Regular protocol liver biopsy is useful to adjust immunosuppressant dose after adult liver transplantation.

INTRODUCTION: Adjusting immunosuppression to minimal levels post-adult liver transplantation (LT) is critical; however, graft rejection has been reported in LT recipients with normal liver function evaluated by liver biopsy (LBx). Continual protocol liver biopsy (PLB) is performed regularly in LT recipients with normal liver function in some centers; however, its usefulness remains inadequately evaluated. This study aimed to assess retrospectively the usefulness of late PLB after adult LT. METHODS: LBx evaluations of LT recipients with normal liver function and hepatitis B and C virus seronegativity were defined as PLB. The cases requiring immunosuppressive therapy for rejection findings based on Banff criteria were extracted from the PLBs, and pathological data collected before and after immunosuppressive dosage adjustment (based on modified histological activity index [HAI] score) were compared. RESULTS: Among 548 LBx cases, 213 LBx in 110 recipients fulfilled the inclusion criteria for PLB. Immunosuppressive therapy after PLB was intensified in 14 LBx (6.6%) recipients (12.7%); of these, nine had late-onset acute rejection, three had isolated perivenular inflammation, one had plasma cell-rich rejection, and one had early chronic rejection. Follow-up LBx after immunosuppressive dose adjustment showed improvement in the modified HAI score grading in 10 of 14 cases (71.4%). No clinical background and blood examination data, including those from the post-LT period, immunosuppressant trough level, or examination for de novo DSA, predicted rejection in PLB. Complications of PLB were found in only three cases. CONCLUSION: PLB is useful in the management of seemingly stable LT recipients, to discover subclinical rejection and allow for appropriate immunosuppressant dose adjustment.

Serum Mac-2 binding protein glycosylation isomer as a biomarker of fibrosis in living donor liver transplant graft.

INTRODUCTION: Non-invasive assessment of graft fibrosis is important in liver transplantation. Mac-2 binding protein glycosylation isomer (M2BPGi) has been reported as a diagnostic marker for this purpose, and thus, this predictive ability of M2BPGi was assessed in this study. PATIENTS AND METHODS: In this retrospective study, 236 patients who received living donor liver transplantation (LDLT) from August 1997 to March 2017 were enrolled. Among them, 94 biopsy patients were analyzed. Further, the predictive ability of fibrotic biopsy using M2BPGi, Fibroscan, and Fib-4 index was compared. RESULTS: Of 94 LDLT patients (53 men, 41 women), the median ages of recipients and donors were 57.5 and 33.0 years, respectively. The median M2BPGi values in patients with F0 (n = 11), F1 (n = 38), F2 (n = 35), and F3/4 (n = 10) were 0.680, 0.760, 1.240, and 4.110 COI, respectively. There were significant correlations between the fibrotic stage and M2BPGi levels (Kruskal-Wallis test, P < .0001). The area under the ROC curve for the diagnosis of F ≥ 2 in M2BPGi was 0.778, which was superior to Fibroscan (0.701) and Fib-4 index (0.639). CONCLUSION: M2BPGi is an accurate, non-invasive detection method for significant fibrosis after LDLT.

Inferior Vena Cava Anomalies with Portal Vein System Continuation Presenting as Portal Hypertension with a Long-term Follow-up.

Inferior vena cava (IVC) anomalies, such as the absence of an intra-hepatic IVC or IVC hypoplasia, are rare. Usually, these anomalies are asymptomatic and cause few clinical issues. We herien report a 53-year-old woman with IVC anomalies who demonstrated both azygos and portal vein system continuation. Over time, this resulted in gradually progressive portal hypertension due to abnormal hemodynamics. The increased inflow from the IVC to the portal vein system for an extended time may contribute to the development of portal hypertension without liver cirrhosis.

Peripheral hepatic sinusoidal obstruction syndrome due to oxaliplatin-based chemotherapy.

Hepatic sinusoidal obstruction syndrome during oxaliplatin-based chemotherapy has been shown to be associated with severe steatohepatitis. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging may identify various features of hepatic sinusoidal obstruction syndrome, even when the lesion cannot be differentiated from sinusoidal obstruction syndrome by other imaging tools.

Two difficulty diagnosis cases of severe veno-occlusive disease.

BACKGROUND: The occurrence of Hepatic veno-occlusive disease (VOD) is rale liver disease. However, severe VOD is often lethal and one of the most common causes of death following stem cell transplantation (SCT). CASE REPORTS: Case 1 was a 30-year-old woman who was diagnosed as Budd-Chiari syndrome with liver failure. She was admitted to our department to undergo liver transplantation. Four days after admission, she underwent liver transplantation. Her liver explant showed VOD. Case 2 was a 74-year-old woman who was admitted to a community hospital for further examination. Her condition continued to deteriorate with liver failure, and she died 39 days after admission. Liver autopsy also showed VOD. Either of the patients had difficulty in diagnose as VOD. Neither of the patients had a history of SCT. CONCLUSIONS: VOD should be considered as a cause of acute hepatic failure, even if the patient has no history of SCT.

Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation.

BACKGROUND AND AIM: Currently, hepatitis B virus (HBV) re-infection after liver transplantation (LT) can be almost completely suppressed by the administration of HBV reverse transcriptase inhibitors and hepatitis B immunoglobulins. However, after transplantation, there is no indicator of HBV replication because tests for the serum hepatitis B surface antigen and HBV-DNA are both negative. Therefore, the criteria for reducing and discontinuing these precautions are unclear. In this study, we examined the serum HBV core-related antigen (HBcrAg) and intrahepatic covalently closed circular DNA (cccDNA) in order to determine if these could be useful markers for HBV re-infection. METHODS: Thirty-one patients underwent LT for HBV-related liver disease at Nagasaki University Hospital from 2001 to 2010. Of these, 20 cases were followed up for more than 1 year (median follow-up period, 903 days). We measured serum HBcrAg and intrahepatic cccDNA levels in liver tissue. In addition, in nine cases, we assessed the serial changes of HBcrAg and intrahepatic cccDNA levels from preoperative periods to stable periods. RESULTS: We examined serum HBcrAg and intrahepatic cccDNA levels in 20 patients (35 samples). HBcrAg and cccDNA levels were significantly correlated with each other (r = 0.616, P < 0.001). From a clinical aspect, the fibrosis stage was significantly lower in both HBcrAg- and cccDNA-negative patients than in HBcrAg- or cccDNA-positive patients. CONCLUSIONS: HBcrAg and cccDNA were useful as HBV re-infection markers after LT. Keeping patients' HBcrAg and cccDNA negative after LT might contribute to long-term graft survival.

The expression of transporter OATP2/OATP8 decreases in undetectable hepatocellular carcinoma by Gd-EOB-MRI in the explanted cirrhotic liver.

PURPOSE: The aim of this study is to evaluate the detectability of hepatocellular carcinoma (HCC) in the explanted cirrhotic liver using gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) and the degree of organic anion transporter OATP2/OATP8 (OATP1B1/1B3) HCC which could not be preoperatively detected by multi-detector computed tomography (MD-CT) and Gd-EOB-MRI. METHODS: Eleven patients (HBV 3, HCV 7, nonBnonC 1) out of 145 recipients of liver transplantation were analyzed. The detectability by each imaging modality and the expression of OATP2/OATP8 of HCC were analyzed using the whole liver thin sliced histological and immunohistochemical examination retrospectively. RESULTS: The imaging examination detected 17 lesions of HCC by MDCT and/or Gd-EOB-MRI. Only one lesion detected by Gd-EOB-MRI had well differentiated and minute (7 mm) HCC. However, the histological examination revealed newly 11 lesions and one false-positive lesion of HCC in the explanted livers. The median diameter of the preoperatively undetectable HCC by imaging was 8 mm (2-12). The histological characteristic of the preoperatively undetectable HCC was well differentiated HCC (10/11). The accuracy rate in MDCT and Gd-EOB-MRI was 53.6 % (15/28) and 57.1 % (16/28). The rate of positive predictive value in MDCT and Gd-EOB-MRI was 93.7 % (15/16) and 94.2 % (16/17), respectively. The expression of OATP2/OATP8 in the preoperatively undetectable HCC was negative in nine lesions, was weak positive in two lesions. CONCLUSIONS: The detectability of Gd-EOB-MRI is almost equal to MDCT in a cirrhotic liver. Small HCCs were difficult to detect even with Gd-EOB-MRI. The transporter of OATP2/OATP8 was less expressed in the preoperatively undetectable HCCs.

Human T-cell leukemia virus type 1 infection worsens prognosis of hepatitis C virus-related living donor liver transplantation.

Severe and life-threatening donor-transmitted human T-cell leukemia virus type 1 (HTLV-1) infections after solid organ transplantation have been reported. However, in HTLV-1-infected recipients, graft and patient survival were not fully evaluated. A total of 140 patients underwent living donor liver transplantation (LDLT). Of these, 47 of 126 adult recipients showed indications of hepatitis C virus (HCV)-related liver disease. The HTLV-1 prevalence rate was 10 of 140 recipients (7.14%) and three of 140 donors (0.02%). In HCV-related LDLT, graft and patient survival was worsened by HTLV-1 infection in recipients (seven cases). The 1-, 3-, and 5-year survival rates in the HCV/HTLV-1-co-infected group were 67%, 32%, and 15%, respectively, and the corresponding rates in the HCV-mono-infected group were 80%, 67%, and 67%, respectively. Only the 5-year survival rates were statistically significant (P=0.04, log-rank method). HTLV-1 infection in recipients is also an important factor in predicting survival in HTLV-1 endemic areas.

Partial internal biliary diversion for patients with progressive familial intrahepatic cholestasis type 1.

We herein report a case of progressive familial intrahepatic cholestasis with partial internal biliary diversion (PIBD). Although by using PIBD an external stoma can be avoided, exposure of the ileocecal junction to bile reflux as well as the effects of the direct bile flow on the colonic mucosa require further investigation.

Two-staged living donor liver transplantation for fulminant hepatic failure.

We reported a first successful and life-saving two-staged living-related liver transplantation for a patient with imminent brain death due to fulminant hepatic failure that otherwise had to be performed after a pre-treated and scheduled blood-type incompatible liver transplantation. The patient was anhepatic for 6 hr 34 min, and continuous hemodiafiltration was given throughout the operation. The patient recovered quickly and was extubated within 24 hr after transplant. This two-staged procedure is useful for emergency living-related liver transplantation that needs to be performed when the operating room is busy with other emergency or scheduled surgical procedures, and may allow clearance of toxic metabolites during the anhepatic period.

Low-dose recombinant human hepatocyte growth factor enhances effect of hepatocyte transplantation in rats treated with retrorsine.

BACKGROUND/AIMS: The aim of this study was to regenerate transplanted hepatocytes selectively in a recipient using retrorsine and recombinant human hepatocyte growth factor (rhHGF). METHODOLOGY: Nagase analbuminemic rats (NARs) received pretreatment with retrosine and were divided into three experimental groups. Group1: Hepatocyte transplantation (HcTx) + 50 microg/kg/day rhHGF. Group2: HcTx + 250 microg/kg/day rhHGF. Group3: HcTx + normal saline. The serum levels of albumin and the albumin-positive hepatocytes in the liver were investigated. The rat endogenous HGF of the rats given only retrorsine was measured. RESULTS: The serum albumin levels of Group11 were higher than those of Group2, while there was no significant difference between Group2 and GroupS. Histological examination of Group1 and 3 showed the presence of a large number of albumin-positive hepatocytes, which frequently consisted of large clusters and occupied 53.90 +/- 2.31% and 31.25 +/- 5.36% of host liver, respectively. The liver sections of Group2 showed numerous albumin-positive hepatocyte, which were not seen as clusters. The rat endogenous HGF concentration was extremely high. CONCLUSION: Low-dose rhHGF enhances the effect of HcTx under the suppressive state of proliferation of host hepatocytes. Because of the high endogenous HGF, the administration of a high concentration of rhHGF suppressed the regenerative activity of the transplanted hepatocytes.

Actual therapeutic efficacy of pre-transplant treatment on hepatocellular carcinoma and its impact on survival after salvage living donor liver transplantation.

BACKGROUND: The exact efficacy of pre-liver transplant (LT) therapy for hepatocellular carcinoma (HCC) and the impact on survival after LT remain controversial in regard to salvage LT. MATERIALS AND METHODS: Of 79 patients transplanted in Nagasaki University Hospital between August 1997 and December 2007, 29 patients (36.7%) were indicated for HCC based on the Milan criteria using computed tomography and magnetic resonance imaging. Pre-LT therapy other than liver resection had been performed in 18 cases (62.1%) for 24 lesions. Treated lesions were analyzed histologically using thin slices of the whole explanted liver. RESULTS: Pre-LT therapy included transarterial chemoembolization (TACE) for 10 lesions, percutaneous ethanol injection (PEI) + TACE for 1 lesion, PEI in 6 lesions and ablation therapy in 7 lesions. Under preoperative imaging study, 19 lesions (79.1%) were "thought-to-be" necrotic by pre-LT therapy. However, histologically, viable HCCs were still observed in 9 lesions (9/19 47%). A median interval between the first pre-therapy and LT was 22 months, while last pre-LT therapy and LT was 11 months. No sarcomatous HCC or forced portal venous tumor thrombus was found in all cases with residual lesions. One peritoneal recurrence has occurred after LT, in whom PEI and RFA had been performed before LDLT. The disease free survival after LDLT was comparable to that of cases without pre-LT therapy. CONCLUSION: Half of the preoperatively "thought-to-be" necrotic lesions still contained viable HCC cells after the pre-LT treatment. Overall, the history of pre-LT therapy does not preclude or interfere with subsequent LT, although percutaneous treatment may spread disseminated tumor cell growth under immunosuppression.

Multicentric occurrence and spread of hepatocellular carcinoma in whole explanted end-stage liver.

AIM: Hepatocellular carcinoma (HCC) arising from the end stages of liver cirrhosis is a fair indication for liver transplantation (LT). To pathologically investigate the multicentric occurrence of relatively early staged HCC in cirrhosis, we studied whole explanted livers. METHODS: Fourteen explanted livers from patients undergoing living donor LT (LDLT) were examined. The stage of the HCCs was judged to be within the Milan criteria (M-C; a single HCC less than 5 cm or three HCCs less than 3 cm). Histological examination was performed using serially sectioned specimens 5-7 mm in width. Characterization of preoperatively detectable and undetectable lesions was also performed. RESULTS: In nine patients (64.3%), a total of 34 nodules were found after whole liver histological examination (WLHE). In five patients (31%), the results exceeded the M-C. The characteristics of undetectable HCCs included a minute (median size 6 mm), well-differentiated appearance (80%), with indistinct margins (85.3%) and without vascular invasion (94%). There was no recurrence in any patients at the time of follow up (median follow-up period, 30.1 months). CONCLUSION: A multicentric occurrence of HCCs was demonstrated in cirrhotic livers with HCCs within the M-C. Undetectable HCCs in cirrhotic livers may have no impact on recurrence after LT.

Acute deterioration of idiopathic portal hypertension requiring living donor liver transplantation: a case report.

Case reports of severe idiopathic portal hypertension (IPH) requiring liver transplantation are very rare. We report the case of a 65-year-old woman who was diagnosed as having IPH. At the age of 60 years, her initial symptom was hematemesis, due to ruptured esophageal varices. Computed tomography of the abdomen showed splenomegaly and a small amount of ascites, without liver cirrhosis. She was diagnosed as having IPH and followed-up as an outpatient. Five years later, she developed symptoms of a common cold and rapidly progressive abdominal distension. She was found to have severe liver atrophy, liver dysfunction, and massive ascites. Living donor liver transplantation was then performed, and her postoperative course was uneventful. Histopathological findings of the explanted liver showed collapse and stenosis of the peripheral portal vein. The areas of liver parenchyma were narrow, while the portal tracts and central veins were approximate one another, leading to a diagnosis of IPH. There was no liver cirrhosis. The natural history of refractory IPH could be observed in this case. Patients with end-stage liver failure due to severe IPH can be treated by liver transplantation.

Glycine reduces hepatic warm ischaemia-reperfusion injury by suppressing inflammatory reactions in rats.

BACKGROUND: Glycine, a non-essential amino acid, is known to have an anti-inflammatory effect on haemorrhagic and endotoxic shock in animals. In the present study, we examined the effects of glycine on inflammatory reactions and hepatocellular damage after hepatic warm ischaemia-reperfusion (I-R) in rats. METHODS: Using Sprague-Dawley rats, ischaemia was induced in 92% of the liver by clamping the hepatic inflows for 60 min, and part of the non-ischaemic lobe was resected after reperfusion. Before the induction of I-R, rats were treated by an intravenous administration of either glycine (Glycine group) or normal saline (Control group). The severity of hepatocellular injury was determined by serum levels of hepatic enzymes and histological necrosis. To evaluate the effect of glycine on inflammatory reactions, tumour necrosis factor (TNF)-alpha mRNA expression in the liver, serum levels of TNF-alpha and chemokine-induced neutrophil chemoattractant (CINC) and the number of neutrophils in the liver were compared between the groups. RESULTS: At 60 min after reperfusion, the serum levels of hepatic enzymes in the Glycine group were significantly lower than those in the Control group (P<0.05). TNF-alpha mRNA expression was also suppressed in the livers in the Glycine group. Furthermore, the serum levels of TNF-alpha and CINC in the Glycine group were significantly lower than those in the Control group (P<0.05). Pretreatment with glycine also significantly reduced hepatic necrosis and the number of neutrophils at 24 h after reperfusion. CONCLUSION: Glycine has a protective effect against inflammatory reactions, and reduces hepatocellular injury induced by hepatic warm I-R in rats.

Protective effects of a hibernation-inducer on hepatocyte injury induced by hypothermic preservation.

BACKGROUND/PURPOSE: For hepatocyte-based cell therapy to be realistic, the method chosen for cryopreservation or hypothermic preservation is critical. The aim of the present study was to clarify whether D-Ala2-Leu5-enkephalin (DADLE), a hibernation inducer, has protective effects on hepatocytes with regard to hypothermic preservation injury. METHODS: A suspension of rat hepatocytes was stored at 4 degrees C for 24 h with or without DADLE. Their viability was measured by the trypan blue dye exclusion method, and alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels in the preservation solution were measured. After 24 h of cold storage, viable hepatocytes were cultured at 37 degrees C for another 24 h. Then albumin production and lidocaine clearance were measured. RESULTS: DADLE significantly improved the survival rate of hepatocytes. The levels of ALT and LDH in the preservation solution with DADLE were significantly lower than those in the preservation solution without DADLE. The treated viable hepatocytes maintained both albumin synthesis and lidocaine clearance. CONCLUSIONS: DADLE appears to have protective effects on hepatocytes with regard to hypothermic preservation injury in vitro. This hibernation-inducer is useful in prolonged hypothermic preservation for hepatocyte-based therapy.

The effect of denervation on liver regeneration in partially hepatectomized rats.

BACKGROUND/AIM: In a partial liver transplantation, the dissected hepatic nerves are left unrepaired during active liver regeneration. In fact, the pathophysiological influence of such hepatic denervation on liver regeneration has not yet been fully clarified. The aim of the present study is to elucidate the effect of total hepatic denervation on liver regeneration. METHODS: Experiment 1: To confirm the effect of hepatic denervation, the hepatic contents of norepinephrine were measured in both denervated (n = 5) and sham (n = 5) rats. The changes in the hepatic microcirculation were also measured in both denervated (n = 5) and sham (n = 5) rats. Experiment 2: The rats (n = 80) were randomly assigned to two groups: DN group (n = 40); hepatic denervation followed by a partial hepatectomy (PH). Control group (n = 40); sham hepatic denervation followed by PH. In both groups, the animals were killed at 12, 24, 36, 48, 72, 120, and 168 h after PH, respectively. The liver to body weight ratio and the proliferating cell nuclear antigen (PCNA) labeling index were measured at each time point. RESULTS: Experiment 1: Nearly a total depletion of norepinephrine (<99%) was observed in the DN rats. In addition, the hepatic tissue blood flow significantly increased in the DN rats. Experiment 2: The liver to body weight ratio of the DN group was also significantly higher than that of the control group at 168 h (P < 0.05). The PCNA labeling index peaked between 24 and 36 h in the control group, while that in the DN group showed a delayed peak. At 72 and 120 h, the PCNA labeling index was significantly higher in the DN group than in the control group (P < 0.05). CONCLUSION: Total hepatic denervation was thus found to enhance liver regeneration after a partial hepatectomy. This phenomenon is partially triggered by the increased hepatic blood flow to the remnant liver.

A case of mucin producing liver metastases with intrabiliary extension.

A 75-year-old man was admitted to our hospital with a diagnosis of liver metastases from colon cancer. He underwent right hemicolectomy for cecal cancer eight years ago, and had a metastatic liver tumor in segment 8 (S8), which was surgically resected about 4 years after the initial operation. Histopathological examination of the resected specimens from both operations revealed a well-differentiated adenocarcinoma with mucinous carcinoma. Four months after the second operation, computed tomography demonstrated a low-density lesion at the cut surface of the remnant liver. Although it was considered to be a postoperative collection of inflammatory fluid, it formed a cystic configuration and increased in size to approximately 5 cm in diameter. With a tentative diagnosis of a recurrence of metastatic cancer, partial hepatectomy of S8 was performed. Histological examination of the resected specimens also revealed mucinous adenocarcinoma, which had invaded into the biliary ducts, replacing and extending along its epithelium. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) 20, but negative for CK7. Therefore, the tumor was diagnosed as a metastatic adenocarcinoma from colonic cancer. Liver metastases of colorectal adenocarcinoma sometimes invade the Glisson's triad and grow along the biliary ducts.

Measurement of portal venous pressure is useful for selecting the optimal type of resection in cirrhotic patients with hepatocellular carcinoma.

BACKGROUND/AIMS: In the present study the importance of measurement of portal venous pressure was focused on to predict the postoperative liver function before liver surgery, particularly in cirrhotic patients. METHODOLOGY: Ninety-two patients who underwent a hepatic resection for hepatocellular carcinoma (HCC) were retrospectively evaluated to predict their postoperative liver function by measuring the portal venous pressure. RESULTS: The portal venous pressure was not significantly correlated with the preoperative value of the indocyanine green (ICG) retention test. In patients with an ICG of over 20%, the risk of occurrence of postoperative hyperbilirubinemia was high when a major hepatic resection was the procedure of choice. Even in patients with an ICG of below 20%, a few patients developed complications after surgery when major resection was carried out. For patients undergoing a small excision, the complications were nil when the ICG was below 20% and the pressure was below 200mm in saline. CONCLUSIONS: The portal venous pressure was found to reflect to what degree the liver parenchyma is damaged. Measuring the portal venous pressure is useful for determining the final indications for surgery also in cirrhotic patients with HCC.

Langerhans' cell histiocytosis after living donor liver transplantation: report of a case.

We report a case of Langerhans' cell histiocytosis (LCH) occurring after a living donor liver transplantation (LDLT) for fulminant hepatitis. A 9-month-old girl underwent an LDLT for fulminant hepatitis of an unknown cause. The histology of the native liver did not show any findings of LCH. On postoperative day 42, her Epstein-Barr virus (EBV)-DNA and cytomegalovirus antigenemia were both found to be positive. As a result, she was treated with antiviral agents and a reduction of the immunosuppression dosage. On postoperative day 98, acute rejection occurred, and she was treated with FK506, methylprednisolone, and finally, anti-CD3 murine monoclonal antibody was added. Subsequently, the EBV was re-activated. Thereafter, skin eruptions, swelling of the systemic lymph nodes, and pancytopenia appeared on postoperative day 127. LCH was diagnosed based on the typical histological findings as LCH, CD1a, and S-100-positive cells in her skin and a lymph nodes biopsy. She was treated by chemotherapy. The symptoms disappeared a few weeks after the start of the chemotherapy, and a clinical remission of LCH was obtained. We could not detect any evidence of EBV infection in the tumor cells. In spite of the fact that her LCH lesions thereafter remained in remission, she died of hepatic failure at 22 months after undergoing the liver transplantation. In conclusion, we discuss the factors influencing the occurrence of LCH in our patient after LDLT, while also evaluating the relationship between LCH and the immunosuppressive therapy administered to this patient.