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.

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.

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.

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.

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.

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.

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.

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.

Living-related right lobe liver transplantation for a patient with fulminant hepatic failure during the second trimester of pregnancy: report of a case.

A 28-year-old pregnant Japanese woman developed fulminant hepatic failure (FHF) with coma grade IV at 15 weeks' gestation and underwent emergency orthotopic living-related liver transplantation (LRLT) using the right hepatic lobe of her father. Blood type was identical. On postoperative day 2, she regained consciousness and was extubated. For fear of possible negative effects of exposure to various drugs and from x-ray examinations on the fetus as well as the maternal burden of a continuing pregnant state on the patient, artificial abortion was a treatment choice in this woman on posttransplant day 31. The patient was discharged and is currently doing well. Until the present, 11 pregnant women were reported to have liver transplantation during the second trimester of pregnancy, including 2 pregnant women with LRLT. This is the third case of LRLT, and the first successful case in which the right hepatic lobe was used for graft.

Changes in serum levels of hepatocyte growth factor in patients undergoing adult-to-adult living-donor liver transplantation.

Changes in the serum concentration of hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, were investigated in adult-to-adult living-donor liver transplantation (LDLT) in which liver regeneration is involved. Between August 2000 and November 2002, 15 consecutive adult-to-adult LDLTs were performed using the right lobe graft. The recipients were divided into two groups: acute liver failure (n=6) and chronic liver failure (n=9). In addition, right lobe donors (n=12) were evaluated. Measurement of HGF was performed on preoperative and postoperative days 1, 3, 7, and 14 after LDLT. The pretransplant levels of serum HGF were higher in the acute liver failure group than in the chronic liver failure group (P<0.05). After liver replacement, serum HGF levels normalized rapidly in both groups and remained rather low. Despite vigorous liver regeneration in all groups, serum HGF levels did not change significantly after adult-to-adult LDLT with right lobe graft.

A 16-year experience in performing hepatic resection in 303 patients with hepatocellular carcinoma: 1985-2000.

BACKGROUND: Hepatic resection is an accepted therapeutic modality for hepatocellular carcinoma (HCC). Over the past 2 decades, liver surgery has evolved to a refined and deliberate operation. In the present study surgical results are analyzed with an aim toward further improving the treatment of HCC. METHODS: We studied 303 patients with HCC who underwent a hepatic resection at 2 university hospitals from 1985 through 2000. Living-related liver transplantation was a procedure of choice in 1 patient with early staged HCC. Fifty-five percent of the patients had associated cirrhosis. Before the operation, the liver function was mainly evaluated with the indocyanine green retention test. RESULTS: The mortality rate within 30 days after the operation was 1.6%. One-, 3-, 5-, 10-, and 15-year cumulative survival rates were 84%, 67%, 51%, 20%, and 11%, respectively. The tumor stage I and II groups showed superior survival rates to those of the tumor stage III and IV groups, respectively, and the difference was statistically significant. The disease-free survival curves, however, showed the rate to be 27% at 5 years and 11% at 10 years. CONCLUSIONS: Although the surgical results have greatly improved in the treatment of HCC, the recurrence rate is still high. In carefully screened patients with poor liver function and small HCC, liver transplantation enhances the possibility of cure.

Occurrence of hepatocellular and cholangiocellular carcinoma in different hepatic lobes.

Separate hepatocellular and cholangiocellular carcinoma (double cancer) in the liver are extremely rare subtypes of primary hepatic carcinomas. We report a case of double primary liver carcinomas that were surgically resected simultaneously. A 66-year-old man was admitted because of elevation of serum levels of alpha-fetoprotein. Abdominal computed tomography and angiography showed two hypervascular masses in S4 and S8 hepatic segments. With the diagnosis of multiple hepatocellular carcinomas, the tumors were surgically resected. Histological examination showed that the tumor in S4 segment was moderately differentiated cholangiocellular carcinoma, the other in S8 segment was trabecular, moderately differentiated hepatocellular carcinoma. Immunohistochemically, a positive staining in carcinoembyonic antigen and cytokeratin 7 supported the diagnosis of cholangiocellular carcinoma for the tumor in S4 segment. The frequency of double cancer in the liver is much lower than mixed or combined cancer (0.1-0.5%). The different epithelial malignant tumors of hepatocellular carcinoma and cholangiocellular carcinoma, which were located in different hepatic lobes and resected simultaneously, has been reported in only two cases including the present case.

Selective suppression of initial cytokine response facilitates liver regeneration after extensive hepatectomy in rats.

BACKGROUND/AIMS: After extensive hepatectomy, the cytokine network plays an important role in injury to the remnant liver and subsequent impairment of liver regeneration. Tumor necrosis factor alpha (TNF alpha) and interleukin 1beta (IL-1beta) are thought to be the initial cytokines associated with liver injury as well as with regeneration. We investigated the effect of the suppression of these cytokines on liver function and on liver regeneration after subtotal hepatectomy in rats. METHODOLOGY: Following 90% hepatectomy, rats were divided into two groups. Animals in the FR group received intraperitoneal FR167653, a selective inhibitor of TNF alpha and IL 1beta, while those in the Control group received vehicle only. Liver chemistry and serum levels of TNF alpha and IL-6 were measured serially. Liver specimens were obtained 48 hr after surgery and regenerative activity assessed by proliferating cell nuclear antigen (PCNA) expression and remnant liver weight. RESULTS: The survival rate was significantly better in the FR group (76.4+/-11.7 hrs) than in the Control group (26.8+/-4.3 hrs, p=0.0014). Liver enzyme and blood sugar levels after surgery were higher in the FR group compared to the Control group (p=0.03 or less). Changes in serum levels of both TNF alpha and IL-6 were suppressed in FR group rats after surgery. Microscopically, hepatocellular damage and steatosis was less prominent in FR group livers. PCNA labeling index and residual liver weights were higher in the FR group (p<0.001). CONCLUSIONS: Following extensive hepatectomy in rats, suppression of early cytokine induction improved liver function and facilitated liver regeneration. Suppression of selective cytokine responses could allow extended liver resection and reduced risk of liver failure.

Hilar bile duct cancer associated with preoperatively undetectable von Meyenburg complex--report of a case.

A 56-year-old man was admitted to our hospital with a diagnosis of hilar bile duct cancer. Abdominal ultrasonography, computed tomography and endoscopic retrograde cholangiopancreatography showed no other concomitant disease. Biochemical data showed 0.6 mg/dL of total bilirubin, 104 IU/L of alanine aminotransferase and 469 mg/dL of alkaline phosphatase. Carbohydrate antigen 19-9 was elevated as 112.1 U/mL. Operative findings included a resectable left hilar bile duct cancer and grayish-white nodules 0.3-0.5cm in diameter on the surface of segments 6 and 4 of the liver. Although intrahepatic metastasis of the bile duct cancer was highly suspected under intraoperative US, frozen section was reported to show the small nodules containing multiple biliary hamartomas, so-called von Meyenburg complex. Therefore, a left hepatic lobectomy together with resection of the extrahepatic bile duct followed by a Roux-en-Y hepaticojejunostomy was the procedure of choice. His postoperative course was uneventful. The intraoperative findings could have been misdiagnosed due to their similarity to intrahepatic metastasis and intraoperative histology is indispensable to differentiate von Meyenburg complex in this case. The possibility of a preoperative imaging diagnosis for von Meyenburg complex seems to depend on the size of the bile duct structure in each hamartoma. To the best of our knowledge, this is the fourteenth case of bile duct cancer associated with von Meyenburg complex reported in the literature. The following case is being reported because of the rarity of the disease and to stress the importance of intraoperative histology to avoid misdiagnosis as the disseminated disease, particularly when malignant neoplasia is surgically treated.