Recurrent Hepatitis B and D Virus Infection in a Liver Transplant Recipient.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) co-infections progress rapidly and lead to cirrhosis. In Japan, the prevalence of HBV and HDV co-infected patients is low. Therefore, there are few reports of patients with HBV and HDV co-infection having undergone liver transplantation. Herein, we report a rare case of recurrence of HBV and HDV in a 41-year-old man who underwent living donor liver transplantation 4 years prior.

The first report of the thyroid function of haemophilic patients with HIV/HCV co-infection in Japan.

INTRODUCTION: A high incidence of thyroid dysfunction is reported in patients with HIV or HCV mono-infection. We have conducted a periodic medical examination including the thyroid function for haemophilic patients with HIV/HCV co-infection due to contaminated blood products. METHODS: We examined the thyroid function (as assessed by the FT3, FT4 and TSH levels) in 45 haemophilic patients, including thyroglobulin and auto-antibody, antithyroglobulin antibody, antithyroid peroxidase antibody and anti-TSH receptor antibody in 28 patients. RESULTS: All the patients were males (median age: 42 years; range: 29-66). The median values of thyroid function were FT3 3.36 pg mL(-1) , FT4 1.125 ng mL(-1) and TSH 1.65 µIU mL(-1) . Five patients (11.1%) had high TSH levels. In 28 patients in whom the presence of auto-antibodies was examined, the median age was 47 years of age. The median value of thyroglobulin was 16 ng mL(-1) and two patients showed high levels of thyroglobulin. The presence of anti-TSH receptor antibody of all the patients was negative, but one patient (3.5%) was positive of antithyroid peroxidase antibody and antithyroglobulin antibody. CONCLUSIONS: Since 0.68-3.6% of the general healthy population is reported to show hypothyroidism, our data showed that the proportion of hypothyroidism in haemophilic patients with HIV/HCV co-infection was more frequent than that of the normal population.

Evaluation of resectability after neoadjuvant chemotherapy for primary non-resectable colorectal liver metastases: A multicenter study.

BACKGROUND/AIM: The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. METHODS: Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. RESULTS: In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons.

Impact of Donor and Recipient Single Nucleotide Polymorphisms in Living Liver Donor Transplantation for Hepatitis C.

INTRODUCTION: Recently, several studies have shown that specific single nucleotide polymorphisms (SNPs) affect liver fibrosis progression in patients with hepatitis C virus (HCV) infection. In this study, we examined the impact of donor and recipient SNPs on the progression of fibrosis after liver transplantation for HCV infection. METHODS: This cohort study enrolled 43 patients with HCV infection who underwent liver transplantation at our hospital. We evaluated 5 genotypes (rs4374383, rs2629751, rs9380516, rs8099917, and rs738409) that have been reported to be significant predictors of fibrosis in HCV infection using a Taqman assay. RESULTS: Liver fibrosis (stage ≥ F1, New Inuyama classification) was detected at 1 year after liver transplantation in 30 cases (70%). The rs2629751 non-AA-genotype was found to be significantly associated with fibrosis progression at 1 year after liver transplantation (AA:GG or GA = 46%:88%, P < .05). The primary outcome was stage ≥F2 (portoportal septa) or liver-related mortality in 22 patients. The time to stage ≥F2 fibrosis or liver-related mortality was significantly different only in terms of the donor rs2629751 genotype (AA:GG or GA = 5.5 ± 0.6 years:3.6 ± 0.7 years, P = .025). CONCLUSIONS: The rs2629751 genotype may be an important predictor of posttransplant outcome in HCV-infected patients. This result might be useful in donor selection for liver transplantation in HCV-infected patients and may guide therapeutic decisions regarding early antiviral treatment.

Hybrid procedure in living donor liver transplantation.

BACKGROUND: We have previously reported a hybrid procedure that uses a combination of laparoscopic mobilization of the liver and subsequent hepatectomy under direct vision in living donor liver transplantation (LDLT). We present the details of this hybrid procedure and the outcomes of the procedure. METHODS: Between January 1997 and August 2014, 204 LDLTs were performed at Nagasaki University Hospital. Among them, 67 recent donors underwent hybrid donor hepatectomy. Forty-one donors underwent left hemihepatectomy, 25 underwent right hemihepatectomy, and 1 underwent posterior sectionectomy. First, an 8-cm subxiphoid midline incision was made; laparoscopic mobilization of the liver was then achieved with a hand-assist through the midline incision under the pneumoperitoneum. Thereafter, the incision was extended up to 12 cm for the right lobe and posterior sector graft and 10 cm left lobe graft procurement. Under direct vision, parenchymal transection was performed by means of the liver-hanging maneuver. The hybrid procedure for LDLT recipients was indicated only for selected cases with atrophic liver cirrhosis without a history of upper abdominal surgery, significant retroperitoneal collateral vessels, or hypertrophic change of the liver (n = 29). For total hepatectomy and splenectomy, the midline incision was sufficiently extended. RESULTS: All of the hybrid donor hepatectomies were completed without an extra subcostal incision. No significant differences were observed in the blood loss or length of the operation compared with conventional open procedures. All of the donors have returned to their preoperative activity level, with fewer wound-related complaints compared with those treated with the use of the conventional open procedure. In recipients treated with the hybrid procedure, no clinically relevant drawbacks were observed compared with the recipients treated with a regular Mercedes-Benz-type incision. CONCLUSIONS: Our hybrid procedure was safely conducted with the same quality as the conventional open procedure in both LDLT donors and recipients.

E-cadherin expression in hepatocellular carcinoma treated with previous local treatment in patients undergoing living donor liver transplantation.

BACKGROUND: The aim of this study was to evaluate the influence of previous local treatment on the E-cadherin (E-cad) expression in cases of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) within the Milan criteria. METHODS: Seventy-four of 204 patients with HCC underwent LDLT between 1997 and 2014. Previous local treatment for HCC was performed for 121 lesions in 47 patients (47/74, 63.5%). Histological and immunohistochemical E-cad expression analyses were conducted on the basis of the whole-liver histological examination technique. RESULTS: The interval to LDLT after the initial and last treatments was 24 months (2-206) and 10.5 months (1-58), respectively. Preoperative imaging showed necrosis in 92 (92/121, 76.0%) lesions caused by the effects of local treatment, whereas the histological examinations revealed viable HCC cells in 22 (22/92, 23.9%) lesions, demonstrating well or moderate differentiation without vascular invasion. Immunohistochemically, the expression of E-cad was maintained in 17 viable (17/22, 77.3%) lesions. There were no signs of malignant transformation or sarcomatous changes in the HCCs treated with previous therapy. The recipients who maintained an E-cad expression in the lesion with local treatment showed no recurrence or distant metastasis after LDLT. CONCLUSIONS: HCC cells remained in approximately 20% of the evaluated lesions, even those exhibiting necrosis on imaging of the explanted cirrhotic liver. However, the expression of E-cad was maintained in most of these lesions. Furthermore, there were no significant differences in the rate of recurrence after LDLT between the patients who did and those did not receive previous local treatment for HCC.

Sleep disturbances and quality of life in patients after living donor liver transplantation.

BACKGROUND: Following improvements in patient and graft survival after liver transplantation (LT), the recipients' quality of life has become an important focus of patient care. Sleep is closely related to physical and mental health; however, sleep disturbances in LT patients have not yet been evaluated. METHODS: We assessed 59 LT patients (aged ≥18 years) between September 2011 and September 2012. The patients completed the restless legs syndrome (RLS), 36-item short-form health survey (SF-36), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS) questionnaires. In addition, laboratory data were obtained and neuropsychological tests (NPT) were performed during study entry. RESULTS: Thirty-eight patients (64%) were included in the poor sleep group (PSQI ≥6 or ESS ≥10). The SF-36 scores were lower in the poor sleep group than in the good sleep group. Eleven patients (18%) had RLS. An NPT score ≥3 indicated minimal hepatic encephalopathy (MHE3). The MHE3 group consisted of 22 patients (43%). The time after LT was shorter; serum albumin, branched chain amino acid/tyrosine molar ratio (BTR), and role limitations due to poor physical health were lower; and serum ammonia levels were higher in the MHE3 group than in the MHE0-2 group. When the poor sleep group was divided into subgroups (control, MHE, RLS, and unknown), MHE patients had high model for end-stage liver disease scores, high ammonia levels, and low BTR, whereas RLS patients showed a short time after LT. CONCLUSION: Sixty-four percent of recipients were classified as poor sleepers. SF-36 scores were lower for poor sleepers than good sleepers. RLS and MHE are major diseases that cause sleep disturbances in patients after LT.

The efficacy of the ImmuKnow assay for evaluating the immune status in human immunodeficiency virus and hepatitis C virus-coinfected patients.

BACKGROUND: The survival of human immunodeficiency virus (HIV)-infected patients has significantly improved since the introduction of antiretroviral therapy (ART). However, the mortality due to hepatitis C virus (HCV)-related liver disease has not been reduced in HIV/HCV-coinfected patients, and HCV has recently become the most significant cause of death in HIV/HCV-coinfected patients. Liver transplantation might be one of the treatments of choice in such cases, but it is very difficult to evaluate the immune status of these patients due to ART, anti-HCV treatment, and HIV-related immunocompromised state. AIM: The aim of this study was to evaluate the immune status in HIV/HCV-coinfected patients using the Cylex ImmuKnow assay, which was designed to monitor the global immune status by measuring the adenosine triphosphate (ATP) levels produced by activated CD4+ T cells. METHODS: Twenty-eight HIV/HCV-coinfected patients were included in this study. We evaluated their immune activity using the ImmuKnow assay, and compared the data with those of HCV mono-infected patients indicated for liver transplantation as well as healthy controls. RESULTS: The ATP levels of HIV/HCV-coinfected patients were significantly higher than those of HCV mono-infected liver transplant recipients (P < .001), and were significantly lower than those of healthy controls (P = .001). CONCLUSION: The ImmuKnow assay was considered to be a useful tool to evaluate the immune status of HIV/HCV-coinfected patients.

Analysis of the hepatic functional reserve, portal hypertension, and prognosis of patients with human immunodeficiency virus/hepatitis C virus coinfection through contaminated blood products in Japan.

BACKGROUND: As the survival of human immunodeficiency virus (HIV)-infected individuals has improved due to the widespread use of antiretroviral therapy, the mortality rate due to hepatitis C virus (HCV)-related liver disease has increased in HIV/HCV-coinfected patients. AIM: The aims of this study were to establish the appropriate therapeutic strategy for HIV/HCV-coinfected patients by evaluating the liver function, including the hepatic functional reserve and portal hypertension, and to investigate the prognosis of HIV/HCV-coinfected patients in Japan. PATIENTS AND METHODS: In addition to regular liver function tests, the hepatic functional reserve of 41 patients with HIV/HCV coinfection was evaluated using the indocyanine green retention rate and liver galactosyl serum albumin-scintigraphy. The data for 146 patients with HIV/HCV coinfection through blood products were extracted from 4 major HIV centers in Japan. In addition to liver function tests, the platelet counts (PLT) were evaluated as a marker of portal hypertension. RESULTS: In spite of the relatively preserved general liver function test results, approximately 40% of the HIV/HCV-coinfected patients had an impaired hepatic functional reserve. In addition, while the albumin and bilirubin levels were normal, the PLT was <150,000/µL in 17 patients. Compared with HCV mono-infected patients with a PLT <150,000/µL, the survival of HIV/HCV-coinfected patients was shorter (HCV, 5 years, 97%; 10 years, 86% and HIV/HCV, 5 years, 87%; 10 years, 73%; P < .05). CONCLUSION: These results must be taken into account to establish an optimal therapeutic strategy, including the appropriate timing of liver transplantation in HIV/HCV-coinfected patients in Japan.

Intraoperative portal venous pressure and long-term outcome after curative resection for hepatocellular carcinoma.

BACKGROUND: Outcomes of liver resection for hepatocellular carcinoma (HCC) have improved owing to better surgical techniques and patient selection. Portal hypertension may influence outcome but the preoperative definition and role of portal hypertension are far from clear. The aim of this study was to elucidate the influence of portal venous pressure (PVP) measured directly during surgery on outcomes of liver resection in patients with HCC. METHODS: Patients who had resection of HCC between 1997 and 2009, and who underwent direct measurement of PVP immediately after laparotomy were enrolled. These patients were divided into groups with high (at least 20 cmH(2)O) and low (less than 20 cmH(2)O) PVP. The influence of PVP on overall and recurrence-free survival was analysed and prognostic factors were identified. RESULTS: A total of 177 patients were enrolled, 129 in the low-PVP group and 48 in the high-PVP group. The 5-year overall survival rate (63·7 versus 31 per cent; P < 0·001) and recurrence-free survival rate (52·5 versus 12 per cent; P < 0·001) were significantly higher in patients with low PVP. In multivariable analysis, two or more tumours, tumour diameter at least 5 cm, high PVP, grade B liver damage and Hepatic Activity Index (HAI) grade 7 or more were significant predictors of poorer survival after liver resection. Two or more tumours, tumour diameter at least 5 cm and HAI grade 7 or more were significant predictors of poorer recurrence-free survival. CONCLUSION: High PVP was associated with poor long-term outcome after liver resection for HCC.

Standardized less invasive living donor hemihepatectomy using the hybrid method through a short upper midline incision.

BACKGROUND: Recently, applications of less invasive liver surgery in living donor hepatectomy (LDH) have been reported. The objective of this study was to evaluate the safety and efficacy of a hybrid method with a midline incision for LDH. METHODS: Hemihepatectomy using the hybrid method was performed in the fifteen most recent among 150 living donors who underwent surgery between 1997 and August 2011. Six donors underwent right hemihepatectomy and 9 underwent left hemihepatectomy. An 8-cm subxiphoid midline incision was created for hand assistance during liver mobilization and graft extraction. After sufficient mobilization of the liver, the hand-assist/extraction incision was extended to 12 cm for the right hemihepatectomy and 10 cm for a left hemihepatectomy. Encircling the hepatic veins and hilar dissection were performed under direct vision. Parenchymal transection was performed with the liver hanging maneuver. Bile duct division was performed after visualizing the planned transection point by encircling the bile duct using a radiopaque marker filament under real-time C-arm cholangiography. RESULTS: All procedures were completed without any extra subcostal incision. All grafts were safely extracted through the 10-12-cm upper midline incision without mechanical injury. No donors required an allogeneic transfusion; all of them have returned to their preoperative activity levels. CONCLUSION: LDH by the hybrid method with a short upper midline incision is a safe procedure.

Is liver-targeted FOXp3 staining beneficial after living-donor liver transplantation?

As treatments for acute cellular rejection (ACR) and recurrent hepatitis caused by hepatitis C virus (HCV) are dramatically different, making a precise diagnosis is considered to be essential in patients after liver transplantation. Therefore, we investigated whether immunohistochemical detection of FOXp3, a marker for regulatory T cells (CD4+ CD25+), could be used to differentiate between recurrent hepatitis C and ACR. From a group of 103 cases of living-donor liver transplantation (LDLT), 48 samples were taken via liver biopsy from 20 patients with HCV infection. An initial diagnosis was made based on hematoxylin and eosin staining, which was scored with the hepatitis activity index (HAI) grading, whereas ARC was scored with the rejection activity index (RAI). The FOXp3 immunohistochemical staining on serial specimens was retrospectively analyzed, scoring from 0 to III. The time after LDLT was a median of 270 (range: 14-2000) days, whereas the median number of biopsies per patient was 3 (range: 1-8). The HAI was significantly different between 0 vs. I, and II vs. III, in terms of the FOXp3 score. On the other hand, a significant difference in the RAI was only found between 0 vs. I. In conclusion, FOXp3 may represent a surrogate marker for recurrent HCV infection after LDLT.

Cerebellar ataxia in a patient receiving calcineurin inhibitors after living donor liver transplantation: a case report.

Neurological complications of calcineurin inhibitors are frequent problems after transplantation. Cerebellar ataxia with other neurological findings and an abnormal density area in the subcortical white matter are found by MRI in the brains of most patients with central nervous system complications caused by calcineurin inhibitors. Such neurological complications are not life-threatening, but have a negative impact on the quality of life. We describe a 58-year-old woman who developed cerebellar ataxia at 4 days after living donor liver transplantation. She walked with a swaying gait, and after walking for 5 minutes she was unable to stand. Her symptoms persisted after a change from tacrolimus to cyclosporine, but dose reduction of cyclosporine and addition of mycophenolate mofetil cured the ataxia. We diagnosed a case of cerebellar ataxia without leukoencephalopathy or other neurological symptoms, as a new complication of calcineurin inhibitor treatment. We concluded that careful attention should be paid to neurological complications of calcineurin inhibitors.

Two-step models to predict binding affinity of chemicals to the human estrogen receptor alpha by three-dimensional quantitative structure-activity relationships (3D-QSARs) using receptor-ligand docking simulation.

Binding of chemicals to the estrogen receptor (ER) is known to be a key mode of action of endocrine disruption effects. In this study, combined quantitative structure-activity relationship (QSAR) models from discriminant and multilinear regression (MLR) analyses, termed a two-step model, were developed. These were used to predict the binding potency to human ERalpha of four chemical groups, namely alkylphenols, phthalates, diphenylethanes and benzophenones. These groups are considered to be important chemical classes of ER-binders. The descriptors investigated were calculated following the simulation of docking between the receptor and ligand. Discriminant analysis in the first step of a two-step model was applied to distinguish binders from non-binders. It had a concordance, following leave-one-out (LOO), of greater than 87% for all chemical classes. Binders were defined as chemicals whose IC50 was reliably measured in a competitive binding assay. The MLR analysis in the second step was performed for the quantitative prediction of the binding affinity of chemicals that were previously discriminated as binders. The q2 values for alkylphenols and diphenylethanes were 0.75 and 0.74, respectively. However good MLR relationships were not obtained for phthalates and benzophenones as the observed binding affinities of chemicals in these categories were weak and in a too narrow range.

Changes in the weights of the accessory sex organs in male CD/IGS rats (Rattus norvegicus) after castration.

This study was designed to detect time-course changes in the weights of accessory sex organs after castration. Crj:CD(SD) IGS rats (Rattus norvegicus) were castrated at age of 6-weeks and sacrificed within 14 days of the procedure. The ventral prostate, vesicular gland, bulbospongiosus/levator ani muscle, glans penis and bulbourethral glands were then weighed. The ventral prostate and vesicular gland had significantly decreased in weight 8 and 6 days after castration, respectively. The other organs did not decrease in weight significantly between time periods though there was an overall decrease in weight.

Weaning of immunosuppression in living donor liver transplant recipients.

BACKGROUND: Some reported studies have indicated the possibility of immunosuppression withdrawal in cadaveric liver transplantation. The aim of this study was to evaluate the possibility and feasibility of weaning living donor liver transplant recipients from immunosuppression. METHODS: From June of 1990 to October of 1999, 63 patients were considered to be weaned from immunosuppression. They consisted of 26 electively weaned patients and 37 either forcibly or incidentally weaned patients (nonelective weaning) due to various causes but mainly due to infection. Regarding elective weaning, we gradually reduced the frequency of tacrolimus administration for patients who survived more than 2 years after transplantation, maintained a good graft function, and had no rejection episodes in the preceding 12 months. The frequency of administration was reduced from the conventional b.i.d. until the start of weaning to q.d., 4 times a week, 3 times a week, twice a week, once a week, twice a month, once a month, and finally, the patients were completely weaned off with each weaning period lasting from 3 to 6 months. The reduction method of nonelective weaning depended on the clinical course of each individual case. When the patients were clinically diagnosed to develop rejection during weaning, then such patients were treated by a reintroduction of tacrolimus or an additional steroid bolus when indicated. RESULTS: Twenty-four patients (38.1%) achieved a complete withdrawal of tacrolimus with a median drug-free period of 23.5 months (range, 3-69 months). Twenty-three patients (36.5%) are still being weaned at various stages. Sixteen patients (25.4%) encountered rejection while weaning at median period of 9.5 months (range, 1-63 months) from the start of weaning. All 16 were easily treated with the reintroduction of tacrolimus or additional steroid bolus therapy. CONCLUSIONS: We were able to achieve a complete withdrawal of immunosuppression in some selected patients. Although the mechanism of graft acceptance in these patients has yet to be elucidated, we believe that a majority of long-term patients undergoing living donor liver transplantation may, thus, be potential candidates to be successfully weaned from immunosuppression.

Strain sensitivity differences in the Hershberger assay.

The Hershberger assay is a test method for detecting androgenic or antiandrogenic properties based on alterations in the weights of accessory sex organs in castrate male animals. We performed this study to examine strain sensitivity differences in the Hershberger assay. Flutamide (FLU) at a dose of 3.2 mg/kg was administered to castrated F344, SD, or Wistar rats, in addition to testosterone propionate (TP) administered at a dose of 0.4 mg/kg. Although FLU significantly attenuated the TP-induced increase in glans penis weight in SD and Wistar rats, this attenuation was not observed in F344 rats. Statistical analysis showed differences among the strains in all sex accessory organ weights. The interaction in the ventral prostate, seminal vesicle, and glans penis weights was significant between SD and F344 rats, and between Wistar and F344 rats, but not between SD and Wistar rats. F344 rats were less suitable than SD or Wistar rats for detecting FLU-induced changes.

Living-donor liver transplantation for Caroli's disease with intrahepatic adenocarcinoma.

A 36-year-old woman who had Caroli's disease with refractory cholangitis and complicated intrahepatic cholangiocarcinoma was successfully treated with living-donor liver transplantation. Preoperative computed tomography and ultrasonography showed a small nodule in the dilated intrahepatic bile duct. In the resected liver specimen, a small papillary tumor was located in the dilated intrahepatic bile duct of the right lobe. The pathological finding revealed a well differentiated papillary adenocarcinoma without invasion to the parenchyma. The patient is currently doing well 2.5 years after transplantation, with no signs of recurrence of the disease. For Caroli's disease, we believe we can achieve good results with liver transplantation, not only for cholangitis but also for the carcinoma when it is localized in the liver and the patient is carefully followed up.