood donors: The multicentre Norwegian donor study.

OBJECTIVES: The aim of this study was to measure blood concentrations of environmental pollutants in Norwegian donors and evaluate the risk of pollutant exposure through blood transfusions. BACKGROUND: Transfused blood may be a potential source of exposure to heavy metals and organic pollutants and presents a risk to vulnerable patient groups such as premature infants. METHODS/MATERIALS: Donors were randomly recruited from three Norwegian blood banks: in Bergen, Tromsø and Kirkenes. Selected heavy metals were measured in whole blood using inductively coupled plasma mass spectrometry (ICP-MS), and perfluoroalkyl substances (PFAS) were measured in serum by ultrahigh-pressure liquid chromatography coupled with a triple-quadrupole mass spectrometer (UHPLC-MS/MS). RESULTS: Almost 18% of blood donors had lead concentrations over the limit suggested for transfusions in premature infants (0.09 µmol/L). About 11% of all donors had mercury concentrations over the suggested limit of 23.7 nmol/L. Cadmium was higher than the limit, 16 nmol/L, in 4% of donors. Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) concentrations were over the suggested limit of 0.91 ng/mL in 68% and 100% of the donors, respectively. PFAS concentrations and heavy metal concentrations increased with donor's age. CONCLUSION: A considerable percentage of donors had lead, PFOS and PFOA concentrations over the suggested limits. In addition, at each study site, there were donors with high mercury and cadmium concentrations. Selecting young donors for transfusions or measurements of pollutants in donor blood may be a feasible approach to avoid exposure through blood transfusions to vulnerable groups of patients such as premature infants.

Paediatric hepatitis B and hepatitis C virus infections: An observational study of a Danish cohort.

AIM: The aim of this study was to describe the epidemiological and clinical characteristics in children with either chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in Denmark. METHODS: In this observational study, children and adolescents with either chronic HBV or HCV infection followed at the largest paediatric departments in Denmark between 2001 and 2013 were included. Data collection included as well epidemiological data as clinical data like virus genotype, viral load, serological markers, liver biochemistry, liver elastography and histology if available. RESULTS: The study included 131 children. None of the patients had decreased liver function or end-stage liver disease during follow-up. Ten of the 18 children who underwent liver biopsy had signs of fibrosis. Thirteen (11%) children with HBV and one (7%) child with HCV received treatment. Different indications and different treatment regimens were used. CONCLUSION: This study confirms that chronic HBV and HCV infections are often mild diseases during childhood. Nevertheless, children are at higher risk of serious liver disease early in life because of the early time of infection and probably also because of the high viral loads.

Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may result in severe bleeding, particularly fetal and neonatal intracranial haemorrhage (ICH). As a result, FNAIT requires prompt identification and treatment; subsequent pregnancies need close surveillance and management. An international panel convened to develop evidence-based recommendations for diagnosis and management of FNAIT. A rigorous approach was used to search, review and develop recommendations from published data for: antenatal management, postnatal management, diagnostic testing and universal screening. To confirm FNAIT, fetal human platelet antigen (HPA) typing, using non-invasive methods if quality-assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen. Women with a previous child with an ICH related to FNAIT should be offered intravenous immunoglobulin (IVIG) infusions during subsequent affected pregnancies as early as 12 weeks gestation. Ideally, HPA-selected platelets should be available at delivery for potentially affected infants and used to increase the neonatal platelet count as needed. If HPA-selected platelets are not immediately available, unselected platelets should be transfused. FNAIT studies that optimize antenatal and postnatal management, develop risk stratification algorithms to guide management and standardize laboratory testing to identify high risk pregnancies are needed.

Opportunities to Prevent Alcoholic Liver Cirrhosis in High-Risk Populations: A Systematic Review With Meta-Analysis.

BACKGROUND: Alcoholic liver cirrhosis is preventable and caused by heavy drinking. Few in the general population may be at risk and interventions targeting individuals at high risk may be a more feasible opportunity for prevention than interventions targeting the whole population. METHODS: We conducted a systematic review to identify opportunities to prevent alcoholic liver cirrhosis in high-risk populations. Following MOOSE guidelines, we included observational studies published between 1980 and 2017. Prospective studies of alcohol-problem cohorts were included to investigate whether alcohol-problem cohorts qualify as high-risk populations for alcoholic liver cirrhosis. Studies on the alcohol amount consumed by alcoholic liver cirrhosis patients were included to compare with the amount consumed by the general population. Moreover, studies on alcohol-related healthcare contacts prior to alcoholic liver cirrhosis diagnosis were included to identify opportunities to offer prevention interventions. Of 7198 screened references, 38 studies (N = 120,928) were included. RESULTS: Alcohol-problem cohorts qualified as high-risk populations with an incidence of alcoholic liver cirrhosis ranging from 7 to 16% after 8-12 years. The alcohol amount consumed by alcoholic liver cirrhosis patients was high compared to the general population. For example, 45% (95%CI 34, 56) of alcoholic liver cirrhosis patients were drinking >110 g alcohol/day. Finally, there were opportunities to reach alcoholic liver cirrhosis patients prior to diagnosis; 40-61% of alcoholic liver cirrhosis patients had a previous alcohol-related healthcare contact. CONCLUSIONS: We conclude that alcohol-problem cohorts are high-risk populations for alcoholic liver cirrhosis and there seems to be opportunities to reach later alcoholic liver cirrhosis cases with preventive interventions in healthcare settings.

Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review.

Several strategies can be used to manage fetal or neonatal alloimmune thrombocytopenia (FNAIT) in subsequent pregnancies. Serial fetal blood sampling (FBS) and intrauterine platelet transfusions (IUPT), as well as weekly maternal IV immunoglobulin infusion (IVIG), with or without additional corticosteroid therapy, are common options, but optimal management has not been determined. The aim of this systematic review was to assess antenatal treatment strategies for FNAIT. Four randomized controlled trials and 22 nonrandomized studies were included. Pooling of results was not possible due to considerable heterogeneity. Most studies found comparable outcomes regarding the occurrence of intracranial hemorrhage, regardless of the antenatal management strategy applied; FBS, IUPT, or IVIG with or without corticosteroids. There is no consistent evidence for the value of adding steroids to IVIG. FBS or IUPT resulted in a relatively high complication rate (consisting mainly of preterm emergency cesarean section) of 11% per treated pregnancy in all studies combined. Overall, noninvasive management in pregnant mothers who have had a previous neonate with FNAIT is effective without the relatively high rate of adverse outcomes seen with invasive strategies. This systematic review suggests that first-line antenatal management in FNAIT is weekly IVIG administration, with or without the addition of corticosteroids.

Maternal HPA-1a antibody level and its role in predicting the severity of Fetal/Neonatal Alloimmune Thrombocytopenia: a systematic review.

BACKGROUND AND OBJECTIVES: In Caucasians, fetal/neonatal alloimmune thrombocytopenia (FNAIT) is most commonly due to maternal HPA-1a antibodies. HPA-1a typing followed by screening for anti-HPA-1a antibodies in HPA-1bb women may identify first pregnancies at risk. Our goal was to review results from previous published studies to examine whether the maternal antibody level to HPA-1a could be used to identify high-risk pregnancies. MATERIALS AND METHODS: The studies included were categorized by recruitment strategies: screening of unselected pregnancies or samples analyzed from known or suspected FNAIT patients. RESULTS: Three prospective studies reported results from screening programmes, and 10 retrospective studies focused on suspected cases of FNAIT. In 8 studies samples for antibody measurement, performed by the monoclonal antibody immobilization of platelet antigen (MAIPA) assay, and samples for determining fetal/neonatal platelet count were collected simultaneously. In these 8 studies, the maternal antibody level correlated with the risk of severe thrombocytopenia. The prospective studies reported high negative predictive values (88-95%), which would allow for the use of maternal anti-HPA-1a antibody level as a predictive tool in a screening setting, in order to identify cases at low risk for FNAIT. However, due to low positive predictive values reported in prospective as well as retrospective studies (54-97%), the maternal antibody level is less suited for the final diagnosis and for guiding antenatal treatment. CONCLUSION: HPA-1a antibody level has the potential to predict the severity of FNAIT.

Minimally invasive assessment of hepatic function in children with indocyanine green elimination: a validation study.

Objectives: Pediatric liver disease (PLD) covers a variety of etiologies and severities, from mild temporary illness to diseases with fatal outcomes. There is a demand for minimally invasive and reliable measures for assessment of the severity of PLD. Indocyanine green (ICG) elimination kinetics to estimate hepatic function has been used in adults for decades, however, due to invasiveness, the use in PLD is still limited. The aim of the present study was to evaluate minimally invasive estimation of ICG elimination by pulse spectrophotometry (ICGLi), in comparison with traditional spectrophotometry using serial blood samples (ICGbs). Methods: One hundred children aged 0-18 years were included in the study. ICG elimination kinetics was measured with ICGLi and ICGbs, and results compared by failure rates, mean difference, limits of agreement, Bland Altman plots and linear regression analysis. Plasma disappearance rates (PDRLi and PDRbs) were used for comparison. Results: One hundred and twelve simultaneous measurements in 87 patients were performed successfully. Mean difference for PDR (%/min) was 3.58 (95% CI 2.69; 4.47). Limits of agreement were -5.06; 12.22. A linear correlation between the two methods with a regression coefficient of 0.83 (SE 0.02 95% CI 0.80; 0.87) was found. For conversion we computed the following equation; PDRbs = 0.83 × PDRLi. Conclusions: The present study shows that ICG PDR can be obtained by a minimally invasive method and thus replace measures by serial blood samples in children with liver disease of different etiologies and severities. However, a systematic relative difference between the two methods exists. Our proposed correction factor needs to be validated in larger cohorts.

Number of hospital contacts with alcohol problems predicts later risk of alcoholic liver cirrhosis.

AIMS: Alcoholic liver cirrhosis is usually preceded by years of heavy drinking. We investigated whether the risk of alcoholic liver cirrhosis increases as the number of hospital contacts with alcohol problems goes up. METHODS: This was a supplementary analysis on a nationwide register-based cohort study. All patients in Denmark with an initial hospital contact with alcohol problems (alcohol intoxication, harmful alcohol use or alcohol dependence) 1998-2002, free of liver disease, were followed for diagnosis of alcoholic liver cirrhosis. The number of subsequent hospital contacts with alcohol problems was estimated as a time-dependent variable for each patient. RESULTS: In all, 36,044 hospital patients with an initial hospital contact with alcohol problems were included. These patients had 301,525 subsequent hospital contacts with alcohol problems. Risk of alcoholic liver cirrhosis increased ( p < 0.0001) with number of alcohol hospital contacts in both men and women for up to nine contacts. CONCLUSIONS: The number of prior hospital contacts with alcohol problems might provide clinicians with a helpful metric in deciding whether to offer preventive interventions for alcoholic liver cirrhosis.

Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study.

Alcoholic liver cirrhosis is usually preceded by many years of heavy drinking, in which cessation in drinking could prevent the disease. Alcohol problems are not consistently managed in hospital patients. We followed all Danish patients with an initial hospital contact with alcohol problems (intoxication, harmful use, or dependence) during 1998-2002 for alcoholic liver cirrhosis development (n = 36,044). In this registry-based cohort, we identified predictors of the absolute risk for alcoholic liver cirrhosis. Incidence rate ratios (IRRs) were estimated as the incidence rate of alcoholic liver cirrhosis in these patients relative to the general population. Age and alcohol diagnosis were significant predictors of alcoholic liver cirrhosis risk in men and women, whereas civil status, education, and type of hospital care were not. In men, the 15-year absolute risk was 0.7% (95% confidence interval [CI], 0.4, 0.8) for 20-29 years, 5.5% (95% CI, 4.9, 6.2) for 30-39 years, 9.8% (95% CI, 9.0, 11) for 40-49 years, 8.9% (95% CI, 8.1, 9.8) for 50-59 years, 6.2% (95% CI, 5.1, 7.2) for 60-69 years, and 2.5% (95% CI, 1.7, 3.3) for 70-84 years. According to alcohol diagnosis in men, the 15-year absolute risk was 2.6% (95% CI, 2.3, 2.9) for intoxication, 7.7% (95% CI, 6.4, 7.9) for harmful use, and 8.8% (95% CI, 8.2, 9.4) for dependence. The IRR for alcoholic liver cirrhosis in the cohort relative to the general population was 11 (95% CI, 10, 12) in men and 18 (95% CI, 15, 21) in women. CONCLUSION: Hospital patients with alcohol problems had a much greater risk for alcoholic liver cirrhosis compared to the general population. The risk was particularly increased for patients 40-59 years and for patients diagnosed with harmful use or dependence. (Hepatology 2017;65:929-937).

Anti-human platelet antigen (HPA)-1a antibodies may affect trophoblast functions crucial for placental development: a laboratory study using an in vitro model.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by maternal antibodies against paternal human platelet antigens (HPAs) on fetal platelets. Antibodies against HPA-1a are accountable for the majority of FNAIT cases. We have previously shown that high levels of maternal anti-HPA-1a antibodies are associated with clinically significant reduced birth weight in newborn boys. Chronic inflammatory placental lesions are associated with increased risk of reduced birth weight and have previously been reported in connection with FNAIT pregnancies. The HPA-1a epitope is located on integrin ß3 that is associated with integrin αIIb (the fibrinogen receptor) on platelets and megakaryocytes. Integrin ß3 is also associated with integrin αV forming the αVß3 integrin heterodimer, the vitronectin receptor, which is expressed on various cell types, including trophoblast cells. It is therefore thinkable that maternal anti-HPA-1a antibodies present during early pregnancy may affect placenta function through binding to the HPA-1a antigen epitope on invasive throphoblasts. The aim of the study was to examine whether interaction of a human anti-HPA-1a monoclonal antibody (mAb) with HPA-1a on trophoblast cells affect adhesion, migration and invasion of extravillous trophoblast cells. METHODS: An in vitro model with human anti-HPA-1a mAb, clone 26.4, and the first trimester extravillous trophoblast cell line HTR8/SVneo was employed. The xCELLigence system was utilized to assess the possible effect of anti-HPA-1a mAb on adhesion and migration of HTR8/SVneo cells. Specially designed chambers precoated with Matrigel were used to assess the effect on the invasive capacity of cells. RESULTS: We found that human anti-HPA-1a mAb 26.4 partially inhibits adhesion and migratory capacity of HTR8/SVneo cells. CONCLUSIONS: Our findings suggest that anti-HPA-1a antibodies may affect trophoblast functions crucial for normal placental development. Future studies including primary throphoblast cells and polyclonal anti-HPA-1a antibodies are needed to confirm these results.

Drug-induced liver injury: a cohort study on patients referred to the Danish transplant center over a five year period.

OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors of poor outcome. MATERIALS AND METHODS: We identified all patients diagnosed with DILI at the Department of Hepatology, Rigshospitalet, from March 2007 to November 2012. The following parameters were registered from patient files: drug causing DILI, symptoms, comorbidity, biochemistry, treatment and outcome. RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome.

Characterization of a human platelet antigen-1a-specific monoclonal antibody derived from a B cell from a woman alloimmunized in pregnancy.

Human platelet Ag (HPA)-1a, located on integrin ß3, is the main target for alloantibodies responsible for fetal and neonatal alloimmune thrombocytopenia (FNAIT) in the white population. There are ongoing efforts to develop an Ab prophylaxis and therapy to prevent or treat FNAIT. In this study, an mAb specific for HPA-1a, named 26.4, was derived from an immortalized B cell from an alloimmunized woman who had an infant affected by FNAIT. It is the only HPA-1a-specific human mAb with naturally paired H and L chains. Specific binding of mAb 26.4, both native and recombinant forms, to platelets and to purified integrins αIIbß3 (from platelets) and αVß3 (from trophoblasts) from HPA-1a(+) donors was demonstrated by flow cytometry and surface plasmon resonance technology, respectively. No binding to HPA-1a(-) platelets or integrins was detected. Moreover, the Ab binds with higher affinity to integrin αVß3 compared with a second HPA-1a-specific human mAb, B2G1. Further in vitro experimentation demonstrated that mAb 26.4 can opsonize HPA-1a(+) platelets for enhanced phagocytosis by monocytes, inhibit binding of maternal polyclonal anti-HPA-1a Abs, and weakly inhibit aggregation of HPA-1a-heterozygous platelets, the latter with no predicted clinical relevance. Thus, mAb 26.4 is highly specific for HPA-1a and could potentially be explored for use as a prophylactic or therapeutic reagent for FNAIT intervention and as a phenotyping reagent to identify women at risk for immunization.

The impact of gastric bypass surgery on sex hormones and menstrual cycles in premenopausal women.

Obesity has adverse effects on ovulation, menstrual cyclicity and oocyte development leading to clinical symptoms such as infertility and menstrual disorders. The Roux-en-Y gastric bypass (RYGB) leads to weight loss, improved insulin sensitivity and may improve ovarian function. In 31 premenopausal women, 18 eu- and 13 oligo-/amenorrhoic, we followed the changes in follicular phase sex hormones 3, 6 and 12 month after RYGB. The average weight loss during the first postoperative year was 39.6 kg. The insulin sensitivity and serum insulin improved markedly especially within the first three postoperative months. SHBG increased progressively and was doubled after 12 months. In contrast, total and free androgens and DHEA declined about 50% during the first three postoperative months and remained fairly constant hereafter. One year after surgery, 85% (11/13) of the women with oligo-/amenorrhea gained regular menstrual cycles. Our results indicate that some of the endocrine changes related to regulation of ovarian function occur very early after bariatric surgery.

Impaired Platelet Aggregation and Rebalanced Hemostasis in Patients with Chronic Hepatitis C Virus Infection.

Increased risk of both cardiovascular disease (CVD) and bleeding has been found in patients with chronic hepatitis C (CHC) infection, and a re-balanced hemostasis has been proposed. The aim of this study was to investigate functional whole blood coagulation and platelet function in CHC infection. The prospective study included 82 patients with CHC infection (39 with advanced liver fibrosis and 43 with no or mild liver fibrosis) and 39 healthy controls. A total of 33 patients were treated for CHC infection and achieved sustained virological response (SVR). Baseline and post-treatment blood samples were collected. Hemostasis was assessed by both standard coagulation tests and functional whole blood hemostatic assays (thromboelastograhy (TEG), and platelet aggregation (Multiplate). Patients with CHC and advanced fibrosis had impaired platelet aggregation both compared to patients with no or mild fibrosis and to healthy controls. Patients with CHC and advanced fibrosis also had lower antithrombin, platelet count, and coagulation factors II-VII-X compared to healthy controls. In contrast, TEG did not differ between groups. In treated patients achieving SVR, post-treatment platelet count was higher than pre-treatment counts (p = 0.033) and ADPtest, ASPItest, and RISTOhightest all increased post treatment (all p < 0.05). All Multiplate tests values, however, remained below those in the healthy controls. CHC-infected patients displayed evidence of rebalanced hemostasis with only partly hemostatic normalization in patients achieving SVR. The implications of rebalanced hemostasis and especially the impact on risk of CVD and bleeding warrants further studies.