Child-Pugh Class Research Articles

#2511 Usefulness of cystatin C in measuring renal function in patients with liver cirrhosis

Abstract Background and Aims Liver cirrhosis (LC) is often accompanied by acute kidney injury, and renal function is known to be a significant factor in mortality of patients with LC. However, LC is a representative protein-energy-wasting disease, and there are limitations in measuring renal function using muscle based creatinine (Cr). Therefore, this study tried to investigate the discrepancy in the estimated glomerular filtration rate (eGFR) using conventional serum Cr and cystatin C in patients with LC Method In total, 121 patients were enrolled, and eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on both serum Cr and cystatin C levels. Each eGFR was classified into three categories with GFR < 10 mL/min/1.73 m2 (group A), 10-50 mL/min/1.73 m2 (group B), and > 50 mL/min/1.73 m2 (group C) mL/min/1.73 m2, distribution was evaluated according to Child-Pugh classification. Results Of the 121 patients, 69 were Child-Pugh A, 32 were Child-Pugh B, and 20 were Child-Pugh C. The mean eGFR using serum Cr was 85.35 mL/min/1.73 m2, which was higher than the eGFR using cystatin C of 69.52 mL/min/1.73 m2 (p < 0.05) After converting eGFRcr to eGFRcystatinC, the number of patient with group change was 11 (15.9%) in the Child-pugh A, 8 (18%) in Child-Pugh B and 5(25%) in Child-Pugh C (Child-Pugh A: 9 in A↔B, 2 in B→C, Child-Pugh B: 5 in A↔B, 3 in B→C, Child-Pagh C: 4 in A→B, 1 in B→C). Except for 2 patients, eGFR decreased when converting eGFRcr to eGFRcystatinC (p < 0.05). Conclusion In patients with LC, the eGFRcystatinC is significantly lower than that of eGFRcr. And this was significant in cirrhotic patient with a high Child-Pugh class.

Treatment of portal hypertension complicated by variceal bleeding

Background. Mortality in variceal bleeding (VB) on the background of portal hypertension (PH) is highest among patients with gastrointestinal bleeding. The treatment of PH complicated by VB is a complex problem that is far from being solved, especially in case of Child-Pugh class B and C decompensation. The aim of the study was to determine the causes of PH complicated by VB, features of conservative and interventional therapy, indications and nature of surgical procedures, treatment efficacy, as well as causes of complications and mortality. Materials and methods. We analyzed treatment outcomes of 923 inpatients with PH complicated by VB who were treated in the clinic of the Department of Surgery of the Faculty of Dentistry of Bogomolets National Medical University on the basis of the Kyiv City Clinical Emergency Hospital from 2012 to 2023. It was possible to talk about the cause of PH based on anamnestic data in 61 % of cases. In 711 (77 %) patients, the source of bleeding was detected endoscopically within 30–60 minutes from the moment of admission to the clinic. Conservative therapy included the administration of hemostatic and agents lowering pressure in the portal system, as well as vasoconstrictors that reduce portal blood flow. For the failure of conservative therapy, unstable hemostasis, and repeated previous bleedings, 59 (6.4 %) patients were operated. The methodology of the research analysis consisted in the fact that the arithmetic mean and standard error (M ± m) were determined as the characteristics of the groups for features with a distribution corresponding to the Gaussian law. This reference method of descriptive statistics was applied to evaluate surgical treatment in comparison with conservative therapy and interventional measures. Results. Endoscopic hemostasis by the ligature method was achieved in 97 (10.5 %) patients. Repeated endoscopy due to VB recurrence was done in 276 (29.9 %) participants. In cases of unsatisfactory endoscopic hemostasis, as well as recurrent VB, a Sengstaken-Blakemore probe was installed. In case of right-sided PH, the formation of varices in the esophagus is caused by the discharge of blood mainly through the coronary vein, which required its transection during еsophagogastric devascularization. In compliance with this rule, the patients underwent esophagogastric devascularization, circular transection of the esophagus, which provided portoazygous disconnection. The total mortality rate was 43.1 %, among operated people — 8.5 %, and among non-operated ones — 42.1 %. Conclusions. PH complicated by VB is evidence of decompensated processes in the liver parenchyma or obstruction in the portal system. Conservative therapy and interventional measures make it possible to stop bleeding and prepare the patient for elective surgery, if necessary. An operation that stops blood flow through dilated veins of the esophagus or stomach is an effective method of treating bleeding in portal hypertension.

Albumin-bilirubin grade as a predictor of survival in hepatocellular carcinoma patients with thrombocytopenia.

The models for assessing liver function, mainly the Child-Pugh (CP), albuminbilirubin (ALBI), and platelet-ALBI (PALBI) classifications, have been validated for use in estimating the prognosis of hepatocellular carcinoma (HCC) patients. However, thrombocytopenia is a common finding and may influence the prognostic value of the three models in HCC. To investigate and compare the prognostic performance of the above three models in thrombocytopenic HCC patients. A total of 135 patients with thrombocytopenic HCC who underwent radical surgery were retrospectively analyzed. Preoperative scores on the CP, ALBI and PALBI classifications were estimated accordingly. Kaplan-Meier curves with log-rank tests and Cox regression models were used to explore the significant factors associated with overall survival (OS) and recurrence-free survival (RFS). The preoperative platelet counts were significantly different among the CP, ALBI and PALBI groups. After a median follow-up of 28 mo, 39.3% (53/135) of the patients experienced postoperative recurrence, and 36.3% (49/135) died. Univariate analysis suggested that α-fetoprotein levels, tumor size, vascular invasion, and ALBI grade were significant predictors of OS and RFS. According to the multivariate Cox regression model, ALBI was identified as an independent prognostic factor. However, CP and PALBI grades were not statistically significant prognostic indicators. The ALBI grade, rather than CP or PALBI grade, is a significant prognostic indicator for thrombocytopenic HCC patients.

Beneficial effects of maintaining liver function during hepatic arterial infusion chemotherapy combined with tyrosine kinase and programmed cell death protein-1 inhibitors on the outcomes of patients with unresectable hepatocellular carcinoma

Background and aimCombination therapy is the primary treatment for unresectable hepatocellular carcinoma (u-HCC). The hepatic functional reserve is also critical in the treatment of HCC. In this study, u-HCC was treated with combined hepatic arterial infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKIs), and programmed cell death protein-1 (PD-1) inhibitors to analyze the therapeutic response, progression-free survival (PFS), and safety.MethodsOne hundred sixty-two (162) patients with u-HCC were treated by combination therapy of HAIC, TKIs, and PD-1 inhibitors. PFS was assessed by Child–Pugh (CP) classification subgroups and the change in the CP score during treatment.ResultsThe median PFS was 11.7 and 5.1 months for patients with CP class A (CPA) and CP class B (CPB), respectively (p = 0.013), with respective objective response rates of 61.1 and 27.8% (p = 0.002) and conversion rates of 16 and 0% (p = 0.078). During treatment, the CP scores in patients with CPA worsened less in those with complete and partial response than in those with stable and progressive disease. In the CP score 5, patients with an unchanged CP score had longer PFS than those with a worsened score (Not reached vs. 7.9 months, p = 0.018). CPB was an independent factor negatively affecting treatment response and PFS. Patients with CPA responded better to the combination therapy and had fewer adverse events (AEs) than those with CPB.ConclusionsThus, triple therapy is more beneficial in patients with good liver function, and it is crucial to maintain liver function during treatment.

The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec.

Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus.This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics. Two open-label, parallel-group, single-dose (1.5U/kg subcutaneously) trialswere conducted. In a renal impairment trial, 58individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60mL/min) or severe (< 30mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35days post-dose. The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7-5.1 g/dL) did not statistically significantly influence icodec exposure. The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment. ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.

Assessment of efficacy and safety of irreversible electroporation versus TACE for treatment of difficult location hepatocellular carcinoma

IntroductionRadiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted as the established treatment options for patients diagnosed with early-stage hepatocellular carcinoma (HCC) who are deemed unfit for surgical procedures. However, the effective implementation of these techniques is hindered by various challenges, primarily associated with the precise targeting of tumors within the liver. The utilization of thermal ablative methods is not recommended for hepatocellular carcinoma (HCC) that is located near intestinal loops, bile ducts, or in eccentric positions. The unmet need for non-thermal methods in the treatment of hepatocellular carcinoma (HCC) was addressed following the introduction of irreversible electroporation (IRE) as an innovative approach.Aim of the workTo assess the efficacy, safety, and outcomes of IRE in the treatment of difficult-located HCC compared to transarterial chemoembolization (TACE).MethodsThis is a prospective study that included 24 patients with HCC who presented to the National Hepatology and Tropical Medicine Research Institute (NHTMRI) during the period from January 2017 to January 2020. Ten patients underwent IRE, while 14 patients underwent TACE.ResultsSixteen patients (66.7%) were males; eight patients were females (33.3%). Their median age was 60.5 years (48–70 years). Seventeen patients (70.8%) were Child–Pugh class A, while seven patients (29.2%) were Child–Pugh class B. All the study population had a single focal lesion; the mean size of the focal lesions was 2.94 ± 0.59 cm. The most frequent difficult locations of HCC were segment V focal lesions adjacent to both the common bile duct and portal vein in eight patients (33.3%) followed by lesions adjacent to the inferior vena cava in five patients (20%) followed by the subcapsular lesions in three patients (12.5%) and lesions adjacent to the right kidney in two patients (8.3%). Complete response (CR) was higher in the IRE group (80%) compared to the TACE group (50%). Clinical decompensation occurred in six patients in the IRE group (60%) and eight patients in the TACE group (57.1%) (P value 1). Recurrence occurred in five patients (50%) treated with IRE and in seven patients (50%) treated with TACE (P value 1). Within the IRE group, two patients (20%) remained alive; on the other hand, within the TACE group six patients (42.9%) remained alive by the end of the study (P value 0.388).ConclusionOur data suggest that IRE is an effective procedure in the treatment of difficult-located HCC in terms of complete response, fewer sessions, and fewer side effects as compared to TACE.

Positive impact of obesity on the prognosis of liver cirrhosis.

The study aims to determine the prognostic impact of obesity, sarcopenic obesity, and dynapenic obesity in patients with chronic liver disease. This retrospective observational study enrolled patients with chronic hepatitis (n=746) and liver cirrhosis (n=434) without hepatocellular carcinoma at entry. The patients were evaluated for sarcopenia and obesity between April 2016 and April 2022. Obesity was defined as a body mass index of ≥25kg/m2. Sarcopenic obesity was defined as low skeletal muscle mass (pre-sarcopenia) with obesity and dynapenic obesity was defined as low muscle strength (dynapenia) with obesity. The effects of obesity on survival were evaluated retrospectively. The mean observation period was 2.5years. Obesity, sarcopenic obesity, and dynapenic obesity were found in 271 (45.5%), 17 (2.9%), and 21 (3.5%) men, and 261 (44.7%), 59 (10.1%), and 53 (9.1%) women, respectively. A multivariate Cox proportional hazards model revealed that Child-Pugh class, dynapenia (hazard ratio [HR] 3.89), elderly (≥65years old) (HR 2.11), and obesity (HR 0.58) were independently associated with overall survival (OS). However, neither sarcopenic nor dynapenic obesity were associated with OS. In patients with cirrhosis, the OS of the obese group was significantly higher than that of the non-obese group. The effect of obesity on OS was significant in elderly patients, but not in younger patients. Sarcopenic and dynapenic obesity seem unrelated to the prognosis of patients with chronic liver disease. Obesity has a positive effect on the prognosis of elderly patients with cirrhosis.

Safety of DOACs in patients with Child-Pugh Class C cirrhosis and trial fibrillation.

Anticoagulation (AC) is used for stroke prevention in atrial fibrillation (AF). Direct Oral Anticoagulants (DOACs) are safe in patients with AF without cirrhosis, they are hardly studied in patients with advanced cirrhosis. Our study evaluates the safety and outcomes of DOACs in patients with Child-Pugh class C cirrhosis (CPC). We queried TriNetX Database. Patients with CPC and AF were divided into three cohorts: patients on DOACs, no AC, and warfarin. Three study arms were created using a 1:1 propensity score matching system (PSM). Totally 16 029 patients met the inclusion criteria. Of those, 20.2% (n = 3235) were on DOACs, 47.1% (n = 7552) were not on AC, and 32.7% (n = 5242) were on warfarin. First arm comparing AC versus no AC, a statistically significant benefit was identified in 3-year mortality risk (47% vs 71%, P < 0.0001) and transplant status (17% vs 5%, p < 0.0001) with AC. However, no significant difference was identified regarding intracranial hemorrhage and GI bleeding risk. Second arm comparing patients on DOACs versus no AC, we identified mortality benefit (40% vs 72%, P < 0.0001) and a higher transplant rate (9% vs 3.2%, P < 0.0001) with DOACs. Intracranial hemorrhage rates (6% vs 4%, P = 0.03) were higher in patients on DOACs. Third arm comparing patients on DOACs versus Warfarin, a statistically significant lower risk of intracranial hemorrhage (6.6% vs 8.7%, P = 0.004) and GI bleed (2% vs 2.4%, P < 0.0001) were identified in patients on DOACs. Anticoagulation is safe in patients with CPC with AF and may provide a mortality benefit. DOACs are a safer alternative to warfarin.

Efficacy of Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Retrospective, Multicenter Study.

The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) is extremely poor, and systemic therapy is currently the mainstream treatment. This study aimed to assess the efficacy and safety of lenvatinib combined with anti-programmed cell death-1 antibodies and transcatheter arterial chemoembolization (triple therapy) in patients with HCC and PVTT. This retrospective multicenter study included patients with HCC and PVTT who received triple therapy, were aged between 18 and 75 years, classified as Child-Pugh class A or B, and had at least one measurable lesion. The overall survival (OS), progression-free survival (PFS), objective response rates, and disease control rates were analyzed to assess efficacy. Treatment-related adverse events were analyzed to assess safety profiles. During a median follow-up of 11.23 months (range, 3.07 to 34.37 months), the median OS was greater than 24 months, and median PFS was 12.53 months. The 2-year OS rate was 54.9%. The objective response rate and disease control rate were 69.8% (74/106) and 84.0% (89/106), respectively; 20.8% (22/106) of the patients experienced grade 3/4 treatment-related adverse events and no treatment-related deaths occurred. The conversion rate to liver resection was 31.1% (33/106), with manageable postoperative complications. The median OS was not reached in the surgery group, but was 19.08 months in the non-surgery group. The median PFS in the surgery and non-surgery groups were 20.50 and 9.00 months, respectively. Triple therapy showed promising survival benefits and high response rates in patients with HCC and PVTT, with manageable adverse effects.

Transplantace jater pro deficit alfa-1-antitrypsinu

Summary: Alpha-1-antitrypsin deficiency (AATD) is an autosomal codominant genetic condition which manifests with lung emphysema at young age and with liver disease. A point mutation in the SERPINA1 gene, which encodes 1-antitrypsin (AAT), causes a defective secondary structure of the protein, which subsequently accumulates in the endoplasmic reticulum of hepatocytes and is not transported into the blood and body fluids. Deficiency of AAT, which inhibits neutrophil elastase in the lung, thus allows proteolytic damage to the connective tissue of the lung, leading to the development of emphysema. Liver disease is caused by the accumulation of the mutant AAT in liver cells, contributing to proteotoxic liver injury that can lead to liver cirrhosis. Liver transplantation (LT) is the only curative method; after LT, the recipient has the phenotype of the donor organ and normal serum AAT concentrations. The indication for LT should be considered in all patients with AATD and end-stage liver disease. The patients should be referred to the transplant centre when severe complications of liver cirrhosis, such as variceal bleeding, ascites, encephalopathy, and hepatorenal syndrome. In patients with hepatocellular carcinoma, LT represents an optimal treatment modality in the case of an early, unresectable tumour. The timing of LT is crucial; LT should be performed before the patient develops life-threatening complications of end-stage liver disease. LT should be considered in patients of Child-Pugh classification B and C and MELD score of 15 points or higher. Survival of patients after LT for AADT is excellent. Key words: 1-antitrypsin – 1-antitrypsin deficiency – liver cirrhosis – end-stage liver disease – hepatocellular carcinoma – live transplantation

Long-term Outcomes of Hepatic Resection Combined With Intraoperative Ablation Versus Hepatic Resection Alone for Multinodular Hepatocellular Carcinoma: Insights from a Single-center Study.

The efficacy of combining hepatic resection (HR) with ablation therapy in treating multinodular hepatocellular carcinoma (mHCC) remains uncertain. This study aimed to compare the long-term survival outcomes of patients with mHCC undergoing HR combined with intraoperative ablation (HRA) versus those undergoing HR alone. A retrospective analysis was conducted on 296 patients diagnosed with early-stage [Barcelona Clinic Liver Cancer (BCLC)-A] or intermediate-stage (BCLC-B) mHCC who underwent initial HR. Patients were divided into two groups: those who received HRA (HRA group, n=159) and those who underwent HR alone (HR group, n=137). Propensity score (PS), estimated as the likelihood of undergoing HRA, was applied to adjust for between-group differences in baseline characteristics. Overall survival (OS) and relapse-free survival (RFS) were compared using Cox regression and Kaplan-Meier analyses. There were no significant differences in survival between the HRA and HR groups, with 5-year OS and RFS rates of 47.7% versus 51.9% (p=0.837) and 17.0% versus 25.9% (p=0.094), respectively. After adjusting for PS, the differences remained non-significant (p=0.579 for OS and p=0.410 for RFS). Consistent results were also observed in PS-adjusted subgroup analysis stratified by factors such as BCLC stage, "Up-to-7" criteria, and Child-Pugh class. HRA may offer comparable long-term efficacy to HR alone in mHCC, suggesting broader treatment options that challenge the guideline-based monotherapy.

Is salvage Plug-Assisted Retrograde Transvenous Obliteration (PARTO) safe and effective for bleeding gastric varices ?- A preliminary single-center experience.

Vascular plug-assisted retrograde transvenous obliteration (PARTO) obliterates the gastric varices and portosystemic shunt, thus resulting in a lower rebleeding rate than endoscopic glue/sclerotherapy. To evaluate the safety and efficacy of PARTO as salvage therapy in liver cirrhosis with gastric variceal bleed (GVB) after failed endotherapy. We assessed the clinical success rate and changes in liver function at 6- months. Patients who underwent salvage PARTO after failed endotherapy for GVB (between December 2021 and November 2022) were searched and analyzed from the hospital database. Clinical success rate and rebleed rate were obtained at six months. Child-Pugh score (CTP) and Model for end-stage liver disease (MELD) score were calculated and compared between baseline and 6-month follow-up. Fourteen patients (n = 14, Child-Pugh class A/B) underwent salvage PARTO. Nine had GOV-2, and five had IGV-1 varices. The mean shunt diameter was 11.6 ± 1.6mm. The clinical success rate of PARTO was 100% (no recurrent gastric variceal hemorrhage within six months). No significant deterioration in CTP (6.79 ± 0.98 vs. 6.21 ± 1.52; p = 0.12) and MELD scores (11.5 ± 4.05 vs. 10.21 ± 3.19; p = 0.36) was noted at 6months. All patients were alive at 6months. One patient (n = 1, 7.1%) bled from esophageal varices after three days of PARTO and was managed with variceal banding. 21.4% (3/14) patients had progression of esophageal varices at 6months requiring prophylactic band ligation. Three patients (21.4%) had new onset or worsening ascites and responded to low-dose diuretics therapy. PARTO is a safe and effective procedure for bleeding gastric varices without any deterioration in liver function even after six months. Patient selection is critical to prevent complications. Further prospective studies with larger sample size are required to validate our findings.

Prognostic Role of Basal Serum Alpha-Fetoprotein in Patients with Hepatocellular Carcinoma Suitable for Curative Treatment.

Background and Objectives: Serum alpha-fetoprotein (AFP) is a recognized affordable oncological marker in patients with hepatocellular carcinoma (HCC). However, AFP's prognostic role has been assessed mainly after specific treatments, and no unanimously recognized cut-offs have been identified. The aim of this study is to investigate the prognostic role of different basal AFP cut-offs on survival and HCC course. Materials and Methods: In this single-center, retrospective study, all patients newly diagnosed with HCC between January 2009 and December 2021 were prospectively enrolled. Only patients suitable for curative HCC treatments were included in the analyses. Patients were stratified according to AFP cut-offs of 20, 200, 400, and 1000 ng/mL, which were correlated with survival outcomes and clinical parameters. Results: A total of 266 patients were analyzed, with a median follow-up time of 41.5 months. Median overall survival (OS) of all cohort was 43 months. At the multivariate Cox-regression analysis, AFP value ≥ 1000 ng/mL correlated with impaired OS (1-year OS: 67% vs. 88%, 5-year OS: 1% vs. 43%; p = 0.005); other risk factors were tumor dimension ≥ 5 cm (HR 1.73; p = 0.002), Child-Pugh class B-C (HR 1.72; p = 0.002), BCLC stage A (vs. 0) (HR 2.4; p = 0.011), and malignant portal vein thrombosis (HR 2.57; p = 0.007). AFP ≥ 1000 ng/mL was also associated with a reduced recurrence-free survival (HR 2.0; p = 0.038), while starting from AFP ≥ 20 ng/mL, a correlation with development of HCC metastases over time (HR 3.5; p = 0.002) was seen. AFP values ≥ 20 ng/mL significantly correlated with tumor size and higher histological grading; starting from AFP values ≥ 400 ng/mL, a significant correlation with Child-Pugh class B-C and female gender was also observed. Conclusions: Basal AFP correlates with relevant outcomes in patients with HCC. It could help identify patients at a higher risk of worse prognosis who might benefit from personalized surveillance and treatment programs. Prospective studies are needed to confirm these results.

Combined effect of histological findings and diabetes mellitus on liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.

Advanced fibrosis has a strong influence on the occurrence of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver-related events. A total of 282 patients with liver biopsy-proven MASLD were included. Liver-related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child-Pugh class B and C, as well as treatment-eligible esophageal and gastric varices. Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver-related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver-related events, including the occurrence of HCC and complications of liver cirrhosis. While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver-related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC.

Hepatic Dysfunction Quantified by HepQuant DuO Outperforms Child-Pugh Classification in Predicting the Pharmacokinetics of Ampreloxetine.

HepQuant tests quantify liver function from clearance of deuterium- and 13C-labeled cholates administered either intravenously and orally (SHUNT) or orally (DuO). Hepatic impairment studies have relied on clinical or laboratory criteria like Child-Pugh classification to categorize the degree of hepatic dysfunction. We compared HepQuant tests with Child-Pugh classification in predicting the pharmacokinetics of ampreloxetine. Twenty-one subjects with hepatic impairment (8 Child-Pugh A, 7 Child-Pugh B, and 6 Child-Pugh C), and 10 age- and sex-matched controls were studied. The pharmacokinetics of ampreloxetine were measured after oral administration of a single dose of 10 mg. Disease severity index (DSI), portal-systemic shunting (SHUNT%), hepatic reserve, and hepatic filtration rates (HFRs) were measured from serum samples obtained after intravenous administration of [24-13C]-cholate and oral administration of [2,2,4,4-2H]cholate. Ampreloxetine plasma exposure (AUC0-inf) was similar to controls in Child-Pugh A, increased 1.7-fold in subjects with Child-Pugh B, and 2.5-fold in subjects with Child-Pugh C and correlated with both Child-Pugh score and HepQuant parameters. The variability observed in ampreloxetine exposure (AUC0-inf) in subjects with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) was explained by HepQuant parameters. Multivariable regression models demonstrated that DSI, SHUNT%, and Hepatic Reserve from SHUNT and DuO were superior predictors of ampreloxetine exposure (AUC0-inf) compared to Child-Pugh score. HepQuant DSI, SHUNT%, and hepatic reserve were more useful predictors of drug exposure than Child-Pugh class for ampreloxetine and thus may better optimize dose recommendations in patients with liver disease. The simple-to-administer, oral-only DuO version of the HepQuant test could enhance clinical utility.

Physiologically Based Pharmacokinetic Modeling to Predict the Impact of Liver Cirrhosis on Glucuronidation via UGT1A4 and UGT2B7/2B4-A Case Study with Midazolam.

Hepatic impairment, due to liver cirrhosis, decreases the activity of cytochrome P450 enzymes (CYPs). The use of physiologically based pharmacokinetic (PBPK) modeling to predict this effect for CYP substrates has been well-established, but the effect of cirrhosis on uridine-glucuronosyltransferase (UGT) activities is less studied and few PBPK models have been reported. UGT enzymes are involved in primary N-glucuronidation of midazolam and glucuronidation of 1'-OH-midazolam following CYP3A hydroxylation. In this study, Simcyp was used to establish PBPK models for midazolam, its primary metabolites midazolam-N-glucuronide (UGT1A4) and 1'-OH midazolam (CYP3A4/3A5), and the secondary metabolite 1'-OH-midazolam-O-glucuronide (UGT2B7/2B4), allowing to simulate the impact of liver cirrhosis on the primary and secondary glucuronidation of midazolam. The model was verified in noncirrhotic subjects before extrapolation to cirrhotic patients of Child-Pugh (CP) classes A, B, and C. Our model successfully predicted the exposures of midazolam and its metabolites in noncirrhotic and cirrhotic patients, with 86% of observed plasma concentrations within 5th-95th percentiles of predictions and observed geometrical mean of area under the plasma concentration curve between 0 hours to infinity and maximal plasma concentration within 0.7- to 1.43-fold of predictions. The simulated metabolic ratio defined as the ratio of the glucuronide metabolite AUC over the parent compound AUC (AUCglucuronide/AUCparent, metabolic ratio [MR]), was calculated for midazolam-N-glucuronide to midazolam (indicative of UGT1A4 activity) and decreased by 40% (CP A), 48% (CP B), and 75% (CP C). For 1'-OH-midazolam-O-glucuronide to 1'-OH-midazolam, the MR (indicative of UGT2B7/2B4 activity) dropped by 35% (CP A), 51% (CP B), and 64% (CP C). These predicted MRs were corroborated by the observed data. This work thus increases confidence in Simcyp predictions of the effect of liver cirrhosis on the pharmacokinetics of UGT1A4 and UGT2B7/UGT2B4 substrates. SIGNIFICANCE STATEMENT: This article presents a physiologically based pharmacokinetic model for midazolam and its metabolites and verifies the accurate simulation of pharmacokinetic profiles when using the Simcyp hepatic impairment population models. Exposure changes of midazolam-N-glucuronide and 1'-OH-midazolam-O-glucuronide reflect the impact of decreases in UGT1A4 and UGT2B7/2B4 glucuronidation activity in cirrhotic patients. The approach used in this study may be extended to verify the modeling of other uridine glucuronosyltransferase enzymes affected by liver cirrhosis.

Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma

BackgroundRadiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT.MethodsWe retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child–Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47–95 years), and the median tumor diameter was 41 mm (range 5–160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child–Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3–41.1 months), and RILD was observed in 11 patients (10.1%).ResultsMultivariate analysis showed that pretreatment Child–Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child–Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively.ConclusionIn conclusion, the pretreatment Child–Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.

Laparoscopic Anatomical Cranial Sub-segmentectomy of Segment VII (S7) with Super-Selective Intra-arterial Nano-ICG Positive Staining-Guided Trans-Parenchymal Approach.

With introduction of "cone unit," which is the smallest resectable anatomical area supplied by a tertiary branch of Glissonean pedicle, more precise subsegmental anatomical resection has been proposed.1 Super-selective intra-arterial ICG staining, delivering ICG and lipiodol mixing to arterial branch using interventional radiology, has been proved feasibility especially for complicated anatomy.2-6 It was difficult to uniformly mix water-soluble ICG with lipophilic lipiodol, rendering to inconsistency development of liver segment between angiography and laparoscopy. Nano-ICG is a uniform mixing of ICG and lipiodol.7 We demonstrated an exclusive "two-step" method to perform LAR for cranial S7 via super-selective intra-arterial nano-ICG staining guidance. A 70-year-old male was admitted. CT scan showed tumor was located in cranial S7 with 2.1*1.9cm. Preoperative AFP was 4.66ng/ml and PIVKA-II was 2332mAU/ml. The liver function was Child-Pugh class A and ICG-15R was 7.8%. Given that tumor was confined to cranial S7, precise anatomical sub-segmentectomy was warranted. This study was approved by the West China Hospital, Sichuan University Ethics Committee (approval number: 2023-2327). The operation was performed "two step." "First step" was super-selective intra-arterial nano-ICG embolization in intervention room, while "second step" was performed in operation room. ICG demarcation line was clearly identified even after 7hr. After full mobilization of right hemiliver, we performed transparenchymal approach to find and clamp pedicle of cranial S7 under fluorescence guidance. Operation time was 150min with 20ml of blood loss with uneventful course. Although LAR of S7 remains challenging, super-selective intra-arterial nano-ICG positive staining guidance might be a feasible and safe option.

Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis

BackgroundHuman epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). MethodsSerum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th–75th percentile). ResultsSerum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15–139.08) vs 73.50 (59.88–82.00) vs 48.75 (43.38–52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child–Pugh class C patients compared with Child–Pugh class B patients and Child–Pugh class A patients [106.50 (83.46–151.25) vs 110.00 (73.83–166.75) vs 77.03 (72.35–83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412–54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146–0.946). ConclusionsSerum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.

Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child-Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0-∞]) to pralsetinib, with AUC0-∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.