[Research progress on hepatitis E virus-related liver failure].

Hepatitis E virus (HEV) is one of the important causes of acute viral hepatitis worldwide, and its incidence rate is increasing year by year. HEV infection can lead to acute, subacute, or acute-on-chronic liver failure with a high mortality rate among some particular patient population, who are pregnant women, older, chronic liver diseases like chronic hepatitis B and cirrhosis, or immunocompromised. The clinical characteristics of HEV infection, the pathogenesis of HEV-related liver failure, and the progress in diagnosis and treatment will be elaborated upon in this article from these three aspects in order to improve clinicians' ability to identify and prevent HEV-related liver failure and its clinical outcomes.

Case report: Recombinant human type II tumour necrosis factor receptor-antibody fusion protein induced occult hepatitis B virus reactivation leading to liver failure.

Recombinant human type II tumour necrosis factor receptor-antibody fusion protein (rh TNFR:Fc) is an immunosuppressant approved for treating rheumatoid arthritis (RA). This case report describes a case of hepatitis B reactivation in a patient with drug-induced acute-on-chronic liver failure. A 58-year-old woman with a history of RA was treated with rh TNFR:Fc; and then subsequently received 25 mg rh TNFR:Fc, twice a week, as maintenance therapy. No anti-hepatitis B virus (HBV) preventive treatment was administered. Six months later, she was hospitalized with acute jaundice. HBV reactivation was observed, leading to acute-on-chronic liver failure. After active treatment, the patient's condition improved and she recovered well. Following careful diagnosis and treatment protocols are essential when treating RA with rh TNFR:Fc, especially in anti-hepatitis B core antigen antibody-positive patients, even when the HBV surface antigen and the HBV DNA are negative. In the case of HBV reactivation, liver function parameters, HBV surface antigen and HBV DNA should be closely monitored during treatment, and antiviral drugs should be used prophylactically when necessary, as fatal hepatitis B reactivation may occur in rare cases. A comprehensive evaluation and medication should be administered in a timely manner after evaluating the patient's physical condition and closely monitoring the patient.

ALBI score combined with FIB-4 index to predict post-hepatectomy liver failure in patients with hepatocellular carcinoma.

Post-hepatectomy liver failure (PHLF) is a potentially life-threatening complication following liver resection. Hepatocellular carcinoma (HCC) often occurs in patients with chronic liver disease, which increases the risk of PHLF. This study aimed to investigate the ability of the combination of liver function and fibrosis markers (ALBI score and FIB-4 index) to predict PHLF in patients with HCC. Patients who underwent hepatectomy for HCC between August 2012 and September 2022 were considered for inclusion. Multivariable logistic regression analysis was used to identify factors associated with PHLF, and ALBI score and FIB-4 index were combined based on their regression coefficients. The performance of the combined ALBI-FIB4 score in predicting PHLF and postoperative mortality was compared with Child-Pugh score, MELD score, ALBI score, and FIB-4 index. A total of 215 patients were enrolled in this study. PHLF occurred in 35 patients (16.3%). The incidence of severe PHLF (grade B and grade C PHLF) was 9.3%. Postoperative 90-d mortality was 2.8%. ALBI score, FIB-4 index, prothrombin time, and extent of liver resection were identified as independent factors for predicting PHLF. The AUC of the ALBI-FIB4 score in predicting PHLF was 0.783(95%CI: 0.694-0.872), higher than other models. The ALBI-FIB4 score could divide patients into two risk groups based on a cut-off value of - 1.82. High-risk patients had a high incidence of PHLF of 39.1%, while PHLF just occurred in 6.6% of low-risk patients. Similarly, the AUCs of the ALBI-FIB4 score in predicting severe PHLF and postoperative 90-d mortality were also higher than other models. Preoperative ALBI-FIB4 score showed good performance in predicting PHLF and postoperative mortality in patients undergoing hepatectomy for HCC, superior to the currently commonly used liver function and fibrosis scoring systems.

Sarcopenia does not affect liver regeneration and postoperative course after a major hepatectomy. A prospective study on 125 patients using CT volumetry and HIDA scintigraphy.

BACKGROUND & OBJECTIVES: Sarcopenia is a morbi-mortality risk factor in digestive surgery, though its impact after major hepatectomy (MH) remains unknown. This prospective pilot study investigated whether volume and function of a regenerating liver is influenced by body composition. METHODS: From 2011 to 2016, 125 consecutive patients had computed tomography and 99mTc-labelled-mebrofenin SPECT-scintigraphy before and after MH at day 7 and 1 month for measurements of liver volumes and functions. L3 vertebra muscle mass identified sarcopenia. Primary endpoint was the impact of sarcopenia on regeneration capacities (i.e. volume/function changes and post-hepatectomy liver failure (PHLF) rate). Secondary endpoint was 3-month morbi-mortality. RESULTS: Sarcopenic patients (SP; N = 69) were significantly older than non-sarcopenic (NSP), with lower BMI and more malignancies, but with comparable liver function/volume at baseline. Postoperatively, SP showed higher rates of ISGLS_PHLF (24.6 % vs 10.9 %; p = 0.05) but with comparable rates of severe morbidity (23.2 % vs 16.4 %; p = 0.35), overall (8.7 % vs 3.6 %; p = 0.3) and PHLF-related mortality (8,7 % vs 1.8 %; p = 0.075). After matching on the extent of resection or using propensity score, regeneration and PHLF rates were similar. CONCLUSION: This prospective study using first sequential SPECT-scintigraphy showed that sarcopenia by itself does not affect liver regeneration capacities and short-term postoperative course after MH.

Decreased mebrofenin uptake in patients with non-colorectal liver tumors requiring liver volume augmentation-a single-center analysis.

BACKGROUND: Posthepatectomy liver failure (PHLF) remains a life-threatening complication after hepatectomy. To reduce PHLF, a preoperative assessment of liver function is indispensable. For this purpose, 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT (MSPECT) can be used. The aim of the current study was to evaluate the predictive value of MSPECT for PHLF in patients with non-colorectal liver tumors (NCRLT) compared to patients with colorectal liver metastasis (CRLM) undergoing extended liver resection. METHODS: We included all patients undergoing extended liver resections via two-stage procedures between January 2019 and December 2021 at the University Medical Center Hamburg-Eppendorf, Germany. All patients received a preoperative MSPECT. RESULTS: Twenty patients were included. In every fourth patient, PHLF was observed. Four patients had PHLF grade C. There were no differences between patients with CRLM and NCRLT regarding PHLF rate and future liver remnant (FLR) volume. Patients with CRLM had higher mebrofenin uptake in the FLR compared to those with NCRLT (2.49%/min/m2 vs. 1.51%/min/m2; p = 0.004). CONCLUSION: Mebrofenin uptake in patients with NCRLT was lower compared to those patients with CRLM. However, there was no difference in the PHLF rate and FLR volume. Cut-off values for the mebrofenin uptake might need adjustments for different surgical indications, surgical procedures, and underlying diseases.

The impact of post-hepatectomy liver failure on long-term survival after liver resection for perihilar cholangiocarcinoma.

BACKGROUND: Although post-hepatectomy liver failure (PHLF) can accurately predict short-term mortality of liver resection for perihilar cholangiocarcinoma (pCCA), its significance in predicting long-term overall survival (OS) is still uncertain. METHODS: Retrospective analysis was performed on patients with pCCA who underwent liver resection between October 2013 and December 2018. The patients were divided into 3 groups; No PHF, PHLF (all grade) and grade B/C PHLF according to The International Study Group of Liver Surgery (ISGLS) criteria. RESULTS: A total of 177 patients were enrolled, 65 (36.7%) had PHLF; 25 (14.1%) had grade A, and 40 (22.6%) had grade B/C. Prior to surgery, patients with PHLF showed significantly greater bilirubin levels and CA 19-9 level than those without (11.5 vs 6.7 mg/dL, p = 0.002 and 232.4 vs 85.9 U/mL, p = 0.005, respectively). Additionally, pre-operative future liver remnant volume in PHLF group was lower than no PHLF group significantly (39.6% vs 43.5%, p = 0.006). Major complication and 90-day mortality were higher in PHLF group than no PHLF group (69.2% vs 20.5%, p < 0.001 and 29.2% vs 3.6%, p < 0.001, respectively). The OS in both grade A PHLF and grade B/C PHLF was significantly worse compared to no PHLF, with median survival times of 8.4, 3.3, and 19.2 months, respectively (p < 0.001 and p < 0.001, respectively). Multivariable analysis revealed that PHLF was independently prognostic factor for long-term survival. CONCLUSION: To achieve negative resection margin, the surgical resection in pCCA was aggressive, however this increased the risk of PHLF, which also affects the OS. Consequently, it is necessary for establishing a balance between aggressive surgery and PHLF.

Prediction of post-hepatectomy liver failure by preoperative gadoxetate disodium-enhanced magnetic resonance imaging.

BACKGROUND: Approximately 15% of patients experience post-hepatectomy liver failure after major hepatectomy. Poor hepatocyte uptake of gadoxetate disodium, a magnetic resonance imaging contrast agent, may be a predictor of post-hepatectomy liver failure. METHODS: A retrospective cohort study of patients undergoing major hepatectomy (≥3 segments) with a preoperative gadoxetate disodium-enhanced magnetic resonance imaging was conducted. The liver signal intensity (standardized to the spleen) and the functional liver remnant was calculated to determine if this can predict post-hepatectomy liver failure after major hepatectomy. RESULTS: In 134 patients, low signal intensity of the remnant liver standardized by signal intensity of the spleen in post-contrast images was associated with post-hepatectomy liver failure in multiple logistic regression analysis (Odds Ratio 0.112; 95% CI 0.023-0.551). In a subgroup of 33 patients with lower quartile of functional liver remnant, area under the curve analysis demonstrated a diagnostic accuracy of functional liver remnant to predict post-hepatectomy liver failure of 0.857 with a cut-off value for functional liver remnant of 1.4985 with 80.0% sensitivity and 89.3% specificity. CONCLUSION: Functional liver remnant determined by gadoxetate disodium-enhanced magnetic resonance imaging is a predictor of post-hepatectomy liver failure which may help identify patients for resection, reducing morbidity and mortality.

Clinician overconfidence in visual estimation of the posthepatectomy liver remnant volume: A proximal source of liver failure after major hepatic resection?

BACKGROUND: Post-hepatectomy liver failure is a source of morbidity and mortality after major hepatectomy and is related to the volume of the future liver remnant. The accuracy of a clinician's ability to visually estimate the future liver remnant without formal computed tomography liver volumetry is unknown. METHODS: Twenty physicians in diagnostic radiology, interventional radiology, and hepatopancreatobiliary surgery reviewed 20 computed tomography scans of patients without underlying liver pathology who were not scheduled for liver resection. We evaluated clinician accuracy to estimate the future liver remnant for 3 hypothetical major hepatic resections: left hepatectomy, right hepatectomy, and right trisectionectomy. The percent-difference between the mean and actual computed tomography liver volumetry (mean percent difference) was tested along with specialty differences using mixed-effects regression analysis. RESULTS: The actual future liver remnant (computed tomography liver volumetry) remaining after a hypothetical left hepatectomy ranged from 59% to 75% (physician estimated range: 50%-85%), 23% to 40% right hepatectomy (15%-50%), and 13% to 29% right trisectionectomy (8%-39%). For right hepatectomy, the mean future liver remnant was overestimated by 95% of clinicians with a mean percent difference of 22% (6%-45%; P < .001). For right trisectionectomy, 90% overestimated the future liver remnant by a mean percent difference of 25% (6%-50%; P < .001). Hepatopancreatobiliary surgeons overestimated the future liver remnant for proposed right hepatectomy and right trisectionectomy by a mean percent difference of 25% and 34%, respectively. Based on years of experience, providers with <10 years of experience had a greater mean percent difference than providers with 10+ years of experience for hypothetical major hepatic resections, but was only significantly higher for left hepatectomy (9% vs 6%, P = .002). CONCLUSION: A clinician's ability to visually estimate the future liver remnant volume is inaccurate when compared to computed tomography liver volumetry. Clinicians tend to overestimate the future liver remnant volume, especially in patients with a small future liver remnant where the risk of posthepatectomy liver failure is greatest.

[A case of neonatal liver failure]. / 新生儿肝衰竭1例.

The patient was a male infant, born full-term, admitted to the hospital at 28 days of age due to jaundice for 20 days and abdominal distension for 15 days. The patient developed symptoms of jaundice, hepatosplenomegaly, massive ascites, and progressively worsening liver function leading to liver failure, severe coagulation disorders, and thrombocytopenia one week after birth. Various treatments were administered, including anti-infection therapy, fluid restriction, use of diuretics, use of hepatoprotective and choleretic agents, intermittent paracentesis, blood exchange, and intravenous immunoglobulin, albumin, and plasma transfusions. However, the patient's condition did not improve, and on the 24th day of hospitalization, the family decided to discontinue treatment and provide palliative care. Sequencing of the patient's liver tissue and parental blood samples using whole-exome sequencing did not identify any pathogenic variants that could explain the liver failure. However, postmortem liver tissue pathology suggested congenital hepatic fibrosis (CHF). Given the rarity of CHF causing neonatal liver failure, further studies on the prognosis and pathogenic genes of CHF cases are needed in the future. This article provides a comprehensive description of the differential diagnosis of neonatal liver failure and introduces a multidisciplinary diagnostic and therapeutic approach to neonatal liver failure.

Establishing the clinical relevance of grade A post-hepatectomy liver failure.

INTRODUCTION: The International Study Group of Liver Surgery's criteria stratifies post-hepatectomy liver failure (PHLF) into grades A, B, and C. The clinical significance of these grades has not been fully established. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) hepatectomy-targeted database was analyzed. Outcomes between patients without PHLF, with grade A PHLF, and grade B or C PHLF were compared. Univariate and multivariable logistic regression were performed. RESULTS: Six thousand two hundred seventy-four adults undergoing elective major hepatectomy were included in the analysis. The incidence of grade A PHLF was 4.3% and grade B or C was 5.3%. Mortality was similar between patients without PHLF (1.2%) and with grade A PHLF (1.1%), but higher in those with grades B or C PHLF (25.4%). Overall morbidities rates were 19.3%, 41.7%, and 72.8% in patients without PHLF, with grade A PHLF, and with grade B or C PHLF, respectively (p < 0.001). Grade A PHLF was associated with increased morbidity (grade A: odds ratios [OR] 2.7 [95% CI: 2.0-3.5]), unplanned reoperation (grade A: OR 3.4 [95% CI: 2.2-5.1]), nonoperative intervention (grade A: OR 2.6 [95% CI: 1.9-3.6]), length of stay (grade A: OR 3.1 [95% CI: 2.3-4.1]), and readmission (grade A: OR 1.8 [95% CI: 1.3-2.5]) compared to patients without PHLF. CONCLUSIONS: Although mortality was similar between patients without PHLF and with grade A PHLF, other postoperative outcomes were notably inferior. Grade A PHLF is a clinically distinct entity with relevant associated postoperative morbidity.

Evaluation and Prediction of Post-Hepatectomy Liver Failure Using Imaging Techniques: Value of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging.

Despite improvements in operative techniques and perioperative care, post-hepatectomy liver failure (PHLF) remains the most serious cause of morbidity and mortality after surgery, and several risk factors have been identified to predict PHLF. Although volumetric assessment using imaging contributes to surgical simulation by estimating the function of future liver remnants in predicting PHLF, liver function is assumed to be homogeneous throughout the liver. The combination of volumetric and functional analyses may be more useful for an accurate evaluation of liver function and prediction of PHLF than only volumetric analysis. Gadoxetic acid is a hepatocyte-specific magnetic resonance (MR) contrast agent that is taken up by hepatocytes via the OATP1 transporter after intravenous administration. Gadoxetic acid-enhanced MR imaging (MRI) offers information regarding both global and regional functions, leading to a more precise evaluation even in cases with heterogeneous liver function. Various indices, including signal intensity-based methods and MR relaxometry, have been proposed for the estimation of liver function and prediction of PHLF using gadoxetic acid-enhanced MRI. Recent developments in MR techniques, including high-resolution hepatobiliary phase images using deep learning image reconstruction and whole-liver T1 map acquisition, have enabled a more detailed and accurate estimation of liver function in gadoxetic acid-enhanced MRI.

A Novel Method Using Gadolinium-Ethoxybenzyl Diethylenetriamine Pentaacetate Acid-Enhanced Magnetic Resonance Imaging for Predicting Post-Hepatectomy Liver Failure in Hepatocellular Carcinoma Patients with a Major Portal Vein Tumor Thrombus.

INTRODUCTION: The usefulness of gadolinium-ethoxybenzyl diethylenetriamine pentaacetate acid-enhanced magnetic resonance imaging (EOB-MRI) in assessing the functional future remnant liver volume (fFRLV) to predict post-hepatectomy liver failure (PHLF) has been previously reported. Herein, we evaluated the efficacy of this technique in patients with hepatocellular carcinoma (HCC) with a major portal vein tumor thrombus (PVTT). METHODS: This study included 21 patients with PVTT in the ipsilateral first-order branch (Vp3) and 30 patients with PVTT in the main trunk/contralateral branch (Vp4). To evaluate fFRLV, the signal intensity (SI) of the remnant liver was determined on T1-weighted images, using both conventional and newly developed methods. The fFRLV was calculated using the SI of the remnant liver and muscle, remnant liver volume, and body surface area. Preoperative factors predicting PHLF (≥grade B) in HCC patients with Vp3/4 PVTT were evaluated. RESULTS: In the Vp3 group, we found fFRLV area under the receiver-operating characteristic curves (AUCs) above 0.70 (AUC = 0.875, 0.750) using EOB-MRI results calculated using either the plot or whole method. None of the parameters in the Vp4 group had an AUC greater than 0.70. CONCLUSION: The fFRLV calculated by EOB-MRI using the whole method can be as useful as the conventional method in predicting PHLF (≥grade B) for HCC patients with Vp3 PVTT.

Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration.

BACKGROUND & AIMS: Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients undergoing hepatectomy, with hepatic vascular reconstitution playing a critical role. However, the regulators of hepatic vascular reconstitution remain unclear. In this study, we aimed to investigate the regulatory mechanisms of hepatic vascular reconstitution and identify biomarkers predicting PHLF in patients undergoing hepatectomy. METHODS: Candidate genes that were associated with hepatic vascular reconstitution were screened using adeno-associated virus vectors in Alb-Cre-CRISPR/Cas9 mice subjected to partial hepatectomy. The biological activities of candidate genes were estimated using endothelial precursor transfusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) models. The level of candidates was detected in biopsies from patients undergoing ALPPS. Risk factors for PHLF were also screened using retrospective data. RESULTS: Downregulation of Gata3 and upregulation of Ramp2 in hepatocytes promoted the proliferation of liver sinusoidal endothelial cells and hepatic revascularization. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor A (VEGFA) played opposite roles in regulating the migration of endothelial precursors from bone marrow and the formation of new sinusoids after hepatectomy. Gata3 restricted endothelial cell function in patient-derived hepatic organoids, which was abrogated by a Gata3 inhibitor. Moreover, overexpression of Gata3 led to higher mortality in ALPPS mice, which was improved by a PEDF-neutralizing antibody. The expression of Gata3/RAMP and PEDF/VEGFA tended to have a negative correlation in patients undergoing ALPPS. A nomogram incorporating multiple factors, such as serum PEDF/VEGF index, was constructed and could efficiently predict the risk of PHLF. CONCLUSIONS: The balance of Gata3 and Ramp2 in hepatocytes regulates the proliferation of liver sinusoidal endothelial cells and hepatic revascularization via changes in the expression of PEDF and VEGFA, revealing potential targets for the prevention and treatment of PHLF. IMPACT AND IMPLICATIONS: In this study, we show that the balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution by promoting a shift from pigment epithelium-derived factor (PEDF) to vascular endothelial growth factor A (VEGFA) expression during hepatectomy- or ALLPS (associating liver partition and portal vein ligation for staged hepatectomy)-induced liver regeneration. We also identified serum PEDF/VEGFA index as a potential predictor of post-hepatectomy liver failure in patients who underwent hepatectomy. This study improves our understanding of how hepatocytes contribute to liver regeneration and provides new targets for the prevention and treatment of post-hepatectomy liver failure.

Rescue Liver Transplantation for Posthepatectomy Liver Failure: A Systematic Review and Survey of an International Experience.

BACKGROUND: Rescue liver transplantation (LT) is the only life-saving option for posthepatectomy liver failure (PHLF) whenever it is deemed as irreversible and likely to be fatal. The goals were to perform a qualitative systematic review of rescue LT for PHLF and a survey among various international LT experts. METHODS: A literature search was performed from 2000 to 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Population, Intervention, Comparison, Outcome framework, and to this, the authors' experience was added. The international online open survey included 6 cases of PHLF extracted from the literature and submitted to 976 LT experts. The primary outcome was whether experts would consider rescue LT for each case. Interrater agreement among experts was calculated using the free-marginal multirater kappa methodology. RESULTS: The review included 40 patients. Post-LT mortality occurred in 8 (20%) cases (7/28 with proven cancer and 1/12 with benign disease). In the long term, 6 of 21 (28.6%) survivors with cancer died of recurrence (median = 38 mo) and 15 (71.4%) were alive with no recurrence (median = 111 mo). All 11 survivors with benign disease were alive and well (median = 39 mo). In the international survey among experts in LT, the percentage agreement to consider rescue LT was 28%-98%, higher for benign than for malignant disease ( P = 0.011). Interrater agreement for the primary endpoint was low, expected 5-y survival >50% being the strongest independent predictor to consider LT. CONCLUSIONS: Rescue LT for PHLF may achieve good results in selected patients. Considerable inconsistencies of decision-making exist among LT experts when considering LT for PHLF.