Chikashi Nakanishi

A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis E in Liver Transplant Recipients in Japan

Background Recently, chronic hepatitis E has been increasingly reported in organ transplant recipients in European countries. In Japan, the prevalence of hepatitis E virus (HEV) infection after transplantation remains unclear, so we conducted a nationwide cross-sectional study to clarify the prevalence of chronic HEV infection in Japanese liver transplant recipients. Methods A total of 1893 liver transplant recipients in 17 university hospitals in Japan were examined for the presence of immunoglobulin G (IgG), IgM and IgA classes of anti-HEV antibodies, and HEV RNA in serum. Findings The prevalence of anti-HEV IgG, IgM and IgA class antibodies was 2.9% (54/1893), 0.05% (1/1893) and 0% (0/1893), respectively. Of 1651 patients tested for HEV RNA, two patients (0.12%) were found to be positive and developed chronic infection after liver transplantation. In both cases, HEV RNA was also detected in one of the blood products transfused at the perioperative period. Analysis of the HEV genomes revealed that the HEV isolates obtained from the recipients and the transfused blood products were identical in both cases, indicating transfusion-transmitted HEV infection. Interpretation The prevalence of HEV antibodies in liver transplant recipients was 2.9%, which is low compared with the healthy population in Japan and with organ transplant recipients in European countries; however, the present study found, for the first time, two Japanese patients with chronic HEV infection that was acquired via blood transfusion during or after liver transplantation.

The Dissection Profile and Mechanism of Tissue-Selective Dissection of the Piezo Actuator-Driven Pulsed Water Jet as a Surgical Instrument: Laboratory Investigation Using Swine Liver

Background/Purpose: The water jet technique dissects tissue while sparing cord-like structures such as blood vessels. The mechanism of such tissue-selective dissection has been unknown. The novel piezo actuator-driven pulsed water jet (ADPJ) system can achieve dissection with remarkably reduced water consumption compared to the conventional water jet; however, the systems characteristics and dissection capabilities on any organ have not been clarified. The purposes of this study were to characterize the physical properties of the novel ADPJ system, evaluate the dissection ability in swine organs, and reveal the mechanism of tissue-selective dissection. Methods: The pulsed water jet system comprised a pump chamber driven by a piezo actuator, a stainless steel tube, and a nozzle. The peak pressure of the pulsed water jet was measured through a sensing hole using a pressure sensor. The pulsed water jet technique was applied on swine liver in order to dissect tissue on a moving table using one-way linear ejection at a constant speed. The dissection depth was measured with light microscopy and evaluated histologically. The physical properties of swine liver were evaluated by breaking strength tests using tabletop universal testing instruments. The liver parenchyma was also cut with three currently available surgical devices to compare the histological findings. Results: The peak pressure of the pulsed water jet positively correlated with the input voltage (R2 = 0.9982, p < 0.0001), and this was reflected in the dissection depth. The dissection depth negatively correlated with the breaking strength of the liver parenchyma (R2 = 0.6694, p < 0.0001). The average breaking strengths of the liver parenchyma, hepatic veins, and Glissons sheaths were 1.41 ± 0.45, 8.66 ± 1.70, and 29.6 ± 11.0 MPa, respectively. The breaking strength of the liver parenchyma was significantly lower than that of the hepatic veins and Glissons sheaths. Histological staining confirmed that the liver parenchyma was selectively dissected, preserving the hepatic veins and Glissons sheaths in contrast to what is commonly observed with electrocautery or ultrasonic instruments. Conclusions: The dissection depth of liver tissue is well controlled by input voltage and is influenced by the moving velocity and the physical properties of the organ. We showed that the device can be used to assure liver resection with tissue selectivity due to tissue-specific physical properties. Although this study uses an excised organ, further in vivo studies are necessary. The present work demonstrates that this device may function as an alternative tool for surgery due to its good controllability of the dissection depth and ability of tissue selectivity.

Combined hepatocellular carcinoma and neuroendocrine carcinoma with sarcomatous change of the liver after transarterial chemoembolization.

Primary hepatic neuroendocrine carcinoma is rare and its origin is not clearly understood. An admixture of hepatocellular carcinoma (HCC) and neuroendocrine carcinoma is particularly rare. Here, we report a patient with an extremely rare combination of HCC and neuroendocrine carcinoma of the liver. To our knowledge, this is the first reported case in which the carcinoma showed sarcomatous change. The patient was a 76‐year‐old man who had received outpatient treatment for chronic hepatitis C. On abdominal computed tomography (CT), the hepatic tumor was enhanced in the arterial phase but its density was lower than that of normal liver in the portal phases. His serum α‐fetoprotein (AFP) level was very high. Therefore, transarterial chemoembolization (TACE) was performed based on the diagnosis of HCC. Ten months after TACE, his serum AFP level had increased to the level measured before TACE. Partial hepatectomy was performed because CT revealed poor enhancement of the recurrent tumor. Histopathologically, the tumor consisted of two distinct components: moderately differentiated HCC was intermingled with a neuroendocrine carcinoma, which was accompanied by sarcomatous changes. Immunohistochemically, the neuroendocrine carcinoma cells were positive for CD56, chromogranin A and neuron‐specific enolase, and negative for AFP. The sarcomatous area was positive for AE1/3 and CD56, consistent with sarcomatous change of neuroendocrine carcinoma. The neuroendocrine carcinoma and/or sarcomatous change may have been due to phenotypic changes and/or dedifferentiation of HCC induced by TACE. Six months after surgery, the patient was diagnosed with metastasis of the neuroendocrine carcinoma to sacral bone. He died 7 months after surgery.

Prevalence and risk factors of obesity, hypertension, dyslipidemia and diabetes mellitus before and after adult living donor liver transplantation.

The development of metabolic abnormalities after liver transplantation (LTx) contributes to cardiovascular events and mortality. We analyzed the prevalence and risk factors of obesity, hypertension, dyslipidemia and diabetes mellitus (DM) after adult living donor liver transplantation.

Edaravone, a Free Radical Scavenger, Improves the Graft Viability on Liver Transplantation From Non–heart-beating Donors in Pigs

BACKGROUND Although liver transplantation from non-heart-beating donors (NHBDs) is an effective way to overcome shortage of donors, primary graft nonfunction is often noted in these grafts. We have previously reported that edaravone, a free radical scavenger, has a cytoprotective effect on warm ischemia-reperfusion injury and improves the function of liver grafts from NHBDs in a rat model of ischemia-reperfusion. The purpose of this study was to investigate the effects of edaravone on liver transplantations from NHBDs. METHODS Pigs were divided into three groups: (1) a heart-beating (HB) group (n = 5), in which liver grafts were retrieved from HB donors; (2) a non-heart-beating (NHB) group (n = 4), in which liver grafts were retrieved under apnea-induced NHB conditions; and (3) an edaravone-treated (ED) group (n = 5), in which liver grafts were retrieved in the same manner as the NHB group and treated with edaravone at the time of perfusion (3 mg/L in University of Wisconsin [UW] solution), cold preservation (1 mg/L in UW solution), and after surgery (1 mg/kg/d). The grafts from all groups were transplanted after 4 hours of cold preservation. RESULTS In the ED group, the 7-day survival rate was significantly higher than that in the NHB group (80% versus 0%, P = .0042, Kaplan-Meier log-rank test). Furthermore, on histologic examination, the structure of sinusoids in the ED group was well preserved and similar to that in the HB group. CONCLUSIONS Edaravone may improve the viability of liver grafts from NHBDs.

Significance of preoperative fluorodeoxyglucose-positron emission tomography in prediction of tumor recurrence after liver transplantation for hepatocellular carcinoma patients: a Japanese multicenter study

In the present study, we conducted a multicenter nationwide survey to investigate the effects of preoperative fluorine‐18‐fluorodeoxyglucose (FDG) positron emission tomography (PET) on the prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT).

Long-Term Survival with Growth Hormone Replacement after Liver Transplantation of Pediatric Nonalcoholic Steatohepatitis Complicating Acquired Hypopituitarism

Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease (NAFLD). In adult patients, liver transplantation (LT) is the treatment of choice for end-stage liver disease secondary to NASH. However, little information is available regarding outcomes of LT in pediatric patients with NASH. We describe here a pediatric patient with NASH associated with hypopituitarism who underwent living donor liver transplantation (LDLT). An 11-year-old boy was diagnosed with a pituitary tumor, which was removed by trans-interhemispheric approach following bifrontal craniotomy. Histopathological examination revealed a mature teratoma. Eighteen months later, magnetic resonance imaging showed recurrence of the pituitary tumor, which was found to be a germinoma. He underwent 3 months of chemoradiotherapy, with a complete response. He gradually became obese, with elevated transaminase levels. At age 15 years, he developed fatigue and dyspnea and was found to have liver cirrhosis secondary to NASH with severe hepatopulmonary syndrome. He underwent LDLT using a right liver graft from his mother. Twelve months later, abdominal computed tomography showed recurrence of NAFLD. Five years after the LDLT, transaminases were slightly elevated. Growth hormone replacement therapy was started, reducing transaminase levels to their normal ranges. Ten years after LDLT, fatty liver remains stable, although his body mass index has not been reduced. Growth hormone replacement therapy may be effective in graft maintenance. This is the first case report of a patient with maintained stable liver function 10 years after LDLT for pediatric NASH.

Arterial and biliary complications after living donor liver transplantation: a single-center retrospective study and literature review

AimThe mortality of patients on the waiting list for deceased donor liver transplantation (DDLT) is high, especially in countries where donation rates are low. Thus, living donor liver transplantation (LDLT) is an attractive option. However, compared with DDLT, LDLT is associated with increased rates of arterial and biliary complications. We examined the rates of complications and risk factors following LDLT.MethodsWe retrospectively investigated and compared the rates of complications of DDLT and LDLT in our institute. We also performed univariate and multivariate analyses to identify the independent risk factors for these complications. The complications and specific disadvantages of LDLT were reviewed and discussed.ResultsThe incidence rate of arterial complications in LDLT was 6.0%, compared with 3.2% (13/441) in DDLT. A multivariate analysis identified low body weight (P = 0.032) as the only independent risk factor for hepatic artery thrombosis. The rate of all biliary complications in LDLT was 17.3%, compared with 18.7% in DDLT. The risk factors for biliary stricture identified by the multivariate analysis were recurrent cholangitis and the number of bile ducts. The durations of hospital stay and overall survival rates were similar between the two groups.ConclusionGiven the shortage of deceased donor organs, we believe that LDLT is acceptable in an attempt to meet demand.

Impact of the Trough Level of Calcineurin Inhibitor on the Prevalence of Donor-specific Human Leukocyte Antigen Antibodies During Long-term Follow-up After Pediatric Liver Transplantation: Antibody Strength and Complement-binding Ability

Background In pediatric patients, long-term immunosuppression after liver transplantation (LT) is typically minimal. However, posttransplant donor-specific HLA antibodies (DSAs) may be prevalent under these conditions. Here, we evaluated the effects of minimized calcineurin inhibitor (CNI) on DSA development to assess the validity of minimized/withdrawn immunosuppression. Methods We retrospectively examined 66 patients who underwent pediatric LT at our institution between July 1991 and October 2013. Patients were divided into 2 groups based on the CNI trough level. The cutoff trough levels were 3 and 30 ng/mL for tacrolimus and cyclosporine, respectively. Luminex single-antigen bead assays were performed, and the cutoff for a positive reaction was set at a mean fluorescence intensity (MFI) of at least 1000. Results The mean recipient ages at the time of LT were 29.1 and 77.2 months for the low and regular CNI groups, respectively (P = 0.0007). Univariate logistic regression analysis revealed that recipient age at LT younger than 3 years (P = 0.0099) and low CNI (P < 0.0001) were significantly associated with DSA development. In multivariate analysis, low CNI was an independent risk factor of DSA development (P = 0.0011). Of 15 high-MFI DSAs, 3 were anti-DR, and 12 were anti-DQ. Two of 3 anti-DR DSAs and 11 of 12 anti-DQ DSAs had complement-binding ability and high MFIs. Conclusions CNI minimization was an independent risk factor for posttransplant DSA during long-term follow-up after pediatric LT. Adjusting CNI to appropriate levels is a safe first step to prevent the immunological effects of DSA.

Effect of Recipient Age at Liver Transplantation on Prevalence of Post-Transplant Donor-Specific HLA Antibody

BACKGROUND Post-transplant donor-specific HLA antibodies (DSA) may have a detrimental effect on long-term outcomes of organ transplantation. The aim of this study was to specifically evaluate the effect of recipient age on the prevalence of DSA over a long-term follow-up after living donor liver transplantation (LDLT). MATERIAL AND METHODS A retrospective analysis of DSA evaluations was performed in 50 pediatric patients with HLA data available. Patients were divided into 2 groups based on their age at the time of LDLT: younger (Y) group, age <3 years; older (O) group, age ≥3 years. DSA evaluation was performed using Luminex single-antigen bead assays, with a mean fluorescence intensity ≥1000 used as a cut-off for positive results. RESULTS There were no between-group differences in terms of sex, ABO incompatibility or acute rejection. Only one of our 50 patients tested positive for class I DSA. Significantly more patients tested positive for HLA-DR DSA in group Y (40.6%) than in group O (11.1%; p=0.02). Recipients <3 years of age at the time of LDLT may be at a higher risk of testing positive for class II DSA. CONCLUSIONS These findings can inform the implementation of cost-effective screening of post-transplant DSA in pediatric LDLT recipients.