Yusuke Tsuchimoto

Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats

Nonalcoholic fatty liver disease (NAFLD) can develop into end-stage disease that includes cryptogenic cirrhosis and hepatocellular carcinoma. Bacterial endotoxin, for example lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. The aim of this study was to assess the role of LPS in the development of NAFLD. Twenty-one male Zucker (fa/fa) rats were divided into three groups: rats fed for twelve weeks on a diet rich in disaccharide (D12 group), rats similarly managed but treated with LPS (LPS group), and those on the same diet for 24 weeks (D24 group). Histological examination demonstrated that this protocol induced hepatic steatosis in the LPS and D24 groups. Significant, marked accumulation of lipid droplets was observed in the LPS group, compared with the D24 group. Rats from the LPS group showed a decrease in plasma adiponectin levels, an increase in plasma leptin levels, and greater expression of FAS and SREBP-1c mRNA in the liver, compared with rats from the D24 group. These finding coincided with histological findings. We therefore suggest that LPS may accelerate the progression of hepatic steatosis.

M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria–Associated Sepsis in Alcoholics

Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγnull mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12+IL-10−CD163−CD14+ cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1+CD163+CD14+ cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12−IL-10−CCL1−CD163−CD14+ cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes.

Sitagliptin can inhibit the development of hepatic steatosis in high-fructose diet-fed ob/ob mice.

The beneficial effect of dipeptidyl peptidase-4 inhibition on diet-induced extra-pancreatic effects, especially on liver tissue remains poorly understood. Thus, we made the experimental designs as follows; five-week-old male ob/ob mice, which develop type 2 diabetic mellitus and nonalcoholic fatty liver disease by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks as control, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks. Hepatic steatosis was seen in all mice, but the mean grade of steatosis in the sitagliptin-administrated mice was significantly decreased. The acetyl-CoA concentrations were lower in sitagliptin-administrated mice, although the differences were not significant. However, the malonyl-CoA concentrations were significantly lower in sitagliptin-administrated mice. The expression of acetyl-CoA carboxylase 1 was inhibited in sitagliptin-administrated mice, irrespective of expressions of carbohydrate responsive element-binding protein (ChREBP) or sterol regulatory element-binding protein (SREBP)-1c. In conclusion, sitagliptin may affect the development of nonalcoholic fatty liver disease by inhibiting the production of malonyl-CoA and thus synthesis of fatty acids in the liver.

Is administrating branched-chain amino acid-enriched nutrition achieved symptom-free in malnourished cirrhotic patients?

Administration of branched-chain amino acids (BCAA) has been reported to improve liver function, quality of life (QOL). However, in some malnourished patients, serum albumin levels do not improve in response to BCAA granules. In this study, we examined the effects of BCAA-enriched enteral nutrition in patients unresponsive to BCAA granules. Thirty-two decompensated cirrhotic patients at Osaka Medical College were enrolled in this study. Since all patients showed no improvement in serum albumin levels despite 3 months of BCAA granule administration, they were administered 50 g of a flavored BCAA-enriched enteral nutrient twice daily, i.e., during the daytime and late evening. Serum albumin levels and major cirrhotic symptoms were examined 1, 3, and 5 months after treatment initiation. Serum albumin levels improved significantly 3 months after treatment initiation (3.14 ± 0.32 g/dl vs 3.5 ± 0.31 g/dl, p<0.01), and Child–Pugh scores decreased significantly (p<0.01). In the majority (53–80%) of patients, muscles cramps, fatigue, fatigability, edema, and sleep disturbance improved within 3 months after therapy initiation. Moreover, approximately 90% of the patients became symptom-free 5 months after treatment initiation. These results indicate that switching to BCAA-enriched nutrients improves QOL of cirrhotic patients unresponsive to BCAA granules.

Su1693 The Clinical Benefit of L-Carnitine Supplement on Muscle Cramp and Peripheral Blood Cell Abnormality in Patients With Liver Cirrhosis

Background: L-carnitine (4-N-trimethyl ammonium 3-hydroxybutyric acid) is a naturally occurring amino acid that functions to transfer long-chain fatty acids across the mitochondrial membrane, enabling oxidative release of energy. The primary sources of l-carnitine are endogenous synthesis by the liver and kidney and dietary intake. It has been shown that cirrhotic patients become gradually l-carnitine deficient because of poor synthesis and reduction in dietary intake. An administration of l-carnitine is an accepted treatment for mitochondrial myopathy and encephalomyopathy, as well as other states of primary and secondary l-carnitine deficiency. In this study, we examined the effect of l-carnitine on muscle cramping and peripheral blood cell abnormality in patients with liver cirrhosis. Methods: A total of 23 cirrhotic patients at Osaka Medical College from December 2011 to October 2012 were enrolled in this study (13 male, mean age 69±9 Y/O, mean Child Pugh score 7.2±1.2). All patients have diagnosed as liver cirrhosis by laboratory data, imaging test or liver biopsy. Patients were administrated a 300mg of l-carnitine tablet twice a day. The evaluation of muscles cramp was investigated by using an original questionnaire and serum creatine kinase (CK) level. Also, peripheral blood cells profile and other liver function parameters were examined 1, 3, 6 months after treatment. Results: Muscle crump was significantly improved in the majority (90%) of patients 1 month after treatment (p , 0.01). Serum CK levels were also significantly decreased after l-carnitine administration (186±121 vs. 106±70 mg/dl, p , 0.05). Blood platelet count was significantly increased 3 months after treatment (10.0±4.5 vs. 11.7±4.0 x104 /dl, p , 0.01). Moreover, serum ammonia levels were significantly decreased 1 month after treatment (136 ±92 μg/dl vs. 64±32 μg/ dl, p, 0.01). Prothrombin time was significantly increased 3 months after treatment (79±14 vs. 84±18, p, 0.05). Serum albumin, bilirubin level and Child-Pugh score were not different after treatment. No serious adverse events have been occurred in this study. Discussion: Currently, l-carnitine supplementation in dialysis patients has been used for the treatment of muscle cramping. On the other hands, l-carnitine has been proposed as a potential adjuvant treatment to improve anemia, thrombocytopenia, leukopenia and immunological function. Thrombocytopenia occurs up to 70% of patients with liver cirrhosis and increases the risk of bleeding. Frequent muscle crump is worsen a QOL of cirrhotic patients. The lcarnitine supplement may offer the possibility of improving the QOL and prognosis in patients with liver cirrhosis.

The preventive effect of the impaired liver function for antiemetic therapy against chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients

Transarterial chemoembolization and hepatic arterial infusion chemotherapy are recommended for the treatment in patients with intermediate stage of hepatocellular carcinoma. Impaired liver function was sometime observed in patients with hepatocellular carcinoma after transarterial chemoembolization or hepatic arterial infusion chemotherapy. However, what kinds of factors deeply influence in impaired liver function are not clear. A retrospective study was performed to evaluate the risk factors of impaired liver function in cisplatin-naïve patients treated with these therapies using cisplatin. Prior to and 2 months after these therapies, we analyzed the liver function by Child-Pugh score in these patients. For assessing the severity of chemotherapy-induced nausea and vomiting, we utilized the Common Terminology Criteria for Adverse Events ver. 4.0. In hepatocellular carcinoma patients received these therapies using cisplatin, the cancer stage and treatment without neurokinin-1 (NK1) antagonist were found to be independent risk factors of the impaired liver function. The treatment with NK1 antagonist was effective in reducing chemotherapy-induced nausea and vomiting and patients treated with NK1 antagonist kept their liver functions after cisplatin-used these therapies. The treatment with NK1 antagonist was effective in chemotherapy-induced nausea and vomiting and prevented the impaired liver function associated with cisplatin-used these therapies in hepatocellular carcinoma patients.

Effects of Oral L-Carnitine on Liver Functions after Transarterial Chemoembolization in Intermediate-Stage HCC Patients.

Transarterial chemoembolization (TACE) is usually followed by hepatic dysfunction. We evaluated the effects of L-carnitine on post-TACE impaired liver functions. Methods. 53 cirrhotic hepatocellular carcinoma patients at Osaka Medical College were enrolled in this study and assigned into either L-carnitine group receiving 600 mg oral L-carnitine daily or control group. Liver functions were evaluated at pre-TACE and 1, 4, and 12 weeks after TACE. Results. The L-carnitine group maintained Child-Pugh (CP) score at 1 week after TACE and exhibited significant improvement at 4 weeks after TACE (P < 0.01). Conversely, the control group reported a significant CP score deterioration at 1 week (P < 0.05) and 12 weeks after TACE (P < 0.05). L-carnitine suppressed serum albumin deterioration at 1 week after TACE. There were significant differences between L-carnitine and control groups regarding mean serum albumin changes from baseline to 1 week (P < 0.05) and 4 weeks after TACE (P < 0.05). L-carnitine caused prothrombin time improvement from baseline to 1, 4 (P < 0.05), and 12 weeks after TACE. Total bilirubin mean changes from baseline to 1 week after TACE exhibited significant differences between L-carnitine and control groups (P < 0.05). The hepatoprotective effects of L-carnitine were enhanced by branched chain amino acids combination. Conclusion. L-carnitine maintained and improved liver functions after TACE.

The utility of the subcuticular suture in hepatic resection

Aim of the study Despite recent technical progress and advances in the perioperative management of liver surgery, postoperative surgical site infection (SSI) is still one of the most common complications that extends hospital stays and increases medical expenses following hepatic surgery. Material and methods From 2001 to 2017 a total of 1180 patients who underwent hepatic resection for liver tumours were retrospectively analysed with respect to the predictive factor of superficial incisional SSI, using a propensity score matching by procedure (subcuticular or mattress suture). Results The incidence of superficial and deep incisional SSIs was found to be 7.1% (84/1180). By propensity score matching (PSM), 121 of the 577 subcuticular suture group patients could be matched with 121 of the 603 mattress suture group patients. Multivariate analysis demonstrated wound closure technique as the only independent risk factor that correlated significantly with the occurrence of superficial incisional SSIs (p = 0.038). C-reactive protein (CRP) levels on postoperative day 4 were significantly higher in patients with incisional SSIs than in those without (p < 0.001). Conclusions Wound closure technique with subcuticular continuous spiral suture using absorbable suture should be considered to minimise the incidence of incisional SSIs. Moreover, wounds should be carefully checked when CRP levels are high on postoperative day 4.

Comparison of resection site of standardized laparoscopic hepatic tumor resection

Introduction The degree of difficulty in laparoscopic hepatic resection (LHR) was higher in tumors involving the suprahepatic segments than other sites. However, thanks to surgical instruments and procedures being improved and standardized, LHR can be performed safely in all regions. Aim We report our standardized surgical techniques and outcomes in a series of patients undergoing LHR in our hospital and analyze the surgical outcomes, particularly with regard to the site of resection. Material and methods We retrospectively analyzed data from 238 patients who underwent standardized laparoscopic partial hepatic resection between 2010 and 2017. In standardized LHR, the operator formed a triangle with the laparoscope in the center, maintaining a co-axial position by changing the port where the laparoscope was inserted. Results Operative time for the resection of tumors of the right hepatic lobe was 202 ±92 min and 140 ±104 min for tumors of the left hepatic lobe (p = 0.0024); intraoperative blood loss was 80 ±170 ml and 19 ±127 ml, respectively (p = 0.0016). No differences were found in the surgical outcomes between the various segments of the right hepatic lobe. In the left hepatic lobe, operative time was significantly shorter with laparoscopic tumor resection in segment III (p = 0.0023). Conclusions During standardized LHR, a better field of vision with the greater ease can be established during resection of the left hepatic lobe compared to that of the right hepatic lobe. Nonetheless, LHR of the right lobe can be performed safely using various surgical instruments and techniques.

The Relationship Between Postoperative Chemotherapy and Remnant Liver Regeneration and Outcomes After Hepatectomy for Colorectal Liver Metastasis

BackgroundPostoperative chemotherapy for treating colorectal liver metastasis (CLM) has been introduced with the aim of improving therapeutic outcomes. However, there is no consensus on the utility of multidisciplinary treatments with postoperative chemotherapy. Therefore, we evaluated surgical outcomes in patients with CLMs who underwent hepatectomy, while focusing on the effects of post-hepatectomy chemotherapy on remnant liver regeneration.MethodsTwo hundred ninety patients who underwent hepatectomy were retrospectively analyzed using propensity score matching. Postoperative outcomes were evaluated with a focus on the effects of post-hepatectomy chemotherapy on regeneration of the remnant liver in patients with CLM. The remnant liver volumes (RLVs) were measured postoperatively using multi-detector computed tomography on day 7 and months 1, 2, 5, and 12 after the operation.ResultsRLV regeneration and postoperative blood laboratory data did not differ significantly between patients who received postoperative chemotherapy and those who did not receive postoperative chemotherapy immediately after surgery or at any time point from postoperative day 7 to postoperative month 12. The recurrence rates, including same and other segmental intrahepatic recurrences, as well as the resection frequency of the remnant liver were not significantly different between the two groups.ConclusionPostoperative chemotherapy may be of small significance for patients with CLM in terms of the remnant liver volume regeneration and functional recovery.