Hypoxic hepatitis with marked elevation of serum ferritin probably due to activation of intrahepatic macrophages: another form of hypoxic hepatitis hitherto not reported?

BACKGROUND AND STUDY AIMS: Hypoxic hepatitis (HH) is an acute liver injury that develops in patients with underlying diseases, such as heart failure, respiratory failure, septic/toxic shock. However, some patients do not have underlying diseases or episodes which are known to result in HH. Here, we analyzed the clinical characteristics of this particular patient group (called 'unknown HH' hereafter) to understand its pathogenesis. PATIENTS AND METHODS: Between October 2010 and January 2016, 157 consecutive patients with acute liver injury were admitted to our hospital. Among these patients, 15 patients were categorized as unknown HH. Medical histories and blood test results of unknown HH were analyzed. RESULTS: Among 15 patients of unknown HH, 11 were habitual drinkers and all experienced one of digestive symptoms which might result in mild hypovolemia such as vomiting, diarrhea, appetite loss, and epigastralgia. All patients of unknown HH presented marked elevation of serum ferritin concentration paralleled with aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) concentrations. The serum levels of ferritin, ALT, LDH, and prothrombin time-international normalized ratio (PT-INR) were rapidly decreased during hospitalization and all 15 patients of unknown HH recovered without any complication. CONCLUSIONS: We found the particular group of HH with marked elevation of serum ferritin probably due to intrahepatic macrophage activation. Anti-inflammatory treatments might be effective for this group of hypoxic hepatitis.

Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure.

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.

Telaprevir-based triple therapy for chronic hepatitis C patients with advanced fibrosis: a prospective clinical study.

BACKGROUND: Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis-related complications. AIM: To evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy for patients with advanced fibrosis in a clinical practice setting. METHODS: This prospective, multicentre study consisted of 102 patients with advanced fibrosis (METAVIR score F3-4) who were infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin (RBV). RESULTS: The sustained virological response (SVR) rate was 69.6% (71 of 102). Notably, for treatment-naïve and prior relapse patients the SVR rate was over 80%. Previous treatment response, interleukin 28B polymorphism (rs8099917) and rapid virological response (undetectable HCV RNA at week 4) were independently associated with SVR. To achieve SVR, an adequate dosage of PEG-IFNα2b (≥1.2 µg/kg/week) and RBV (≥7.5 mg/kg/day) is preferable; however, the mean weight-adjusted TVR dosage had little impact on treatment outcome. Although severe blood cytopaenia and a dermatological disorder were frequently found, the rate of discontinuation due to adverse effects was 12.7%. The inosine triphosphatase CC allele (rs1127354) was independently associated with the development of severe anaemia, and lower serum albumin level (<35 g/L) was associated with the occurrence of infection. CONCLUSIONS: The great gain in the SVR rate by telaprevir-based triple therapy offsets the problems with adverse effects; thus, it should be considered as a potent treatment protocol for patients with advanced fibrosis, especially for those with treatment-naïve and prior relapse.

Expression profiles of genes associated with viral entry in HCV-infected human liver.

Recent studies have demonstrated that several cellular factors are involved in entry of hepatitis C virus (HCV) into host cells. Detailed gene expression profiles of these factors in HCV-infected livers have not been reported for humans. Transcriptional levels of LDL receptor (LDLR), CD81, scavenger receptor class B type I (SR-BI), claudin-1, and occludin genes in liver samples from patients with chronic hepatitis C were investigated. Serum levels of LDL-cholesterol (LDL-C) and HCV core antigen were also evaluated, and expression of claudin-1 and occludin were immunohistochemically analyzed. Compared with normal liver, transcription of LDLR and claudin-1 genes was significantly suppressed (P < 0.0001) and occludin transcription was significantly up-regulated in HCV-infected livers (P < 0.0001). Significant positive correlations were found for LDLR versus occludin, LDLR versus claudin-1, occludin versus claudin-1, and CD81 versus SR-BI in HCV-infected (P = 0.0012, P < 0.0001, P = 0.0004, and P < 0.0001, respectively) and normal livers (P < 0.0001, P = 0.0051, P < 0.0001, and P < 0.0001, respectively). Positive correlation was observed between serum levels of HCV core antigen and LDL-C (P = 0.0147), with their levels negatively correlated to LDLR (P = 0.0270 and P = 0.0021, respectively). Immunohistochemically, hepatocellular expression of claudin-1 and occludin was increased in HCV-infected livers. Different levels of expression were demonstrated at the mRNA and protein levels for occludin and claudin-1 in HCV-infected and normal livers. Correlation of elements associated with viral entry was comparable in HCV-infected and normal livers.

Therapeutic effect of bezafibrate against biliary damage: a study of phospholipid secretion via the PPARalpha-MDR3 pathway.

OBJECTIVE: Bezafibrate (BF) has been used to treat biliary damage, particularly in patients with primary biliary cirrhosis (PBC), and its clinical efficacy has been demonstrated. The mechanism of action is thought to involve activation of the PPARalpha-MDR3-phospholipid (PL) secretion pathway. We tried to confirm this hypothesis in patients with hepatobiliary disease. METHODS: The levels of serum gamma-glutamyl transpeptidase and alkaline phosphatase, and those of bile components were examined before and after BF administration in patients with obstructive jaundice undergoing percutaneous transhepatic biliary drainage (PTBD). Hepatic expression of PPARalpha and MDR3 was quantified by real-time PCR in patients with PBC or non-alcoholic fatty liver disease (NAFLD). RESULTS: In patients with obstructive jaundice, BF decreased the serum levels of biliary enzymes and increased the bile concentration of PL. In patients with PBC or NAFLD, the expression levels of MDR3 were already up-regulated before starting the BF treatment. Although BF treatment did not further up-regulate MDR3 expression in NAFLD patients, PPARalpha expression was significantly increased. CONCLUSIONS: BF enhanced the secretion of PL into bile in cholestatic patients undergoing PTBD. However, in patients with PBC or NAFLD, diseases that represent cholesterol overload, MDR3 was already expressed at a high level to compensate for bile acids overproduction, and its expression was hardly affected by BF. In patients with chronic liver diseases such as PBC, BF may induce clinical effects via mechanisms independent of PL secretion.

The benefits of interferon treatment in patients without sustained viral response after living donor liver transplantation for hepatitis C.

UNLABELLED: Although it has been recognized that interferon (IFN) treatment is crucial for recurrent hepatitis C after liver transplantation, its benefits have not been determined among patients without a sustained viral response (SVR). METHODS: Eighty patients who received IFN plus ribavirin treatment after living donor liver transplantation were grouped as follows: group I (n = 18) SVR; group II (n = 25) no-SVR but viral response [VR] positive; Group III (n = 13) no-VR but biochemical response [BR] positive; and group IV (n = 24) no-VR and no-BR. RESULTS: In groups II and III, not only the histological activity grade and fibrosis stage, but also the serum parameters including transaminases and type IV collagen were stable for 3 years after induction of IFN-based treatment. In group I, the activity grade and fibrosis stage significantly improved (P < .01). In group IV, the fibrosis stage significantly deteriorated (P < .01); the serum transaminases and type IV collagen were significantly higher than the other groups (P < .01). The mean duration of IFN treatment was significantly longer among group II (96 weeks) compared with the other cohorts (P < .05). The 5-year graft survival rate in groups II (91%) and III (100%) were comparable to those of group I (100%); group IV (62%) was significantly lower than the other groups (P < .05). CONCLUSION: IFN treatment was beneficial even among subjects with IFN-dependent VR or BR, although they did not achieve SVR.

Early surgery for treatment of spontaneous hemopneumothorax.

PURPOSE: Spontaneous hemopneumothorax (SHP) is a rare life threatening disorder. We retrospectively investigated patients with SHP who were treated with video- assisted thoracic surgery (VATS), and report our results. METHODS: From January 1993 to July 2006, 239 patients with spontaneous pneumothorax were treated, among whom 11 (4.6%) were diagnosed with SHP. RESULTS: All 11 patients had a collapsed lung condition worse than moderate and a chest tube inserted, of whom 10 underwent an emergency operation. The points of hemorrhaging, each of which were in the apical portion of the lung, were easily revealed during VATS, and we were able to distinguish between brisk flow and seepage. Hemostasis was acquired using VATS in all surgery cases, while the other was treated with tube drainage. The single patient who did not undergo surgical treatment had recurrent spontaneous pneumothorax 3 months later. CONCLUSION: It is important to perform surgery for SHP at the appropriate time. VATS was found to be an easily performed and safe procedure for initial treatment in patients with active hemorrhaging and massive blood clotting in the thorax. The long-term outcome of our patients with early surgical indication was excellent and we recommend early surgical treatment for SHP.

[New technique to determine graft length using the proximal anastomotic system during off-pump coronary artery bypass grafting].

For determining the graft length for an aortic connector, grafts to the circumflex (Cx) and the posterior descending (PD) regions often present problems. Difficulties in determining the appropriate distance between the aorta and coronary artery have been reported to be due to changes in the morphology of the heart following the evolution of Cx and PD. We set an intermediate point (IMP) in advance and then determine graft distance in 2 steps. When using the IMP method, determination of the graft length in the Cx region is not difficult. However, attention should be paid to determine the distance between the IMP and anastomosed site without deforming the heart, as the graft length becomes shorter if the heart as a whole is pulled up by traction of the diaphragm during evolution to the PD region.

Urinary N1,N12-diacetylspermine levels correlate with HCV amount in patients with chronic hepatitis C.

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Cyclosporine suppresses cell growth and collagen production in hepatic stellate cells.

BACKGROUND: In HCV-related graft hepatitis, immunosuppression has been implicated in rapid progression to cirrhosis, a serious clinical issue. We investigated the effects of cyclosporine or tacrolimus on cell growth and collagen production by hepatic stellate cells (HSC), which play a role in hepatic fibrosis. MATERIALS AND METHODS: Cultured rat HSCs and human HSC-derived TWNT-4 cells were evaluated for proliferation, type I collagen, phosphorylation states of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2; [MAPKs Erk1/2], c-Jun N-terminal kinase (JNK, p38), as well as the expression of collagen, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) genes. RESULTS: Cyclosporine suppressed cell growth and collagen production in a concentration-dependent manner. At clinically relevant concentrations of 0.125 micromol (150 ng/mL) cyclosporine significantly reduced collagen production per cell by more than 50%. Similarly, tacrolimus also reduced both collagen concentration and cell number; however, tacrolimus at a clinically relevant concentration of 12.5 nmol (10 ng/mL) did not significantly reduce collagen production. Treatment with cyclosporine reduced type I collagen and TIMP-1 expression and enhanced MMP-1 expression. Cyclosporine also inhibited phosphorylation strongly for JNK and p38, and weakly inhibited for Erk1/2. CONCLUSION: These findings demonstrated that cyclosporine suppresses cell growth and collagen production, suggesting that it may have an antifibrogenic effect.

[A constrictive pericarditis on oral steroid and immunosuppressant treated with bilateral anterolateral thoracotomy; report of a case].

A successful case of pericardiectomy without median sternotomy for an immunosuppressive 59-year-old man with constrictive pericarditis (CP) was reported. He had a history of invasive thymoma, myasthenia gravis and pure red cell aplasia, and he was on oral steroid and immunosuppressant. Pericardiectomy was performed by the approach of bilateral anterolateral thoracotomy to avoid troubles due to median sternotomy under immunosuppression, and there was no postoperative infection such as mediastinitis. Bilateral anterolateral thoracotomy was considered to be useful for immunosuppressive cases.

[Beating heart coronary artery bypass grafting for acute myocardial infarction].

We consider that off-pump coronary artery bypass grafting (CABG) [OPCAB], which results in local myocardial ischemia, is more effective for patients with acute myocardial infarction (AMI) than conventional CABG under cardiac arrest with global myocardial ischemia. Twenty-one patients (15 males, 6 females) received OPCAB for AMI, among whom surgery was performed following percutaneous coronary intervention (PCI) failure in 4 and PCI was performed prior to OPCAB in 2, while PCI was not performed in the remaining 15. Preoperatively, 16 patients had intraaortic balloon pumping (IABP), and 4 had IABP and percutaneous cardiopulmonary support (PCPS). The mean interval from onset to surgery was 11.7 (range 3 to 40) hours. In 20 cases, a complete revascularization was performed. The mean number of bypasses was 2.3 and OPCAB was carried out in 14 patients. In 2 cases, OPCAB was converted to on-pump beating CABG for complete revascularization. Fourteen patients (67%), each maintained with preoperative left ventricular ejection fraction (EF), were discharged with an elective bypass. Four patients died after on-pump beating CABG, in whom EF was lower than 10%. In addition, 3 died of low cardiac output syndrome (LOS) under PCPS and 1 of ventricular fibrillation. Based on our results, we considered that complete revascularization using OPCAB was effective for cases of AMI with PCI difficulty. However, in shock cases requiring PCPS, cardiac function was not improved even after revascularization. Therefore, it is necessary to study new procedures for shock cases during the period from onset to surgery.

Movement of a novel serum tumour marker, RCAS1, in patients with biliary diseases.

BACKGROUND: We have demonstrated immunohistochemically that RCAS 1 antigen is expressed in biliary neoplasms. Serum RCAS 1 levels are also elevated in a high percentage of patients with intra-hepatic cholangiocarcinoma. AIM: The study was designed to determine whether serum levels of RCAS1 are of clinical significance as a tumour marker for biliary tract tumour, in comparison to CA19-9. PATIENTS AND METHODS: In 38 patients with biliary carcinoma (gallbladder carcinoma, extra-hepatic and intra-hepatic cholangiocarcinoma and ampullary carcinoma), we measured serum RCAS1 and CA19-9 levels. For control, serum samples from patients with benign biliary disease and healthy volunteers were also examined. RESULTS: We established a threshold value for RCAS1 of 17.5 U/ml, which permitted discrimination between malignant and non-malignant biliary diseases. In comparison to CA 19-9, serum RCAS1 was more sensitive and specific for malignancy, and was not influenced by cholestasis. RCAS1 levels varied with respect to the disease course and the effect of clinical treatment. CONCLUSIONS: Serum RCAS1 appears to be valuable as a diagnostic index for biliary carcinomas, as well as for evaluating the progression of cancers during therapy. We speculate that RCAS1 is a clinically more significant serum marker for biliary neoplasms than CA19-9.

Clinical significance of urinary N1,N12-diacetylspermine levels in patients with hepatocellular carcinoma.

BACKGROUND/AIM: N1,N12-diacetylspermine (DiAcSpm), a diacetylpolyamine which was recently identified in urine, appeared to be a useful tumor marker for urogenital cancers. Here we examined the clinical significance of urinary DiAcSpm as a tumor marker for hepatocellular carcinoma (HCC). METHODS: Urine samples were collected from patients with HCC and benign liver diseases. Urinary levels of DiAcSpm were measured by ELISA, which was newly developed in order to analyze large numbers of samples. RESULTS: The appropriate threshold value was set at 325 nM/g x creatinine. The sensitivity of the DiAcSpm assay for HCC was 65.5% and the specificity calculated between HCC and liver cirrhosis was 76.0%. The percentage of DiAcSpm-positive HCC patients was similar to that for AFP or PIVKA-II. At more advanced clinical stages, the positive percentage of these three markers increased but the DiAcSpm levels appeared to move independently of AFP and PIVKA-II. In HCC patients, the DiAcSpm levels reflected the progression of disease or the effect of treatment. CONCLUSIONS: DiAcSpm levels were found to reflect the severity, activity or viability of HCC. Urinary DiAcSpm can therefore be considered one of the useful indexes for patients with HCC.

[The method of skeletonized right gastroepiploic artery is useful for following upper abdominal cancer operations].

We reported 5 cases of upper abdominal malignant tumors in patients with previously underwent coronary artery bypass grafting (CABG) using in situ gastroepiploic artery (GEA) graft. In our cases, we found that the GEA grafts were easily identified during abdominal operation when the GEA were collected by the skeletonize method.

A novel tumour marker RCAS1 in a case of extramammary Paget's disease.

A 66-year-old male, whose primary skin lesion in extramammary Paget's disease had been surgically resected 4 years previously, was hospitalized with liver metastases. Hepatic arterial infusion chemotherapy was carried out and the tumours clearly reduced in size. Serum levels of some common tumour markers were not elevated, even prior to therapy. We measured serum levels of a novel tumour-associated antigen, RCAS1, because its expression was detected in the tumour cells. The patient's serum RCAS1 level was elevated (22.0 U/mL) before therapy and fell during (10.5 U/mL) and after (5.0 U/mL) therapy. Therefore, serum RCAS1 levels may be valuable as a potential biomarker for monitoring therapeutic efficacy against Paget's disease.

Multiple minimally invasive direct CABG for the complete revascularization: the figure L approach.

BACKGROUND: Coronary artery bypass grafting on the beating heart via median sternotomy causes significant hemodynamic compromise during displacement of the heart, especially in patients with low ejection fraction or those who have potential catastrophic sternal reentry injuries. We have developed an innovative minimally invasive surgical approach (figure L Approach) for the treatment of multi-vessel coronary artery disease; especially in cases with huge hearts (> CTR 50 %) including tracheostomy requiring COLD, and redo cases. The objective of this study was to assess the efficacy and safety of this alternative surgical incision. METHODS: From January 1998 to March 2001, 22 patients underwent complete revascularization using this figure L Approach. Left submammary anterior thoracotomy incisions are made with the medial part of the incision vertically extending downward to the upper abdomen. The costal margin was divided. The pleural and peritoneal spaces were then entered. A chest retractor was placed to elevate the chest wall, exposing the heart and stomach. Two to four arterial grafts including LIT A, RGEA, RA and IEA were harvested. Revascularization of the LAD, LCX and distal RCA were performed in 22 patients without cardiopulmonary bypass on complex performed arterial grafts using this approach. In four patients, triple and quadruple vessel grafting was performed. RESULTS: No early deaths or postoperative complications occurred. The mean coronary clamp time was 12.5 +/- 5.1 minutes for the LAD, 10.8 +/- 1.8 minutes for diagonal branch, 14.1 +/- 2.9 minutes for the LCX and 16.0 +/- 5.1 minutes RCA time. There were no late deaths or angina during the mean follow-up of 37.3 +/- 9.0 months. Postoperative coronary angiography demonstrated widely patent grafts in all but one patient. Hemodynamics did not change significantly during the distal anastomoses. No wound-healing problems were experienced. CONCLUSIONS: Multiple MIDCABG using the figure L Approach represents a novel way of approaching both the LAD, CX and distal RCA in patients with multi-vessel disease, especially in those with low ejection fraction, huge heart (> CTR 50 %), or hemodynamically unstable patients, without any hemodynamic deterioration or sternal related complication.

[Off-pump coronary artery bypass grafting/beating coronary artery bypass grafting for a patient with low left ventricular ejection fraction].

Beating coronary artery bypass grafting could be performed for a 47-year-old man with left ventricular ejection fraction (LVEF) of 9.3%. Post-operative LVEF was improved to 51.6%. Conventional coronary artery bypass grafting (CABG) used to be contraindicative for patients with LVEF below 20%. Recently, such patients are involved to indication of off-pump CABG (OPCAB) or beating CABG, because we consider OPCAB are lower complications than conventional CABG. We were able to bypass the circumflex for the patient while we had been used percutaneous cardio-pulmonary support (PCPS). We could perform beating coronary artery bypass grafting for a patient of the low LVEF.

[The treatment for the acute occlusion of a coronary artery by PTCA failure with the acute occlusion of a femoral artery by the IABP insertion].

A 68-year-old woman had the acute occlusion of a coronary artery by PTCA failure acute occlusion of a femoral artery by the IABP insertion. The patient underwent on pump beating coronary bypass and axillo-femoral bypass simultaneously.