Child-Pugh Category Research Articles

Pre-Treatment Trends in Child-Pugh Score as an Indicator of Post-Treatment Survival in Patients Receiving Liver SBRT for HCC

We sought to understand the value of Child-Pugh (CP) score trends prior to undergoing stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma in patients with advanced cirrhosis, as an indicator of post-treatment morbidity and mortality. We hypothesize that an uptrend in CP score prior to RT increases risk of post-treatment cirrhosis progression, or death. We retrospectively reviewed all patients who underwent definitive SBRT for HCC between 2014-2022 in our health system. Most patients were referred for treatment in the 2nd or 3rd line setting, allowing us to determine CP score at multiple points before SBRT. Response to treatment was evaluated with RECIST or mRECIST criteria. Acute treatment toxicities were assessed by CTCAE v5. OS was assessed using the Kaplan-Meier method, and differences between groups were evaluated using log-rank test. A total of 61 patients were identified, 26 had an immediate pre-SBRT CP score of A5, 11 with A6, 10 with B7, 4 with B8, 4 with B9, 5 with C10, and 1 with C11. Median prescribed dose was 40Gy in 5fx. Median OS of all patients was 24 months. When stratified by CP category, median OS for CP A was not reached (NR) at time of analysis, CP B had a median OS of 14.8mo, and CP C with 1.9mo (p < 0.01). Local control rate at 6mo was 87.5%. 5 patients (8.3%) had CTCAE grade 2 acute toxicity. 10 patients had CP score progression of 2pts or more within 6mo after treatment, and 7 patients had a cause of death attributed to end stage liver disease. Median time interval between HCC diagnosis and start of RT was 338 days. In this time interval, patients with a CP score increase of 2 pts or more prior to starting RT had a median OS of 362 days, compared to NR for patients without increase (p = 0.02). When excluding the CP A group, patients with 2 pt increase had median OS of 362 days vs 445 days (p = 0.34). Again excluding the CP A group, patients with a 1 pt increase had median OS of 362 days vs NR (p = 0.23). Of 9 patients who had a pre-RT CP score increase of 2 pts or more, 7 experienced continued CP progression after treatment. In this multi-institutional retrospective analysis, we found 24 patients with advanced CP B/C cirrhosis who underwent SBRT, none of whom received orthotopic liver transplant. While CP C patients did relatively poorly, we find that some patients with CP B cirrhosis may tolerate SBRT well with good oncologic effect. When taking pre-treatment CP score increase into consideration, we saw a trend but no statistical significance indicating that a pre-SBRT increase in CP score may be associated with worse OS after treatment among CP B/C patients. We conclude that there may be a subset of patients with advanced cirrhosis who, if well selected, are appropriate candidates for SBRT. We suggest a novel use of the CP score and pre-RT trends as an additional clinical tool to aid in decision making when selecting patients. We also suggest that patients with marked up-trending scores pre-treatment have a high likelihood of continued cirrhosis progression after treatment.

Polypharmacy in chronic liver disease patients: Implications for disease severity, drug-drug interaction, and quality of life

Multiple prescriptions for different medications may be needed for chronic conditions, increasing the risk of polypharmacy. The WHO defined polypharmacy as “the administration of many drugs at the same time or the administration of an excessive number of drugs”. The primary goal of this study was to evaluate polypharmacy in patients with chronic liver disease and to identify potential drug-drug interactions associated with it. A cross-sectional study was conducted at a tertiary care hospital in Mangalore, Karnataka, for six months, from November 2020 to April 2021.The study involved 118 patients with chronic liver disease from various age groups. Data was gathered by analyzing patients' medical records kept on the ward and interviewing them individually. In admission and discharge prescriptions, polypharmacy was examined. Online interaction checkers from Drugs.com and Medscape were used to interpret potential drug-drug interactions. The SF-36 and Chronic Liver Disease Questionnaire were used to measure the quality of life. The data obtained were analyzed statistically to determine the significant correlation. The number of prescribed drugs was significantly correlated (P = 0.018) with the severity of liver disease in Child-Pugh categories B and C. Additionally, moderate polypharmacy reduced quality of life (P < 0.05), and the physical health category was significantly associated with disease severity (P < 0.05). Drug-drug interactions were found in 108 out of the 118 examined prescriptions, totaling 586 interactions in the admission list and 405 interactions in the discharge list. If the potentially serious main drug interaction identified in this study is not well monitored, it could lead to a serious, potentially fatal health condition. Despite being advised, safety is not always guaranteed by liver enzyme monitoring. Therefore, healthcare providers must take additional precautions to avoid inappropriate prescribing, minimize side effects, and ensure drug safety.

Brigatinib pharmacokinetics in patients with chronic hepatic impairment

SummaryBrigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. This open-label, parallel-group study investigated the effect of chronic hepatic impairment on the pharmacokinetics (PK) of brigatinib to inform dosing recommendations for these patients. Participants with hepatic impairment classified according to Child-Pugh categories of mild (A), moderate (B), or severe (C) and matched-healthy participants with normal hepatic function received a single oral dose of 90-mg brigatinib. Plasma samples were collected for the determination of brigatinib plasma protein binding and estimation of plasma PK parameters. Twenty-seven participants were enrolled (Child-Pugh A–C, n = 6 each; matched-healthy participants, n = 9). The mean fraction of free plasma brigatinib was comparable for the Child-Pugh A (11.1%), Child-Pugh B (10.8%), and healthy participant groups (8.5%); free brigatinib was higher in the Child-Pugh C group (23.1%). There were no clinically meaningful effects of mild or moderate hepatic impairment on unbound systemic exposures (area under the plasma concentration-time curve [AUC]) of brigatinib (geometric least-squares mean ratios [90% CI] of 89.32% [69.79%–114.31%] and 99.55% [77.78%–127.41%], respectively). In the severe hepatic impairment group, brigatinib unbound AUC was approximately 37% higher (geometric least-squares mean ratio [90% CI] of 137.41% [107.37%–175.86%]) compared with healthy participants with normal hepatic function. Brigatinib was well tolerated in healthy participants and in participants with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. The brigatinib dose should be reduced by approximately 40% for patients with severe hepatic impairment.

The Prognostic Role of Spot Urinary Sodium and Chloride in a Cohort of Hospitalized Advanced Heart Failure Patients: A Pilot Study.

Recent studies have demonstrated the prognostic value of spot urinary sodium (UNa+) in acutely decompensated chronic HF (ADCHF) patients. However, data on the prognostic role of UNa+ and spot urinary chloride (UCl-) in patients with advanced HF are limited. In the present prospective pilot study, we examined the predictive value of UNa+ and UCl- concentration at baseline, at 2 h and at 24 h after admission for all-cause mortality and HF rehospitalization up to 3 months post-discharge. Consecutive advanced HF patients (n = 30) admitted with ADCHF and aged > 18 years were included in the study. Loop diuretics were administered based on the natriuresis-guided algorithm recommended by the recent HF guidelines. Exclusion criteria were cardiogenic shock, acute coronary syndrome, estimated glomerular filtration rate < 15 mL/min/1.73 m2, severe hepatic dysfunction (Child-Pugh category C), and sepsis. UNa+ at baseline (Area Under the Curve (AUC) = 0.75, 95% Confidence Interval (CI) (0.58-0.93), p = 0.019) and at 2 h after admission (AUC = 0.80, 95% CI: 0.64-0.96, p = 0.005) showed good and excellent discrimination, respectively. UCl- at 2 h after admission (AUC = 0.75, 95%CI (0.57-0.93), p = 0.017) demonstrated good discrimination. In the multivariate logistic regression analysis, UNa+ at 2 h (p = 0.02) and dose of loop diuretics at admission (p = 0.03) were the only factors independently associated with the study outcome. In conclusion, UNa+ and UCl- may have a prognostic role in hospitalized advanced HF patients.

Nutritional Assessment and Clinical Determinants in Patients Awaiting Liver Transplant

Background: Malnutrition is a usual problem in liver cirrhosis patients, progressing with advancement of disease. Protein-calorie malnutrition is related with illness and death, and the value of nutritional status assessment tools for malnutrition is debated. We conducted this study to monitor undernutrition assessment among cirrhotics using subjective global assessment (SGA) and standard anthropometric parameters and to observe the association of different clinical characteristics with SGA score and Child-Pugh classification. Methods: Patients enrolled were end-stage liver disease (ESLD) patients and obtained informed consent. The nutritional screening was performed using the SGA and standard anthropometry along with mid-upper arm circumference (MUAC), mid-arm muscle circumference (MAMC), triceps skin fold thickness (TST), and hand grip strength (HGS). Results: 141 ESLD patients awaiting liver transplant (LT) were enrolled in the study and among them, 113 (80.1%) were males and 28 (19.9%) females. Patient’s average age at presentation was 49.5 years. Alcoholism was the major etiological factor (51.1%) and its median duration was 10 years. The liver disease severity as per Child-Pugh classification was as follows: the majority, 66 (46.8%), were in Child-Pugh category B, and 27 (19.1%) were in Child-Pugh category C. The comparison of nutritional parameters with the Child-Pugh classification showed a statistical significance (P&lt;0.05) with BMI (body mass index) and MAMC between the Child-Pugh categories. The comparison of SGA nutrition scores shows that it does not significantly differ on average between gender, Child-Pugh classification, aetiologies, co-morbidity, oedema, and ascites status. The nutritional score was further categorized as normal, moderately malnourished, and severely malnourished based on the SGA score, and it shows that the nutritional level is significantly correlated with Child-Pugh classification and co-morbidity. The level of liver function parameters was not correlated with the level of different nutritional parameters. Conclusion: SGA and HGS can be used as an easy and economical tool for evaluating the level of nutrition among cirrhotics and can be consistently used in liver clinics for malnutrition screening, and one can plan for nutrition education and counselling. Nutritional level monitoring is challenging in patients with ESLD due to fluid retention, and SGA will be a better nutritional screening tool for nutritional assessment./p&gt;

Anticoagulation in atrial fibrillation and liver disease: a pooled-analysis of >20000 patients.

Anticoagulation for atrial fibrillation patients with liver disease represents a clinical dilemma. We sought to evaluate the efficacy/safety of different anticoagulation, i.e. vitamin K antagonist (VKA) and non-VKA oral anticoagulants (NOACs) in such patient group. This was a pooled-analysis enrolling up-to-date clinical data. Two subsets: subset A (VKA vs. Non-Anticoagulation) and subset B (NOACs vs. VKA) were pre-specified. The study outcomes were ischaemic stroke (IS)/thromboembolism (TE), major bleeding (MB), intracranial bleeding (ICB), gastrointestinal bleeding (GIB), and all-cause mortality. A total of 20042 patients' data were analysed (subset A: N = 10275, subset B: N = 9767). Overall mean age: 71 ± 11 years, mean CHA2DS2-VASc score: 4.0 ± 1.8, mean HAS-BLED score: 3.6 ± 1.2. The majority of the patients had Child-Pugh category (A-B). As compared with Non-Anticoagulation, VKA seemed to reduce the risk of IS/TE [odds ratio (OR): 0.60, P = 0.05], but heighten the risk of all-bleeding events including MB (OR: 2.81, P = 0.01), ICB (OR: 1.60, P = 0.01), and GIB (OR: 3.32, P = 0.01). When compared with VKA, NOACs had similar efficacy in reducing the risk of IS/TE (OR: 0.82, P = 0.64), significantly lower risk of MB (OR: 0.54, P = 0.0003) and ICB (OR: 0.35, P < 0.0001), and trend towards reduced risk of GIB (OR: 0.72, P = 0.12) and all-cause mortality (OR: 0.79, P = 0.35). The favourable effects were maintained in subgroups of individual NOAC. VKA appears to reduce the risk of IS/TE but increase all-bleeding events. NOACs have similar effect in reducing the risk of IS/TE and have significantly lower risk of MB and ICB as compared with VKA. NOACs seem to be associated with better clinical outcome than VKA in patients with mild-moderate liver disease.

Evaluating the Short-Term Clinical Efficacy of Magnetic Resonance Elastography in Patients with Budd-Chiari Syndrome

To investigate the clinical relevance of liver stiffness (LS) in evaluating liver function properties in patients with Budd-Chiari syndrome (BCS) with different severities and LS variation before and after endovascular intervention. Between December 2016 and March 2019, patients with a diagnosis of BCS were considered for enrollment consecutively in our study. Liver function of these patients was classified according to Child-Pugh grading standard before treatment. Liver function parameters were recorded, including albumin, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and total bilirubin. LS was measured with MR elastography (MRE) before and after treatment. Pearson correlation analysis was performed to measure the correlation between LS and liver function-related parameters. Univariate analysis of variance test was used to compare LS and clinical quantitative variables of patients in three different Child-Pugh categories. Paired t test with a significant threshold of p = 0.05 was used to compare LS and pressure gradient of these patients before and after treatment. Correlation analysis between changes in LS and that in pressure gradient was performed by linear regression. A total of 43 patients (23 males and 20 females) were finally enrolled in this study. The mean LS in the three groups was 5.67 ± 1.15 kPa (Child-Pugh A), 6.31 ± 1.13 kPa (Child-Pugh B), and 8.27 ± 2.22 kPa (Child-Pugh C), respectively. LS showed significant difference for patients with different Child-Pugh grades (F = 9.536, p < 0.001). Prothrombin time and total bilirubin were positively correlated with LS (p < 0.05). After treatment, mean LS in three groups was 4.83 ± 1.06 kPa, 5.12 ± 0.93, and 7.37 ± 1.96, respectively. LS decreased significantly in all three Child-Pugh grades (p < 0.001 from Child-Pugh A, p < 0.001 from Child-Pugh B, p = 0.009 from Child-Pugh C). The mean pressure gradient before intervention was 17.6 ± 4.9 mm Hg, and 8.7 ± 7.2 mm Hg after the treatment (p < 0.001). The changes in LS were correlated to that in pressure gradients (r = 0.439; r2 = 0.193; p = 0.015). MR elastography for LS measurement has been demonstrated to act as an effective tool to evaluate liver function, and to monitor the BCS patients in follow-up treatments.

Incidence of complications associated with liver cirrhosis

Introduction. Liver cirrhosis is the final stage of various chro­nic liver diseases, being characterized by abnormal struc­ture due to fibrosis and regenerating nodules. The Child-Pugh score is calculated to assess the prognosis in pa­tients with liver cirrhosis. The specific aim of this study was to create an overview of the complications associated with each Child-Pugh category, which will lead to closer mo­ni­to­ring and a targeted, tailored and individualized the­ra­peu­tic approach. Materials and method. We made a retrospective study on a series of 144 consecutive patients who were admitted in the Gastroenterology Department of the Târgu-Mureş County Clinical Emergency Hospital between the 1st of January 2019 and the 31st of December 2019. In order to eva­luate the complications associated with each Child-Pugh category, the enrolled participants were stratified in three groups ac­cor­ding to Child-Pugh score. Results. The major patho­phy­sio­lo­gical consequence of liver cirrhosis remains portal hypertension, followed by its complications, such as ascites and esophageal varices. According to the Child-Pugh score, the distribution was as follows: 47% for class C, 29% for class B and 24% for class A. Regarding the etiology of liver disease, the one with the highest involvement was the ethanolic one, in proportion of 71%, followed by the viral one – 20% and other causes – 9%. As cirrhosis stage progresses, com­pli­ca­tions are more frequent, with multiple side effects as­so­cia­tions, which lead to therapeutic approaches adapted to each case. Conclusions. Regarding the complications as­so­cia­ted with each degree of cirrhosis, an increase in their prevalence was observed as the result of the Child-Pugh score increases. The management of patients with cir­­rhosis must take this score into account, in order to pre­vent complications or to properly treat the secondary ma­ni­fes­ta­tions that have already occurred.

Spectrum of bacterial infections and predictors of mortality in adult cirrhotic patients.

BackgroundBacterial infections are more frequent in patients with decompensated cirrhosis than those with compensated liver disease and account for significant morbidity and mortality in them. Once an infection develops, it induces excessive production of pro-inflammatory cytokines leading to organ failure and death.AimsThis study aims to identify the clinical characteristics and outcome of bacterial infections affecting various organ systems in patients with liver cirrhosis and to determine factors associated with mortality.MethodsA cross sectional study was performed on subjects with cirrhosis having microbiologically proven bacterial infection involving various organ systems, admitted to a tertiary care hospital in southern India. Demographic, clinical data, laboratory parameters and outcome details were noted. Univariate associations and subsequent multivariate logistic regression analysis was performed to determine factors associated with mortality.ResultsThe study included 158 patients. Chronic alcohol intake was the most common etiology of cirrhosis (66.4%). Community acquired infections occurred more frequently than hospital acquired infections (85.5% vs 14.5%). The common site of isolation of etiological agent was ascitic fluid (38.3%) followed by blood (24.3%), respiratory tract (15.5%) and urinary tract (14.5%). Gram negative bacterial infections were more common (74.3%), Escherichia coli being the most frequent pathogen (38.5%). Mortality was noted in 38 (24%) patients. The factors associated with mortality were the type of infection, Child Pugh category, acute kidney injury, hepatic encephalopathy, urinary tract infection, and creatinine and bilirubin levels. Multivariate logistic regression analysis revealed that type of infection (OR: 0.33, 95% CI: 0.11–1.01), ascitic fluid infection (OR: 2.81, 95% CI: 1.11–7.12), hepatic encephalopathy (OR: 0.17, 95% CI: 0.070–0.422) and acute kidney injury (OR: 0.19, 95% CI: 0.077–0.502) were significantly associated with in-hospital mortality.ConclusionThis study indicates that the type of infection, hepatic encephalopathy, ascitic fluid infection and acute kidney injury are associated with mortality in cirrhotic patients. Early effective treatment and prevention of these complications may help modify the outcome.

Guidance for Transitioning Among Anticoagulants.

Guidance for Transitioning Among Anticoagulants.

Evaluating Safety and Dosimetry of SBRT following 90Y for Hepatocellular Carcinoma

Liver directed therapy is fundamental in the treatment of HCC. SBRT is the only non-invasive local therapy characterized by precise target delineation and accurate, quantifiable dosimetry. Often, SBRT is utilized following interventional therapy; however, there is a lack of data reporting safety and outcomes of patients receiving liver SBRT after yttrium-90 (90Y). We performed a safety and dosimetric evaluation in our series of HCC patients who received SBRT after 90Y by compiling post 90Y PET imaging fusions with SBRT treatment plans for accurate quantification of liver exposed to both SBRT and 90Y. An institutional review board-approved liver SBRT registry of 197 patients was used for data collection. All patients had post-90Y PET (measuring Bremsstrahlung component of 90Y) fused to SBRT treatment planning CT creating composite plans for dosimetric analysis. Volume of ablated liver was estimated using the sharp gradient edge of post-90Y PET, and the 30 Gy isodose line for SBRT (V30). Clinical and laboratory follow up 3 months post SBRT were used to evaluate safety. Changes in chemistry and hematology related to hepatic function, using CTCAE v4.0, were analyzed. Sixteen patients with non-metastatic HCC and prior 90Y were treated with SBRT to 18 intrahepatic sites. Patients received 23 prior 90Y administrations; six patients were treated twice and one patient treated three times. Child-Pugh (CP) category at SBRT was A in 12, and two each of B and C. SBRT dose was 35-50 Gy in 3-5 fractions (median 50 Gy/5). Median time between 90Y and SBRT was 4.6 months (range 1.3-34.8). Mean follow up was 14 months, and 11 patients were alive at analysis. Treatment intent was definitive for 13 patients and downstaging in 3. Mean total liver volume was 2,000 cc (range 986-3304), SBRT PTV 209 cc (range 26-494), and individual 90Y treatment volume 308 cc (range 36-1477). Liver ablative results summarized in Table 1.Abstract SU_13_2123; Table 1Mean valueMean %RangeV30 liver (SBRT)273 cc13.7%36-739 cc (3-34.8%)90Y volume (sum)436 cc22.6%95-1512 cc (3.5-52.6%)V30 volume within prior 90Y93 cc33.2%0-306 cc (0-75%) Open table in a new tab Laboratory data was available for 75% of patients. At 3 months post SBRT there were no new grade ≥2 changes from baseline in bilirubin, hemoglobin, INR, AST, ALT, and albumin in CP-A/B patients. The two CP-C patients, who had higher 90Y volumes and more overlap of 90Y with V30, demonstrated clinically significant hepatic decompensation. Although toxicity was noted, both patients were successfully down-staged within Milan then rescued with transplant 10 and 15 weeks post SBRT. This is the first series to incorporate PET delineation of 90Y ablation distribution in a composite plan with SBRT. Our experience of CP-A /B patients demonstrates minimal toxicity, but notable decompensation in CP-C patients. SBRT can be an effective tool to downstage within Milan but extra caution is warranted in this group, such that risk matches treatment intent, especially in patients that may not be rescued with transplant.

Serum BTP concentrations are not affected by hepatic dysfunction

BackgroundBeta Trace Protein (BTP) is a promising marker of glomerular filtration rate (GFR). Equations to estimate GFR using BTP have been proposed. Very little is known about BTP’s production and metabolism. It has been hypothesized that the liver metabolizes certain BTP isoforms. As such, hepatic dysfunction may influence serum levels independently of GFR. This would impact on the accuracy and precision of GFR estimates using BTP. The purpose of this study was to assess the impact of cirrhosis on serum BTP concentrations.MethodsBTP, cystatin C (cysC) and creatinine (Cr) were measured in 99 cirrhotic subjects and in matched controls. BTP/cysC and Cr/cysC ratios were compared between cases and controls. This was repeated after stratification by Child Pugh category. Comparisons of ratios between Child Pugh category A and combined B and C case subjects were also performed.ResultsThere were no differences in BTP/cysC ratios between cases and controls for the entire cohort (0.80 vs 0.79) or for any of the Child Pugh categories (p > 0.10). There were significant differences between cases (1.09) and controls (0.73) for the BTP/Cr ratios (p < 0.001). The BTP/Cr ratio was higher in those with more advanced cirrhosis as compared to those with less severe cirrhosis (1.20 vs 1.03, p < 0.01). There were no differences in BTP/cysC ratios between those with less severe and more advanced cirrhosis (p = 0.25).ConclusionsThis study suggests that hepatic dysfunction does not influence serum BTP levels and argues against a significant role for the liver in BTP metabolism. Confirmation in a larger group of patients with advanced cirrhosis is required.

Stereotactic ablative radiation therapy prior to liver transplantation in hepatocellular carcinoma.

Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable effectiveness to other local therapies. Only scant information is available concerning the role of SABR prior to liver transplantation (LT) for HCC. We present a consecutive case series investigating the role of SABR as a bridge or downstaging option in HCC patients subsequently submitted to LT. Between September 2012 and May 2014, 8 patients for a total of 13 lesions underwent SABR prior to LT. Inclusion criteria were a pathological or radiological diagnosis of HCC, lesion size ≤6cm or lesion number ≤3 with a total diameter ≤6cm, no extrahepatic metastases, Child-Pugh class A-B, ECOG performance status ≤1. Patients were prescribed 36-48Gy in 3-5 fractions (8Gy×5 fractions or 16Gy×3 fractions), in 3-5 consecutive days according to clinical and dosimetric decision making. Radiological response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Pathological response was assessed through the rate of tumor necrosis relative to the total tumor volume. Acute and late toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (CTCAE v 4.0). Among the 13 pathologically evaluated lesions, 8 (61.5%) lesions had a complete response 2 (15.3%) had a minimal pathological response and other 2 (15.3%) showed stable disease. The remaining lesion had a significant pathological response. Maximum detected toxicity included a G2 GGT increase in two patients (at 1 and 3months respectively). One patient developed a non-classic RILD with a fivefold increase in transaminase enzymes level and a shift in Child-Pugh category from B7 to C10 due to bilirubin increase. Only one modification in the surgical strategy was needed during LT. SABR proved to be a safe and effective local therapy prior to LT in HCC patients. Prospective controlled clinical trials are needed to evaluate its efficacy compared to other local therapies in this setting.

Phosphatidylserine on blood cells and endothelial cells contributes to the hypercoagulable state in cirrhosis.

The mechanism of thrombogenicity in cirrhosis is largely unknown. Our objective was to study the relationship between phosphatidylserine on blood cells and endothelial cells and the hypercoagulable state in cirrhotic patients. Patients with cirrhosis and healthy controls were studied. Lactadherin was used to quantify phosphatidylserine exposure on blood cells and endothelial cells. Procoagulant activity of cells was evaluated using clotting time and purified coagulation complex assays. Fibrin production was determined by turbidity. Phosphatidylserine exposure, fibrin strands and FVa/Xa binding on cells were observed using confocal microscopy. Our study showed that phosphatidylserine exposure on erythrocytes, platelets and leucocytes in cirrhotic patients increased progressively with Child-Pugh categories. In addition, we found that endothelial cells treated with cirrhotic serum in vitro exposed more phosphatidylserine than those exposed to healthy serum. The exposed phosphatidylserine supported a shorter coagulation time and increased FXa, thrombin and fibrin formation. Notably, phosphatidylserine+ erythrocytes also promoted shorter coagulation times and more fibrin generation in cirrhotic microparticle-depleted plasma, regardless of Child-Pugh categories. Confocal microscopy data showed that the FVa/FXa complex and fibrin fibrils colocalized with phosphatidylserine on endothelial cells. Lactadherin significantly inhibited FXa and thrombin generation and consequently decreased fibrin production in normal or cirrhotic plasma. These results lead us to believe that exposed phosphatidylserine on activated or injured erythrocytes, platelets, leucocytes and endothelial cells plays an important role in the hypercoagulable state in cirrhotic patients. Thus, blocking phosphatidylserine binding sites might be a new therapeutic target for preventing thrombosis.

CT-guided Interstitial Brachytherapy of Hepatocellular Carcinoma before Liver Transplantation: an Equivalent Alternative to Transarterial Chemoembolization?

Transarterial chemoembolization (TACE) is established as bridging therapy of HCC listed for transplantation (LT). CT-guided brachytherapy (CTB) has not been evaluated as a bridging concept. We compared CTB and TACE for bridging before LT in HCC patients. Twelve patients with HCC received LT after CTB (minimal tumour dose, 15-20Gy). Patients were matched (CTB:TACE, 1:2) by sex, age, number and size of lesions, and underlying liver disease with patients who received TACE before transplantation. Study endpoints were extent of necrosis at histopathology and recurrence rate after OLT. There were no significant differences between the CTB and TACE groups regarding Child-Pugh category (p = 0.732), AFP (0.765), time on waiting list (p = 0.659), number (p = 0.698) and size (p = 0.853) of HCC lesions, fulfilment of Milan-criteria (p = 0.638), or previous liver-specific treatments. CTB achieved higher tumour necrosis rates than TACE (p = 0.018). The 1- and 3-year recurrence rate in the CTB group was 10 and 10% vs. TACE, 14 and 30% (p = 0.292). Our data show comparable or even better response and post-LT recurrence rates of CTB compared to TACE for treating HCC in patients prior to LT. CTB should be further evaluated as an alternative bridging modality, especially for patients not suited for TACE. • CT-guided interstitial brachytherapy (CTB) is a promising alternative to transarterial chemoembolization (TACE). • CTB instead of TACE is possible for bridging to liver transplantation in HCC patients. • HCC recurrence was not associated with CTB despite potential tumour seeding.

Association between pretreatment retention rate of indocyanine green 15 min after administration and life prognosis in patients with HCC treated by proton beam therapy

PurposeThe Child-Pugh score is often used to judge the outcome of radiotherapy for hepatocellular carcinoma (HCC). The retention rate of indocyanine green 15min after administration (ICG R15) can also be used to predict prognosis after liver resection. We evaluated the utility of ICG R15 for prediction of outcomes after proton beam therapy (PBT) for HCC. Methods and materialsA retrospective evaluation was performed in 250 patients who received PBT between 2002 and 2007. The patients (178 males and 72 females) had a median age of 71years (range: 43–88). Child-Pugh categories were A (score 5–6), B (7–9), and C (10–15) in 197, 51, and 2 patients, respectively. ICG scores were 0–<10, 10–<20, 20–<30, 30–<40 and ⩾40 in 27, 99, 59, 28 and 37 patients, respectively; including 26, 92, 45, 16 and 18 Child-Pugh A patients and 1, 8, 14, 11, and 17 Child-Pugh B patients, respectively. Survival times from the start of PBT were compared between Child-Pugh A and B patients, and among each ICG group. ResultsThe median survival times were 61months (95% CI: 50–72months) in all patients, and 64 and 20months in Child-Pugh A and B patients, respectively (p=0.001), The 3-year survival rates were 72%, 72%, 75%, 63%, and 26% in patients with ICG scores of 0–<10, 10–<20, 20–<30, 30–<40, and ⩾40 (p=0.001); 70%, 75%, 77%, 65%, and 38% in these respective groups in Child-Pugh A patients (p=0.02); and 100%, 57%, 67%, 36%, and 14% in Child-Pugh B patients (p=0.173, not significant). Multivariate analysis showed that low ICG R15 and the absence of portal vein tumor thrombus were associated with good survival. ConclusionsPretreatment ICG R15 is a useful prognostic factor for prediction of outcome of PBT in HCC patients, especially in those with Child-Pugh A liver function.

Effect of moderate liver impairment on the pharmacokinetics of opicapone

Opicapone (OPC) is a novel catechol-O-methyltransferase (COMT) inhibitor to be used as adjunctive therapy in levodopa-treated patients with Parkinson's disease. The purpose of this study was to evaluate the effect of moderate liver impairment on the pharmacokinetics (PK) and pharmacodynamics (PD; effect on COMT activity) of OPC. An open-label, parallel-group study in patients (n = 8) with moderate liver impairment (Child-Pugh category B, score of 7 to 9) and matched healthy subjects (n = 8, control) with normal liver function. All subjects received a single 50-mg oral dose of OPC, with plasma and urine concentrations of opicapone and its metabolites measured up to 72h post-dose, including soluble COMT (S-COMT) activity. A one-way analysis of variance (ANOVA) was used to compare the main PK and PD parameters between groups. Point estimates (PE) of geometric mean ratios (GMR) and corresponding 90% confidence intervals (90%CI) for the ratio hepatic/control subjects of each parameter were calculated and compared with the reference interval (80-125%). Exposure to opicapone (AUC and Cmax) increased significantly in patients with moderate hepatic impairment (PE [90%CI]: AUC0-∞, 184% [135-250%]; Cmax, 189% [144-249%]). Although apparent total clearance (CL/F) of opicapone was decreased by ∼35%, similar elimination half-life and unbound/bound fractions of opicapone were observed between the two groups. Both rate and extent of exposure to BIA 9-1103 were higher in the hepatically impaired group, but not statistically significant compared with the control group. Similar to the parent (opicapone), the observed increase in exposure to BIA 9-1106 was statistically significant in the hepatically impaired group over the control group. BIA 9-1106 was the only metabolite detected in urine and its urine PK parameters were in accordance with plasma data. Maximum S-COMT inhibition (Emax) occurred earlier for the hepatically impaired group with values of 100% and 91.2% for the hepatically impaired and control groups respectively. Both Emax and AUEC for the hepatically impaired group reached statistical significance over the control group. OPC was well tolerated in both hepatically impaired and control groups. The bioavailability of an orally administered single dose of 50mg OPC was significantly higher in patients with moderate chronic hepatic impairment, perhaps by a reduced first-pass effect. As the tolerability profile of OPC was favourable under the conditions of this study and its exposure is completely purged from systemic circulation before the subsequent dose administration, no OPC dose adjustment is needed in patients with mild to moderate chronic hepatic impairment. However, as OPC is under clinical development for use as adjunctive therapy in levodopa-treated patients with Parkinson's disease, an adjustment of levodopa and/or OPC regimens in patients should be carefully considered based on a potentially enhanced levodopa dopaminergic response and the associated tolerability.

Coagulation imbalance may not contribute to the development of portal vein thrombosis in patients with cirrhosis

IntroductionThe relationship between the imbalance in pro- and anti-coagulant factors and portal vein thrombosis (PVT) in individuals with cirrhosis is unclear. The aim of this study was to determine whether the imbalance in pro- and anti-coagulant factors contributes to the development of PVT in cirrhotic patients. Materials and methodsBlood samples were collected from 30 consecutive cirrhotic patients with PVT and 30 age-, sex-, and Child-Pugh score-matched cirrhotic patients without PVT (controls), and the plasma levels of coagulation factors II, V, VII, VIII, IX, X, XI and XII and of protein C (PC), protein S (PS) and antithrombin (AT) were analyzed. The ratios of pro- vs. anti-coagulant factors were further investigated. ResultsThe levels of pro- and anti-coagulant factors were not statistically different between the PVT and control groups. Similar results were obtained when the patients were divided according to Child-Pugh classification. No difference was observed for the ratios of pro- vs. anti-coagulant factors between the two groups but the ratios of factor II-to-PC and factor VII-to-PC which were significantly decreased in the PVT group. Most of the ratios did not reach statistical significance in each Child-Pugh category except the followings: factor VIII-to-PS, factor XII–to-PC and factor XII-to-PS in class A patients; factor II-to-PS, factor VII-to-PC and factor VII-to-PS in class B patients. But the difference might not be so convincing. ConclusionsPVT in cirrhotic patients may not result from coagulation imbalance.

Female-to-Male Match Predicted Poor Survival After Living-Donor Liver Transplantation—Some Issues Needed to be Clarified

We read with great interest the recent article by Yoshizumi et al. (1), which evaluated the risk factors that increased mortality after living-donor liver transplantation. Their study found that male recipients of transplants from female donors (FM), those having pretransplantation diabetes mellitus (DM), and having a model for end-stage liver disease score of 20 or more were independent risk factors that predicted poor survival for LDLT recipients. Nevertheless, close inspection of the study revealed some methodological issues that are worth mentioning and clarifying. First, Yoshizumi et al. (1) reported 335 cases of living-donor liver transplantation (LDLT), which included 180 cases of benign end-stage liver diseases and 155 cases of hepatocellular carcinoma (HCC). HCC accounts for nearly half of the cohort patients, and HCC recurrence is the main cause of death in the study (14/80). However, none of the risk factors that increased mortality after LDLT in the study, to our knowledge, is related to HCC recurrence. Tumor recurrence is the main cause of death after liver transplantation for HCC, as demonstrated by previous studies (2, 3). Not surprisingly, some factors associated with biologic aggressiveness, such as tumor number, tumor differentiation grade, presence of a peritumoral capsule, and microscopic vascular invasion, were independent predictors of survival (4–7). In other words, tumor biology determines outcome after liver transplantation for HCC, whereas for benign end-stage liver diseases, the factors that predicted survival were model for end-stage liver disease scores and Child-Pugh category (8–10). Recently, Li et al. (11) reported that preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 U, and female-to-male gender match were independent risk factors that predicted poor survival for LDLT recipients with benign end-stage liver diseases. Therefore, it is not very proper to analyze the factors that predicted poor survival of LDLT recipients, which were mixed by benign end-stage liver diseases and HCC. The authors should separately analyze the factors that predicted survival of LDLT for HCC and benign end-stage liver diseases. Second, the authors reported that the 1-year, 3-year, and 5-year survival rates after LDLT for HCC were 91.7%, 80%, and 69%, whereas rates for benign end-stage liver diseases were 80.5%, 74.7%, and 73.0% (in Table 2 of Yoshizumi et al. (1)). Patients in the HCC group showed higher 1-year, 3-year, 5-year survival rates compared with patients in the benign end-stage liver diseases group, although this difference was not statistically significant (P=0.077). Did the authors consider that the long-term survival rates of LDLT for HCC were equal to LDLT for benign liver diseases? What criteria were used to screen HCC patients for LDLT in the authors’ institute? Milan criteria, University of California San Francisco criteria, or other criteria? Third, the distribution of the HCC was markedly skewed among the four groups (in Table 1 of Yoshizumi et al. (1)), and the FM group owned the highest proportion of HCC in the four groups (P<0.001). Although the HCC was not identified as a risk factor that predicted poor survival in the study, a subgroup analysis in the FM group should be performed according to the HCC to exclude the effect of HCC on survival. Moreover, the pretransplantation DM is another risk factor that predicted poor survival after LDLT. Similarly, the distribution of the pretransplantation DM was markedly skewed among the four groups (in Table 1 of Yoshizumi et al. (1)). The female donor to female recipient group owned the lowest proportion of pretransplantation DM (0%), whereas the FM group owned a significantly higher proportion of pretransplantation DM (20.33%) (P=0.001). In contrast, the FM group showed significantly worse patient survival rates compared with the female donor to female recipient group (P<0.01). In order to exclude the effect of pretransplantation DM on survival in the FM group, a subgroup analysis should be performed according to the pretransplantation DM. The authors can perform a subgroup analysis in the FM group according to the graft weight-standard liver weight ratio. Why did the authors not perform a subgroup analysis in the FM group according to the pretransplantation DM?

Pharmacokinetics of Nilotinib in Subjects with Normal or Impaired Hepatic Function.

Nilotinib, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity at 400 mg twice daily dosing against imatinib-resistant forms of Bcr-Abl in patients with CML or Ph+ALL in an open label phase I/II study. In this patient population, elevated liver transaminases levels over baseline, which may be related to a combination of past medical history and the hepatotoxic effects of previous medications, are frequently observed but are generally mild and self-limiting. Nilotinib is metabolized in the liver by CYP3A4, and the metabolites are excreted exclusively via the bile into feces. This study was designed to assess pharmacokinetics of nilotinib across a broad spectrum of hepatic impairment in comparison to a control group with normal hepatic function in order to provide guidance for the safe use of the drug in patients with hepatic impairment. Hepatic impairment was categorized using the three Child-Pugh categories (mild, moderate, and severe). The demographics of the impaired and control group were similar with respect to ethnicity, age (years) impaired (47–64) control (48–62), BMI (kg/m2) impaired (23.6–34.7) control (22.8–32.0), and weight (kg) impaired (73.9–103.9) control (73.3–109.5). Serum samples for determination of nilotinib serum concentration by liquid chromatography tandem mass spectrometry were collected up to 120 hours following a single oral 200 mg dose of nilotinib after an overnight fast. Pharmacokinetic parameters were derived from the individual serum concentration-time data by non-compartmental methods. Pre-dose (nilotinib-free) serum samples were obtained to determine ex vivo nilotinib serum protein binding. The results from 14 subjects (6 subjects in each of the mildly and moderately impaired groups and 8 in the control group) in this ongoing study are reported here. Nilotinib exposure at 200 mg dose was similar in patients from a previous clinical study and subjects in the control group of this study. Nilotinib AUC was increased on average by 18% in the mild impairment group, and 23% in the moderate impairment group as compared to the control group. A total of 6 grade 1 and 2 adverse events were reported comprising of back pain, worsening abdominal pain, headache, nausea, heart burn, and indigestion. One adverse event (grade 2 worsening back pain) was reported in the control group. No laboratory or cardiac monitoring findings were considered as adverse events during the treatment period. The currently available results suggest that the pharmacokinetic profile of nilotinib is comparable between subjects with normal hepatic function and subjects with mild or moderate hepatic impairment.