Michitaka Imai

Increased Susceptibility to Severe Chronic Liver Damage in CXCR4 Conditional Knock-Out Mice

BackgroundThe chemokine SDF-1 and its receptor CXCR4 are essential for the proper functioning of multiple organs. In the liver, cholangiocytes and hepatic progenitor cells (HPCs) are the main cells that produce SDF-1, and SDF-1 is thought to be essential for HPC-stimulated liver regeneration.AimsIn this study, CXCR4 conditionally targeted mice were used to analyze the role of SDF-1 in chronically damaged liver.MethodsChronic liver damage was induced in MxCre CXCR4f/null mice and the control MxCre CXCR4f/wt mice by CCl4. Serum markers were analyzed to assess liver function and damage, the number of cytokeratin-positive cells as a measure of HPCs, and the extent of liver fibrosis. Additional parameters relating to liver damage, such as markers of HPCs, liver function, MMPs, and TIMPs were measured by real-time PCR.ResultsSerum ALT was significantly higher in MxCre CXCR4f/null mice than MxCre CXCR4f/wt mice. The number of cytokeratin-positive cells and the area of fibrosis were also increased in the MxCre CXCR4f/null mice. The expression of mRNAs for several markers related to hepatic damage and regeneration was also increased in the liver of MxCre CXCR4f/null mice, including primitive HPC marker prominin-1, MMP9, TNF-α, and α-SMA.ConclusionsMxCre CXCR4f/null mice were susceptible to severe chronic liver damage, suggesting that SDF-1-CXCR4 signals are important for liver regeneration and preventing the progression of liver disease. Modulation of SDF-1 may therefore be a promising treatment strategy for patients with chronic liver disease.

Granulocytapheresis for the Treatment of Severe Alcoholic Hepatitis: A Case Series and Literature Review

Severe alcoholic hepatitis has a high mortality rate due to limited therapeutic methods. Although corticosteroids have been used to control the inflammatory response, the outcomes vary and no standardized therapy has been established. Novel therapeutic approaches, such as anti-TNF-α, pentoxifilline, and others have been tested clinically on the basis of their cytokinemic pathophysiology with limited success. However, treatment of leukocytosis that causes cytokinemia and hepatic inflammation in patients via granulocytapheresis and leukocytapheresis showed promising results in a number of reports. Here, we report two cases of severe alcoholic hepatitis treated with granulocytapheresis. The liver function and inflammation recovered after the therapy. A review of 35 cases treated with granulocytapheresis and leukocytapheresis demonstrated their efficacy in treating alcoholic hepatitis by controlling leukocytosis as well as cytokines such as IL-8. Multidisciplinary treatment for severe alcoholic hepatitis should be considered case by case on the basis of the complexity and severity of the condition.

Percutaneous transhepatic obliteration and percutaneous transhepatic sclerotherapy for intractable hepatic encephalopathy and gastric varices improves the hepatic function reserve

Percutaneous transhepatic obliteration (PTO) and percutaneous transhepatic sclerotherapy (PTS) are widely performed as an emergency measure in cases of variceal hemorrhage and intractable hepatic encephalopathy. The PTO/PTS technique is capable of directly blocking the blood supply in cases in which balloon-occluded retrograde transvenous obliteration (B-RTO) is not effective, or in cases with complicated collateral flow. Although PTO/PTS is not currently the first choice due to the invasiveness of transhepatic puncture, this procedure can modify the blood flow in an antegrade manner. The present study examined the changes in hepatic function reserve following PTO/PTS for intractable hepatic encephalopathy and/or gastric varices. In total, the study included 37 patients (mean age, 61.75±12.77 years; age range, 32-88 years; male to female ratio, 23:14) with a variety of gastrorenal shunts, or B-RTO-intractable hepatic encephalopathy and gastric varices without gastrorenal shunts. The patients underwent PTO/PTS by embolizing a microcoil or injection of a sclerosing agent (5% ethanolamine oleate iopamidol). Alterations in hepatic function reserve prior to and following the procedure were compared. The patients were treated for hepatic encephalopathy in 11 patients, gastric varices in 19 patients, and both conditions in 7 patients. The results indicated that the blood ammonia level improved from 135.76±75.23 mg/dl to 88.00±42.16 and 61.81±33.75 mg/dl at 3 and 6 months after therapy, respectively. In addition, the Child-Pugh score improved from 8.48±2.01 prior to therapy to 7.70±1.84 and 7.22±2.01 at 3 and 6 months after the procedure, respectively. Although there was a concern that PTO/PTS may cause complications due to an increase in portal venous pressure (PVP) arising from shunt occlusion, no severe complications were observed. In conclusion, for patients with various gastrorenal shunts or those with B-RTO-intractable hepatic encephalopathy and gastric varices without gastrorenal shunts, PTO/PTS can improve the antegrade blood flow to the liver, as demonstrated by improvement in the hepatic function reserve.

Successful Ombitasvir/Paritaprevir/Ritonavir plus Ribavirin Retreatment for a Chronic Hepatitis C Genotype 2a Patient who Relapsed after Sofosbuvir plus Ribavirin Treatment: A Case Report

The optimum retreatment strategy for chronic hepatitis C virus (HCV) patients who failed directly-acting antiviral agents (DAA)-based therapy is unknown. We herein report the outcomes of an HCV genotype (GT) 2a-infected patient with virologic failure following treatment with sofosbuvir plus ribavirin (SOF+RBV) who was successfully retreated with ombitasvir/paritaprevir/ritonavir plus ribavirin (OBV/PTV/r+RBV).

Evaluation of the branched-chain amino acid-to-tyrosine ratio prior to treatment as a prognostic predictor in patients with liver cirrhosis

This study evaluated whether the branched-chain amino acid-to-tyrosine ratio (BTR) is a prognostic predictive factor in patients with liver cirrhosis by determining the relationship of the BTR with event-free survival in a retrospective, observational cohort study. The medical records of patients with liver cirrhosis who visited our institution from February 2000 to May 2012 were examined. Events due to liver cirrhosis were defined as death, worsening of esophageal and/or gastric varices, hepatocellular carcinoma, and liver failure. The primary endpoint was the period from the date of BTR measurement until the first onset of these events. Event-free survival was compared between patients with BTR ≥ 4 and BTR < 4. Relationships between the BTR and other factors predicting prognosis were also examined. Event-free survival was evaluated in patients with and without branched-chain amino acid supplementation using propensity score matching. Significantly longer event-free survival was found in liver cirrhosis patients with BTR ≥ 4 (n = 425) compared with those with BTR < 4 (n = 105), and the BTR was associated with liver cirrhosis events. The BTR showed significant relationships with other predictive factors evaluated. In subcohorts matched by propensity score, branched-chain amino acid supplementation significantly improved event-free survival in patients with BTR <4. The BTR is clinically useful for predicting prognosis in liver cirrhosis patients. BCAA supplementation may be beneficial in those with BTR < 4.This study evaluated whether the branched-chain amino acid-to-tyrosine ratio (BTR) is a prognostic predictive factor in patients with liver cirrhosis by determining the relationship of the BTR with event-free survival in a retrospective, observational cohort study. The medical records of patients with liver cirrhosis who visited our institution from February 2000 to May 2012 were examined. Events due to liver cirrhosis were defined as death, worsening of esophageal and/or gastric varices, hepatocellular carcinoma, and liver failure. The primary endpoint was the period from the date of BTR measurement until the first onset of these events. Event-free survival was compared between patients with BTR ≥ 4 and BTR < 4. Relationships between the BTR and other factors predicting prognosis were also examined. Event-free survival was evaluated in patients with and without branched-chain amino acid supplementation using propensity score matching. Significantly longer event-free survival was found in liver cirrhosis patients with BTR ≥ 4 (n = 425) compared with those with BTR < 4 (n = 105), and the BTR was associated with liver cirrhosis events. The BTR showed significant relationships with other predictive factors evaluated. In subcohorts matched by propensity score, branched-chain amino acid supplementation significantly improved event-free survival in patients with BTR <4. The BTR is clinically useful for predicting prognosis in liver cirrhosis patients. BCAA supplementation may be beneficial in those with BTR < 4.

Effect of treatment support on preventing local recurrence of hepatocellular carcinoma directly adjacent to the diaphragm

Treatment support is anticipated to improve the results of radiofrequency ablation (RFA) treatment in cases in which visualization of tumors using the conventional B-mode is unclear. In the present study, the effectiveness of treatment support for RFA reducing the local recurrence rate of hepatocellular carcinoma (HCC) that are located directly adjacent to the diaphragm, and which are difficult to visualize with B-mode ultrasound imaging, was investigated. A total of 103 HCC tumors measuring <5 cm, which were located abutting the diaphragm, and which were difficult to visualize using the B-mode, were treated using RFA. Thirty-three of those HCC tumors were treated using RFA without treatment support, whereas the remaining 70 HCC tumors were treated using RFA with treatment support, including artificial pleural effusion, contrast-enhanced ultrasonography (CEUS) with the contrasting agent, Sonazoid™, and fusion imaging, either alone or in combination to improve the visualization of the tumors. The rate of local recurrence, and factors affecting local recurrence, were analyzed. Local recurrences were confirmed in 17 of the 103 nodules (16.50%). The overall rate of local recurrence was 13.1% at 6 months, and 20.2% at 12 months. The rate of local recurrence using RFA with artificial pleural effusion was significantly lower compared with those cases of HCC tumors treated without artificial pleural effusion (P=0.008). Similarly, the rate of local recurrence for CEUS RFA with Sonazoid™ was significantly lower compared with those cases of HCC tumors treated without Sonazoid™ (P=0.00081). In a multivariate analysis, CEUS RFA with Sonazoid™ and artificial pleural effusion contributed to the decrease in the rate of local recurrence (hazard ratios, 0.075 and 0.143, respectively). Based on these results, it is possible to conclude that CEUS with Sonazoid™ as a treatment support was the most effective method for reducing the rate of local recurrences abutting the diaphragm that are difficult to visualize using B-mode ultrasonography.

Immediate efficacy of percutaneous transhepatic obliteration and sclerotherapy for giant pipeline esophageal varices hemorrhage in a patient with liver cirrhosis type C

Received: May 08, 2017; Accepted: May 19, 2017; Published: May 22, 2017 A 49-year-old man was referred to us with a diagnosis of hematemesis by giant pipeline esophageal varices due to liver cirrhosis hepatitis C infection after carving a tattoo at 20-year age (Figures 1A & 1B). We reviewed the treatment strategy. Endoscopic injection sclerotherapy (EIS) was generally treated esophageal varices. However, we diagnosed to need a large amount of sclerosing agent, namely 5% ethanolamine oleate iopamidol (Oldamin; Mochida Pharmaceutical, Tokyo, Japan) for successful treatment. So, we decided to perform percutaneous transhepatic obliteration (PTO) and sclerotherapy (PTS) safely. Percutaneous transhe patic puncture of the intrahepatic branch of the portal vein was performed using an 18-gauge needle under sonographic guidance. A 5-French gauge sheath catheter was then intro duced into the portal vein. Direct portography was performed to identify the feeding and draining veins from the left gastric vein to the collateral veins including paraesophageal vein, which caused esophageal varices hemorrhage (Figure 2A). A coaxial catheter was inserted into these feeding veins while avoiding the main feeding vein. The feeding veins were embolized with microcoils or a sclerosing agent, namely 5% ethanolamine oleate iopamidol (Oldamin; Mochida Pharmaceutical, Tokyo, Japan). PTO is usually performed by placing metallic coils in the afferent veins to reduce blood flow. Hence, PTS is usually performed by injec tion of sclerosing agent in the afferent veins to reduce blood flow [1] (Figure 2B). Percutaneous transhepatic portography after treatment showing that the varix and its feeder were embolized (Figure 2C). One day after PTO/PTS, giant pipeline esophageal varices disappeared (Figure 1C). PTO was firstly reported by Lunderquist in 1974 [2]. This treatment had been widely performed as an emergency measure in cases of variceal hemorrhage [2]. Moreover, PTS is usually performed by placing metallic coils in the afferent veins to reduce blood flow into the gastric varix, after which a sclerosing agent is injected in the antegrade direction into the gastric varix [1]. When there are multiple afferent veins, this procedure may need to be performed for all these veins. Percutaneous transhepatic obliteration (PTO) and percutaneous transhepatic sclerotherapy (PTS) are widely performed as an emergency measure in cases of variceal hemorrhage. Furthermore, hepatic functional reserve is improved in this case because portal flow improved in the antegrade direction [3].

Portosystemic shunt occlusion with balloon-occluded retrograde transvenous obliteration improve refractory hepatic encephalopathy

Post admission, oral administration of lactulose and intravenous transfusion of a branced-chain amino acid (BCAA)-enriched solution were performed. However, his venous ammonia level did not decrease significantly. The encephalopathy was refractory to medical management such as lactulose. We decided to perform balloon occluded retrograde obliteration (BRTO) for portosystemic shunt occlusion to prevent hepatic encephalopathy,

Hepatic splenosis mimicking hepatocellular carcinoma in a patient with chronic hepatitis C

A 51-year-old man was referred to us with a diagnosis of chronic hepatitis, secondary to hepatitis C infection after receiving blood transfusion at splenectomy for traffic accident at 16-year age. He had undergone ultrasonographic examination, and a homogeneous and slight hyperechoic mass, measuring 18 × 20 mm in diameter, was detected in liver segment IV (Figure 1). Contrast-enhanced computed tomography (CT) scan showing a marked hyper-attenuation of the lesion during the hepatic arterial phase and a fast wash-out during the venous phase, mimicking hepatocellular carcinoma (HCC) (Figure 2).

Distinct activities of HTLV-1 Tax1 from HTLV-2 Tax2 play key roles in pathogenesis

While human T cell leukemia virus type 1 (HTLV-1) is an etiological agent of adult T-cell leukemia (ATL), its close relative HTLV-2 is not associated with any leukemia. HTLV-1 and HTLV-2 encode Tax1 and Tax2 proteins, respectively, which are essential for immortalization of T-cells by the respective viruses, thereby persistent infection. Tax1 and Tax2 have more than 75% amino acid similarities, but we show here that Tax1 and Tax2 have multiple distinct activities. Tax1 induced IL-2-independent growth of a T-cell line CTLL-2 more efficiently than Tax2. By contrast, Tax2 immortalized human T-cells in the presence of IL-2 more efficiently than Tax1. These results suggest that HTLV-1 and HTLV-2 have distinct IL-2 requirements to immortalize T-cells. We also found that Tax1 altered cellular oxidative stress response. Arsenite, a pro-oxidant, induced stress granule (SG) formation, which functions as a protective role against oxidant-induced cell damages, but the formation was inhibited by Tax1. We will discuss these findings in terms of the HTLV-1-specific pathogenesis.