Efficacy of steroid therapy for improving native liver survival after pediatric acute liver failure with immune activation.

AIM: Recent evidence suggests that acute liver failure (ALF) in some patients may reflect a dysregulated immune response, and that corticosteroids improve survival of the native liver in ALF patients with high serum alanine aminotransferase levels, which are an indication of liver inflammation. However, it is unclear whether steroids are effective for pediatric acute liver failure (PALF). The aim of this retrospective case-control study is to examine whether steroid therapy for PALF accompanied by immune activation improves the survival of native liver and to identify factors that predict responses to steroid treatment. METHODS: Of 38 patients with PALF treated at Kyoto University Hospital from February 2006 to August 2022, 19 receiving steroids who met the specific criteria for identifying the pathophysiology of immune activity in the liver (the "Steroid group"), and seven steroid-free patients who also met the criteria ("Nonsteroid group") were enrolled. Patients in the "Steroid group" were categorized as "responders" or "nonresponders" according to treatment outcome. Clinical and histological data were analyzed. RESULTS: Survival of the native liver in the Steroid group was significantly higher than that in the Nonsteroid group (68% vs. 0%, respectively; p = 0.0052). Nonresponders were significantly younger, with higher Model for End-stage Liver Disease and pediatric end-stage liver disease scores, higher prothrombin time - international normalized ratio, and higher serum ferritin levels than responders. Massive hepatic necrosis was more common in nonresponders. CONCLUSION: Steroid therapy is effective for PALF patients with liver inflammation; however, liver transplantation should be prioritized for young children with ALF accompanied by severe coagulopathy or massive hepatic necrosis.

Deceased donor non-composite split liver and intestinal transplantation for children.

Children with intestinal failure suffer liver damage associated with parenteral nutrition: a condition known as intestinal failure-associated liver disease (IFALD), which requires transplantation of both liver and intestine. In many countries, simultaneous transplantation of these two organs is performed using grafts from a deceased donor, but there have been no such cases in Japan, and the details of the procedure are not clear. Recently, we performed simultaneous split liver and intestinal transplantation in two premature infants with IFALD, using organs from identical deceased donors and achieved good results. These are the first two cases of this procedure being performed in Japan. We report these cases and discuss the important aspects of the surgical and perioperative management.

Chronological alterations in de novo malignancies after living-donor liver transplantation: A cohort study of 1781 recipients using annual comparisons of standardized incidence ratios.

BACKGROUND: De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living-donor liver transplantation (LDLT) remain unclear. METHODS: We retrospectively reviewed 1781 primary LDLT recipients (1990-2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age-adjusted Japanese general population. RESULTS: After 21 845 person-years follow-up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person-years. DNMs included 81 post-transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5- and 10-year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR1993-1995: 8.12 (95% CI: 3.71-15.4, p < .001) and SIR1996-1998: 3.11 (1.34-6.12, p = .01) were significantly high, but had decreased time-dependently to SIR2005-2007: 1.31 (0.68-2.29, p = .42) and SIR2008-2010: 1.34 (0.75-2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR2014-2016: 2.27 (1.54-3.22, p < .001) and SIR2017-2019: 2.07 (1.40-2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non-PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor-recipient HLA-mismatches, the less the post-transplant DNMs development. CONCLUSION: DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993-1998), but once became equivalent (2005-2013), then significantly increased again (2014-2019) due to recent recipient aging and resultant increase in solid cancers.

Living donor liver transplantation for myocerebrohepatopathy spectrum due to POLG mutations.

BACKGROUND: POLG is one of several nuclear genes associated with mitochondrial DNA maintenance defects and is a group of diseases caused by mitochondrial DNA deficiency that results in impaired adenosine triphosphate production and organ dysfunction. Myocerebrohepatopathy spectrum (MCHS) is the most severe and earliest presentation of POLG mutations, and liver transplantation (LT) for MCHS has never been reported. CASE PRESENTATION: The patient was a 3-month-old boy with acute liver failure and no neurological manifestations (e.g., seizures). We performed a living donor LT using a left lateral segment graft from his father. The postoperative course was uneventful. Subsequently, a homozygous POLG mutation (c.2890C>T, p. R964C) was identified by multigene analysis of neonatal/infantile intrahepatic cholestasis. Moreover, respiratory chain complex I, II, and III enzyme activities and the ratio of mtDNA to nuclear DNA in the liver were reduced. Therefore, we considered that these clinical manifestations and examination findings met the definition for MCHS. During meticulous follow-up, the patient had shown satisfactory physical growth and mental development until the time of writing this report. CONCLUSION: We presumed that the absence of remarkable neurologic manifestations prior to LT in patients with MCHS is a good indication for LT and contributes to a better prognosis in the present case.

Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.

Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.

Management and outcomes after liver transplantation for progressive familial intrahepatic cholestasis: A systematic review and meta-analysis.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous rare congenital cholestatic liver disease. Disease progression might necessitate liver transplantation (LT). The aim of this study was to describe the outcome of PFIC1-4 patients after LT. METHODS: Electronic databases were searched to identify studies on PFIC and LT. Patients were categorized according to PFIC type, genotype, graft type, age at LT, time of follow-up, and complications and treatment during follow-up. RESULTS: Seventy-nine studies with 507 patients met inclusion criteria; most patients were classified as PFIC1-3. The median age at LT was 50 months. The overall 5-year patient survival was 98.5%. PFIC1 patients with diarrhea after LT were at significant risk of developing graft steatosis ( p < 0.0001). Meta-analysis showed an efficacy of 100% [95% CI: 73.9%-100%] for surgical biliary diversion to ameliorate steatosis and 94.9% [95% CI: 53.7%-100%] to improve diarrhea (n = 8). PFIC2 patients with bile salt export pump (BSEP)2 or BSEP3-genotype were at significant risk of developing antibody-induced BSEP deficiency (AIBD) ( p < 0.0001), which was reported in 16.2% of patients at a median of 36.5 months after LT. Meta-analysis showed an efficacy of 81.1% [95% CI: 47.5%-100%] for rituximab-based treatment regimens to improve AIBD (n = 18). HCC was detected in 3.6% of PFIC2 and 13.8% of PFIC4 patients at LT. CONCLUSIONS: Fifty percent of PFIC1 patients develop diarrhea and steatosis after LT. Biliary diversion can protect the graft from injury. PFIC2 patients with BSEP2 and BSEP3 genotypes are at significant risk of developing AIBD, and rituximab-based treatment regimens effectively improve AIBD. PFIC3 patients have no PFIC-specific complications following LT.

Adrenocortical carcinoma mimicking hepatocellular carcinoma: A case report.

INTRODUCTION AND IMPORTANCE: Adrenocortical carcinoma (ACC) is a relatively rare tumor arising in the adrenal cortex. Its imaging and histopathologic findings are not well known to be similar to those of hepatocellular carcinoma (HCC). We report here a case of ACC with hepatic resection in the preoperative diagnosis of HCC. CASE PRESENTATION: A 46-year-old woman was noted to have a tumor 45 mm in size in the segment 7 of the liver on CT during a medical checkup. The tumor had consistent imaging findings as HCC on Ultrasound, CT, and MRI examinations, and the result of the liver tumor biopsy was a diagnosis of intermediate differentiated HCC. We considered the tumor to be HCC and performed a posterior segmentectomy with combined resection of the right adrenal gland, which had adhesions suspected to direct invasion. The pathology of the resected specimen confirmed the diagnosis of ACC with direct invasion into the liver. CLINICAL DISCUSSION: ACC may show a contrast pattern similar to that of HCC on imaging, and histopathology may show atypical cells with eosinophilic sporulation, similar to that of HCC. Our case serves to alert physicians that ACC should be considered a differential diagnosis in patients with suspected HCC in the posterior segment. CONCLUSION: Tumors suspected of HCC in the dorsal posterior segment of the liver should be considered as possible ACC.

Clinical outcomes after tracheostomy in patients with coronavirus disease 2019: a single-center experience in Japan.

PURPOSE: Many patients with coronavirus disease 2019 require mechanical ventilation and tracheostomy. However, the timing and indications for tracheostomy are controversial. This study assessed 11 patients with coronavirus disease 2019 who underwent tracheostomy with clinical information and retrospective analyses. METHODS: A single-center retrospective observational study was performed on patients with coronavirus disease 2019 who underwent tracheostomy between 2020 and 2021. RESULTS: Failure to wean was the most common indication for tracheostomy, followed by extracorporeal membrane oxygenation decannulation and the need for secretion management. After tracheostomy, six patients (54.5%) were liberated from the ventilator. The time from intubation to tracheostomy (21.1 ± 9.14 days) was correlated with the duration of ventilator dependency (36.83 ± 20.45 days, r2 = 0.792, p = 0.018). The mean Acute Physiological and Chronic Health Evaluation II score was significantly lower in the ventilator-liberated group (23 ± 2.77) than in the non-ventilator-liberated group (31 ± 6.13, p = 0.0292). Furthermore, patients with Acute Physiological and Chronic Health Evaluation II scores of < 27 points achieved ventilator liberation and a long-term survival (p = 0.0006). CONCLUSIONS: This study describes the outcomes of a cohort of patients who underwent tracheostomy after intubation for coronavirus disease 2019. The Acute Physiological and Chronic Health Evaluation II score predicted whether or not the patient could achieve ventilator liberation.

Nonsuperiority of technetium-99m-galactosyl human serum albumin scintigraphy over conventional volumetry for assessing the future liver remnant in patients undergoing hepatectomy after portal vein embolization.

BACKGROUND: Technetium-99m-galactosyl human serum albumin scintigraphy is preferred for assessing the liver functional reserve in patients undergoing hepatectomy, but its superiority over computed tomography volumetry after portal vein embolization and subsequent hepatectomy remains elusive. We aimed to compare technetium-99m-galactosyl human serum albumin scintigraphy with conventional computed tomography volumetry for predicting posthepatectomy liver failure in patients after portal vein embolization. METHODS: This retrospective study analyzed 152 consecutive patients who underwent hepatobiliary cancer resection after portal vein embolization between 2006 and 2021. Posthepatectomy liver failure was graded according to the International Study Group of Liver Surgery criteria. The predictive abilities for posthepatectomy liver failure were compared between the future remnant uptake (%) by technetium-99m-galactosyl human serum albumin scintigraphy and the future remnant volume (%) by computed tomography volumetry. RESULTS: Future remnant uptake (%) was significantly greater than future remnant volume (%) after portal vein embolization (47.9% vs 40.8%; P < .001), while the values were comparable before portal vein embolization (32.7% vs 31.2%; P = .116). Receiver operating characteristic curve analysis revealed that post-portal vein embolization future remnant volume (%) had a significantly higher area under the curve than post-portal vein embolization future remnant uptake (%) (0.709 vs 0.630; P = .046) for predicting posthepatectomy liver failure. Multivariable analysis revealed that post-portal vein embolization future remnant volume (%) independently predicted posthepatectomy liver failure, but future remnant uptake (%) did not. Although the incidence of posthepatectomy liver failure grade ≥B was 17.8% when indocyanine green-clearance of the future liver remnant based on both future remnant volume (%) and future remnant uptake (%) was ≥0.05, it was higher in other combinations: 55.6% for indocyanine green clearance of the remnant volume ≥0.05/indocyanine green clearance of the remnant uptake ≤0.05; 50.0% for indocyanine green clearance of the remnant volume ≤0.05/indocyanine green clearance of the remnant uptake ≥0.05; and 50% for indocyanine green clearance of the remnant volume ≤0.05/indocyanine green clearance of the remnant uptake ≤0.05. CONCLUSIONS: Technetium-99m-galactosyl human serum albumin scintigraphy is not superior to computed tomography volumetry for assessing the future liver remnant in patients undergoing major hepatectomy after portal vein embolization.

Low Friction of Graphene Oxide Aggregates in Lubricant Oil between a Steel Ball and Glass Disk under Boundary Lubrication.

Previously, isolated nanocarbons in lubricating oils were considered essential for good lubrication. However, we observed that graphene oxide (GO) aggregates in lubricating oil have lower frictional properties than isolated dispersed GO. The GO was dispersed in polyα-olefin (PAO) using alkylamine at different ratios of GO and alkylamine, or it was heated at different temperatures to synthesize high- and low-dispersible GO-dispersed PAO. X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and Raman spectroscopy measurements showed that low-dispersible modified GOs retained many of the original GO chemical and structural features. Macrotribological tests between a steel ball and glass disk in GO-dispersed oil were conducted with a load of 5 N under boundary lubrication. The friction interface was observed in situ using an optical microscope. In the low-dispersible GO-dispersed PAO, many GO aggregates were observed through optical microscopy. Surprisingly, the friction coefficients decreased when the GO aggregates entered the friction interface and covered the contact area. The low-dispersible GO-dispersed PAO using alkylamine had the lowest friction coefficient of 0.05, as the GO aggregates covered the contact area. From microtribological tests with a load of 0.8 mN as well, it is assumed that the low friction of the GO aggregates originates due to the sliding between the weakest shear layers in the aligned multiple GO layers.

Application of laparoscopic distal pancreatectomy for normal anatomy after hiatal hernia repair: A case report.

We describe a case of pancreatic tumor associated with a giant type IV hiatal hernia that had prolapsed into the posterior mediastinum. Hiatal hernia repair should be performed first because it enables laparoscopic distal pancreatectomy to be performed in the normal anatomical position.

Hepatocellular carcinoma with situs inversus totalis treated by caudate lobectomy: A case report.

INTRODUCTION: Situs inversus totalis (SIT) is a congenital anatomical variant in which organs and vasculature are positioned in a mirror-image relationship to the normal condition. Therefore, the surgical procedures need to be carefully planned with these factors in mind. CASE PRESENTATION: A 57-year-old man with SIT was diagnosed with a hepatocellular carcinoma (HCC) and was planned for caudate lobectomy. As preoperative preparation, 3D reconstructed images were created based on the contrast-enhanced CT images, and careful simulations were performed on the vascular anomalies and location of the tumor. There was a replaced left hepatic artery forming a common trunk with a left gastric artery. In addition, using media player software, a previous caudate lobectomy video was played in right and left inverted mode to simulate the abdominal surgical field image in SIT. The operative time was 285 min, and the blood loss was 440 ml. The preoperative careful simulation allowed us to proceed with the surgery without significant discomfort. CONCLUSION: Even in the case of hepatocellular carcinoma with SIT, hepatectomy for hepatocellular carcinoma can be safely performed by careful preoperative simulations.

Management of Epstein-Barr Virus Infection and Post-Transplant Lymphoproliferative Disorder in Pediatric Liver Transplantation.

With the advancement of immunosuppressive strategies, the outcome of liver transplantation during childhood has dramatically improved. On the other hand, Epstein-Barr virus (EBV) infection and associated post-transplant lymphoproliferative diseases (PTLD), such as malignant lymphoma, are serious complications that contribute to morbidity and mortality, and are still an important issue today. Recently, an early diagnosis by quantitative PCR and PET-CT testing, and treatment with rituximab (an anti-CD20 antibody) has been established, and long-term remission has been achieved in many cases. However, the optimal immunosuppression protocol after remission of PTLD needs to be determined, and it is hoped that a treatment for refractory PTLD (e.g., PTL-NOS) will be proposed.

Progress in living donor liver transplantation for biliary atresia and challenges faced: A thirty-year single institutional experience.

BACKGROUND: Biliary atresia (BA) is the most common indication for liver transplantation in the pediatric population, and living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) have been established as a radical treatment for BA .The aim of this study was to clarify the long term outcomes and risk factors affecting the LDLT outcomes, as well as the challenges faced. METHODS: Between 1990 and 2019, 666 BA patients underwent LDLT in our institution and were enrolled in this study. Data regarding the recipient's age, anatomic findings of the biliary tree at Kasai's portoenterostomy, basic characteristics at transplantation, transplant profiles, donor characteristics, and outcomes of LDLT were analyzed. RESULTS: The 1-, 5-, 10-, 15-, 20-, and 25-year graft survival rates of BA patients who underwent LDLT were 88.1%, 85.4%, 81.5%, 78.9%, 76.6%, and 75.5%, respectively. The transplant era, age at transplantation, ABO incompatible transplant, and presence of pulmonary vascular complications were identified as significant risk factors for overall graft survival. When the study period was divided into the first (1990-1999) and second (2000-2019) phases and re analyzed, the outcomes of ABO-incompatible transplants and LDLT for adult BA patients remained inferior to others in the second phase. The 20-year graft survival rate in patients who underwent re transplantation in the second phase was 54.2%. CONCLUSIONS: The outcomes of LDLT in children are generally good, but the immunosuppression procedures need to be further improved for ABO-incompatible cases in the future. Further improvements in LDLT results for adult patients and re transplantation remain challenges to be addressed in this field, and future attempts, including revision to the organ allocation system of deceased donors, are necessary. LEVEL OF EVIDENCE: Level III (case control study).

Case Report: A Case of Epstein-Barr Virus-Associated Acute Liver Failure Requiring Hematopoietic Cell Transplantation After Emergent Liver Transplantation.

Hepatic manifestations of Epstein-Barr virus (EBV) infection are relatively common, mild, and self-limiting. Although fulminant hepatic failure has been reported in a few cases, the contributing factors are unclear. This report discusses a pediatric case of EBV-associated acute liver failure that required urgent liver transplantation; however, liver damage continued to progress post-liver replacement. Monoclonal CD8+ T cells that preferentially infiltrated the native and transplanted liver were positive for EBV-encoded small RNA, suggesting a pathophysiology similar to that of EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Therefore, subsequent chemotherapy and hematopoietic cell transplantation was conducted, which led to cure. This is the first case of EBV-associated acute liver failure that relapsed post-liver transplant. As such, it sheds light on an under-recognized clinical entity: liver-restricted hyperinflammation caused by EBV-infected monoclonal CD8+ T cells. This phenomenon needs to be recognized and differentiated from hepatitis/hepatic failure caused by EBV-infected B cells, which has a relatively benign clinical course.

Direct percutaneous access to an omental vein for embolization of Roux-en-Y limb varices in a child.

An 11-year-old boy with a history of hepatoblastoma treated with chemotherapy, radiation therapy, and liver transplantation presented with bleeding from Roux-en-Y limb varices. The transhepatic approach for portal intervention posed a risk of liver graft injury. An omental vein that was dilated as a collateral vein due to portal hypertension was found and compressible under ultrasound. The omental vein was percutaneously punctured, and the varices were embolized through a jejunal vein. No complication occurred. Direct percutaneous access to the portal venous system is a useful technique for portal embolization.

Autopsy findings of a patient with severe COVID-19 treated with long-term extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) therapy in patients with coronavirus disease 2019 (COVID-19) has a low frequency of use, and thus pathological findings in such patients are valuable. In this case report, a 62-year-old man with a history of hypertension presented with a runny nose. After an at-home COVID-19 positive test, he developed dyspnea and fever. Once admitted to our hospital, his oxygenation worsened, and ECMO was initiated. He died from respiratory failure 69 days after ECMO induction. Macroscopically, the lungs gained mass, were partially consolidated, and were airless. Histological analysis revealed diffuse bronchial epithelial metaplasia and adenoid metaplasia in the alveolar epithelium. Although the lung parenchyma was partially preserved, there was organizing and fibrosis that filled pulmonary alveolus due to COVID-19 and changes resulting from disuse and long-term ECMO.

Percutaneous Transhepatic Biliary Intervention in Adult Biliary Atresia Patients After Kasai Portoenterostomy.

Kasai portoenterostomy (KP) is a standard treatment for patients with biliary atresia (BA). After KP, patients with BA occasionally develop biliary complications, such as recurrent cholangitis, biliary stricture, and cystic dilatation of the intrahepatic bile duct. Percutaneous transhepatic biliary drainage is one of the treatment options for these biliary complications. However, limited information is available on percutaneous transhepatic biliary drainage performed after KP in adult BA patients with native livers. Herein, we describe 8 cases of percutaneous transhepatic biliary interventions performed after KP in 7 adult BA patients with native livers. Cholangiography showed multiple cystic dilatation of the intrahepatic bile ducts. Advancing a guidewire and catheter was difficult due to the multiple dilatations and strictures of the bile duct. Successful biliary drainage tube placement and clinical improvement was achieved in 5 and 3 cases, respectively. Because of its technical difficulty and limited clinical effectiveness, it is not recommended that it be performed easily.