BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver injury and mortality in Western countries and China. However, as to date, there is no direct and effective therapy for this disease. The aim of this review is to analyze the key progress and challenges of main current therapeutic approaches in NAFLD.
DATA SOURCE:  We carried out a PubMed search of English-language articles relevant to NAFLD therapy.
RESULTS: There are two major therapeutic strategies for NAFLD treatment: (1) lifestyle interventions (including weight reduction, dietary modification and physical exercise) and (2) pharmaceutical therapies. Lifestyle interventions, particularly chronic and moderate intensity exercise, are the most effective and recognized clinical therapies for NAFLD. For pharmaceutical therapies, although their effects and mechanisms have been extensively investigated in laboratory studies, they still need further tests and investigations in clinical human trials.
CONCLUSION: Future advancement of NAFLD therapy should focus on the mechanistic studies on cell based and animal models and human clinical trials of exercise, as well as the combination of lifestyle intervention and pharmaceutical therapy specifically targeting main signaling pathways related to lipid metabolism, oxidative stress and inflammation.

BACKGROUND: Gallbladder adenomyomatosis (GBA) is a hyperplastic disease affecting the wall of the gallbladder, with some typical features. It has historically been considered a benign condition, nevertheless recent reports highlighted a potential role of GBA in predisposing to malignancies of the gallbladder.
DATA SOURCES: We reviewed the literature concerning GBA from its identification until July 2012. Owing to the relative rarity of the disease, studies often are case reports or case series. Thus we herein report a summary of the key-points concerning diagnosis and treatment of GBA, easily applicable in everyday practice, rather than a systematic review. Also, results are integrated with our recent experience.
RESULTS: In our experience, we observed a trend toward an increase of GBA during the last years, probably due to enhanced ultrasonographic technical advancements and physician's expertise. GBA has distinctive imaging features. Several recent reports highlight the potential risk of cancer associated with GBA; however the disease is still classified as a benign condition. Although its correlation with malignancy has not been demonstrated, it is prudent to recommend cholecystectomy in some cases. However, in selected asymptomatic patients, a wait-and-see policy is a viable alternative. We propose an algorithm, based on GBA pathological pattern (diffuse, segmental, localized or fundal), suitable for decision-making.
CONCLUSIONS: In symptomatic patients and if the diagnosis is doubtful, cholecystectomy is mandatory. Postponing surgery is an option to be offered to asymptomatic patients with low-risk GBA pattern who adhere to scheduled follow-ups.

BACKGROUND: Congenital biliary atresia is a rare condition characterized by idiopathic dysgenesis of the bile ducts. If untreated, congenital biliary atresia leads to liver cirrhosis, liver failure and premature death. The present study aimed to evaluate the outcomes of orthotopic liver transplantation in children with biliary atresia.
METHOD: We retrospectively analyzed 45 patients with biliary atresia who had undergone orthotopic liver transplantation from September 2006 to August 2012.
RESULTS: The median age of the patients was 11.0 months (5-102). Of the 45 patients, 41 were younger than 3 years old. Their median weight was 9.0 kg (4.5-29.0), 34 of the 45 patients were less than 10 kg. Thirty-one patients had undergone Kasai portoenterostomy prior to orthotopic liver transplantation. We performed 30 living donor liver transplants and 15 split liver transplants.  Six patients died during a follow-up. The median follow-up time of surviving patients was 11.4 months (1.4-73.7). The overall 1-, 2- and 3-year survival rates were 88.9%, 84.4% and 84.4%, respectively.
CONCLUSION: With advances in surgical techniques and management, children with biliary atresia after liver transplantation can achieve satisfactory survival in China, although there remains a high risk of complications in the early postoperative period.

BACKGROUND: Lamivudine and hepatitis B immunoglobulin (HBIG) are widely used to treat patients with hepatitis B recurrence after liver transplantation. However, the outcomes are inconclusive. The present study was undertaken to evaluate the effect of combined therapy on patients with hepatitis B recurrence after liver transplantation.
METHODS: Twenty-two patients with hepatitis B recurrence after liver transplantation from August 2000 to October 2011 were enrolled in this study. Of these patients, 16 received lamivudine plus HBIG (combination therapy group) and 6 were treated with lamivudine alone (lamivudine-treated group). The clinical features were matched in the two groups. HBV recurrence parameters, HBsAg clearance rate, patient survival rate, and survival time were compared.
RESULTS: The average time of follow-up was 47.2 months (range 13-99). Significant difference was noted in the HBsAg clearance rate in the lamivudine-treated and combination therapy groups (50% vs 93.8%, P<0.05). There was no significant difference in the time of HBV recurrence, patient survival rate and survival time between lamivudine-treated and combination therapy groups (P>0.05).
CONCLUSION: Compared with lamivudine monotherapy, combination therapy significantly increased the HBsAg clearance rate in patients with HBV recurrence after liver transplantation.

BACKGROUND: Selection of drugs for antiviral therapy of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remains difficult. This study was undertaken to evaluate the short-term efficacy of entecavir versus lamivudine on hepatitis B e antigen (HBeAg)-negative patients with ACLF.
METHODS:  The data of 182 HBeAg-negative patients with ACLF were retrospectively collected from patient profiles of the hospital. In these patients, 93 HBeAg-negative patients with ACLF were treated orally with 0.5 mg of entecavir and 89 were treated orally with 100 mg of lamivudine every day. The gender and age were matched between the two groups. Biochemical items, the model for end-stage liver disease (MELD) score, and HBV DNA level were matched at baseline between the two groups and monitored during treatment. The 3-month mortalities of the two groups were compared.
RESULTS: No significant differences were found in biochemical items, MELD score, and HBV DNA level at baseline (P>0.05). HBV DNA level decreased within 3 months in both groups (P<0.05), regardless of the pretreatment MELD score. In patients with the same range of pretreatment MELD scores, treatment duration, posttreatment HBV DNA levels, percentage of HBV DNA level <2.7 lg copies/mL, biochemical items, MELD scores and 3-month mortality were similar in the two groups (all P>0.05). Pretreatment MELD score was not related to posttreatment HBV DNA levels (P>0.05), but related to a 3-month mortality in both groups (both P<0.001).
CONCLUSIONS: In HBeAg-negative patients with ACLF, the short-term efficacy of entecavir versus lamivudine was similar. The degree of pretreatment liver failure significantly affected the outcome of treatment.

BACKGROUND: Hepatolithiasis is very common in East Asia. It is benign in nature, but has a high recurrence rate. It is likely to lead to biliary cirrhosis and increase the risk of cholangiocarcinoma. Hence, the treatment of hepatolithiasis is difficult but vital. In this report, we present a novel approach to manage hepatolithiasis using the choledochoscopic Frequency-Doubled Double pulse Nd:YAG (FREDDY) laser lithotripsy combined with or without hepatectomy.
METHODS: Between July 2009 and October 2012, 45 patients underwent choledochoscopic FREDDY laser lithotripsy combined with or without hepatectomy (laser lithotripsy group). Forty-eight patients underwent a traditional operation (traditional method group) from January 2009 to June 2009. Comparative analysis was made of demographic and clinical characteristics of the two groups.
RESULTS: The final stone clearance rate of the laser lithotripsy group was 93.3%, whereas that of the traditional method group was 85.4% (P=0.22). In the laser lithotripsy group, 2 patients experienced hemobilia and 3 patients had acute cholangitis. In the traditional method group, 3 patients had intraoperative hemorrhage, 1 patient had bile leakage, 6 patients had acute cholangitis, and 1 patient died of liver failure. Moreover, the operative time in the traditional method group was significantly longer than that in the laser lithotripsy group (P=0.01). The mean hospital stay of the patients in the traditional method group was longer than that in the laser lithotripsy group (9.8 vs 8.2 days, P=0.17). Recurrent intrahepatic bile duct stones were not found during the follow-up period in the two groups.
CONCLUSION: Operative choledochoscopic FREDDY laser lithotripsy combined with or without hepatectomy may be an effective and safe treatment for hepatolithiasis.

BACKGROUND: Acoustic radiation force impulse (ARFI) imaging is a new elastography method for the evaluation of tissue stiffness. This study aims to evaluate the performance of ARFI in noninvasive assessment of the tissue stiffness of focal liver lesion (FLL) and to explore its potential value in the differential diagnosis of FLL.
METHODS:  ARFI was performed in 140 patients with 154 FLLs, which included 28 hemangiomas (ANGIs), 14 focal nodular hyperplasias (FNHs), 61 hepatocellular carcinomas (HCCs), 39 metastases and 12 cholangiocellular carcinomas (CCCs). Virtual touch tissue quantification (VTTQ) values were obtained, analyzed and compared. The area under the receiver operating characteristic curve (AUROC) and optimal cut-off values were obtained using a receiver operating characteristic (ROC) curve analysis to assess diagnostic performance. All cases were definitively diagnosed using histopathology, CT, MRI or contrast-enhanced ultrasound.
RESULTS: The VTTQ median values of ANGI, FNH, HCC, metastasis and CCC were 1.30, 1.80, 2.52, 3.08 and 3.89 m/s, respectively. A significant increase in the VTTQ values of different lesions was observed: ANGI<FNH<HCC<metastasis <CCC (P<0.001). The AUROC (95% CI) of VTTQ values was 0.94 (0.90-0.98) for ANGI, 0.91 (0.87-0.96) for malignant lesions and 0.87 (0.79-0.94) for CCC. The sensitivity and specificity for ANGI (86.5%, 89.3%, respectively), malignancy (81.3%, 92.9%, respectively), and CCC (91.7%, 72.5%, respectively) were associated with VTTQ cut-off values of 1.76, 2.22 and 3.00 m/s, respectively.
CONCLUSIONS: ARFI can accurately and objectively assess the elasticity of lesions by obtaining the shear wave elastic value of FLL with VTTQ. Therefore, ARFI is a novel, simple, noninvasive and useful diagnostic method for the characterization of FLL.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) is poor and its early diagnosis is of the utmost importance. This study aimed to investigate the values of glypican-3 (GPC-3) expression in the liver and sera and its gene transcription for diagnosis and monitoring of metastasis of HCC.
METHODS:  Liver GPC-3 was analyzed in HCC tissues from 36 patients by immunohistochemistry and Western blotting. GPC-3 mRNA from circulating peripheral blood mononuclear cells from 123 HCC patients or 246 patients with other diseases or 36 HCC tissues was amplified by RT-PCR, quantitative real-time PCR, and confirmed by DNA sequencing. Circulating GPC-3 level was detected by ELISA.
RESULTS: The increasing expression of GPC-3 was observed from non-cancerous to cancerous tissues, with brown granule-like staining localized in tumor parts of atypical hyperplasia and HCC formation. The positive rate of GPC-3 was 80.6% in HCC, 41.7% in their paracancerous tissues, and none in distal cancerous tissues (P<0.001), with no significant difference in differentiation grade and tumor number except for size (Z=2.941, P=0.003). Serum GPC-3 was detected only in HCC (52.8%) and significant difference was found between GPC-3 and tumor size (χ2=6.318, P=0.012) or HBV infection (χ2=23.362, P<0.001). Circulating GPC-3 mRNA was detected in 70.7% of HCC tissues, with relation to TNM stage, periportal cancerous embolus, and extra-hepatic metastasis (P<0.001). The combination of circulating GPC-3, GPC-3 mRNA and alpha-fetoprotein is of complementary value for HCC diagnosis (94.3%).
CONCLUSION: Both GPC-3 overexpression and GPC-3 mRNA abnormality could be used as markers for the diagnosis of HCC and monitoring its metastasis.

BACKGROUND: The pathogenesis and progression of acute liver failure (ALF) are closely associated with intestinal endotoxemia because of the high permeability of the intestinal wall. Treatment with ethyl pyruvate (EP) has been shown to protect liver failure effectively. The current study aimed to explore the relationship between proinflammatory cytokines and intestinal permeability, and to investigate whether EP administration might prevent the release of multiple proinflammatory cytokines and decrease intestinal permeability and therefore, protect the liver from injury.
METHODS:  The ALF model was induced by D-galactosamine in rats. The rats were randomly divided into control (saline, i.p.), model (D-galactosamine, 1.2 g/kg, i.p.), prevention [EP injection (40 mg/kg) 2 hours ahead of D-galactosamine] and treatment groups (EP injection 2 hours after D-galactosamine). Samples were obtained at 12 and 24 hours after ALF induction, respectively. The histology of liver and intestinal tissue was accessed. Serum alanine aminotransferase, endotoxin, D(-)-lactate, diamine oxidase (DAO), tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ) and high mobility group box-1 (HMGB1) were evaluated. The survival of rats was also recorded.
RESULTS: The rats in model group showed severe damage to liver tissue and intestinal mucosa 12 and 24 hours after ALF induction. EP significantly improved liver or intestinal injury. In addition, serum endotoxin, D(-)-lactate, DAO, TNF-α, IFN-γ and HMGB1 levels were significantly increased in the model group compared with the control group. There was a positive correlation between intestinal permeability and proinflammatory cytokines. EP significantly reduced serum endotoxin, D(-)-lactate, DAO, TNF-α, IFN-γ and HMGB1 levels. The median survival time was significantly prolonged in both prevention and treatment groups (126 and 120 hours compared with 54 hours in the model group).
CONCLUSIONS: EP has protective and therapeutic effects on intestinal mucosa. EP decreases intestinal permeability, and inhibits the release of multiple proinflammatory cytokines in rats with ALF.

BACKGROUND: Gallbladder cancer (GBC) is one of the most aggressive malignant neoplasms with an extremely poor prognosis. Early diagnosis significantly increases the survival rate. The present study was undertaken to evaluate the diagnostic and prognostic value of sphingosine-1-phosphate receptor 1 (S1P1) and endoplasmic reticulum protein 29 (ERp29) in benign and malignant gallbladder lesions and to develop a possible alternative treatment for GBC.
METHODS:  A total of 100 gallbladder adenocarcinoma, 46 peritumoral, 30 gallbladder adenomatous, 15 gallbladder polyp, and 35 chronic cholecystitis tissues were included. S1P1 and ERp29 expressions were evaluated by immunohistochemistry. The correlation between S1P1 and ERp29 expression and tumor pathological features and prognosis was analyzed.
RESULTS: S1P1 positive rate was significantly higher in gallbladder adenocarcinomas than that in peritumoral, adenomatous, polyp, and chronic cholecystitis tissues. On the contrary, ERp29 positive rate was significantly lower in adenocarcinomas than that in peritumoral, adenomatous, polyp, and chronic cholecystitis tissues. Benign lesions with positive S1P1 or negative ERp29 expression showed moderate or severe atypical hyperplasia in the gallbladder epithelium. The overexpression of S1P1 or non-expression of ERp29 was significantly associated with tumor differentiation, tumor mass, lymph node metastasis, and adenocarcinoma invasion. Univariate Kaplan-Meier analysis showed that the elevated S1P1 (P=0.008) or absence of ERp29 (P=0.043) was closely associated with decreased survival rate. Multivariate Cox regression analysis showed that S1P1 positive (P=0.004) or ERp29 negative (P=0.029) was an independent predictor of poor prognosis in gallbladder adenocarcinoma.
CONCLUSION: S1P1 overexpression or ERp29 absence is related to the carcinogenesis and progression, and may be potential biomarkers for early detection of gallbladder adenocarcinoma.

BACKGROUND: Pancreaticoduodenectomy (PD) is the standard procedure for resecting tumors arising from the periampullary area and the pancreatic head. Nevertheless this procedure is inherently difficult and associated with high morbidity and mortality. Besides, the technique applied for exposing the portal and superior mesenteric veins is time-consuming, difficult and associated with the risk of major venous injury. Recently we have introduced a modified approach for making this part of the procedure quick, safe and bloodless, which constitutes the subject of this study.
METHODS: Patients who underwent pylorus preserving pancreaticoduodenectomy (PPPD) either by superior approach technique (group 1) or by classical Whipple's technique (group 2) were retrospectively identified. Age-sex composition, body mass index (BMI), total operative time, operative blood loss, intraoperative blood transfusion requirement, morbidity, mortality and length of hospital stay were compared between the two groups.
RESULTS: Between January 1997 and December 2011, 72 patients underwent PPPD by the superior approach technique (group 1) and 38 underwent PPPD by the classical Whipple's technique (group 2) at our institution. Statistically significant differences were observed in operative time (208.1±46.3 minutes in group 1 vs 322.0±33.8 minutes in group 2), operative blood loss (601.0±250.3 mL in group 1 vs 1371.5±471.8 mL in group 2), and intraoperative blood transfusion requirement [10 (13.9%) patients in group 1 and 24 (63.2%) in group 2]. Among 18 (16.4%) obese patients, significant differences in operative time, operative blood loss and intraoperative blood transfusion requirement were observed between groups 1 and 2. There was no significant inter-group difference in complication rate among obese patients, but comparing obese patients with normal weight patients revealed higher rates of complications like pancreatic fistula (27.8% vs 6.5%), delayed gastric emptying (16.7% vs 5.4%), and infective complications like wound infection and intra abdominal collection (44.4% vs 5.4%).
CONCLUSIONS: On the basis of analytical data, we conclude that the superior approach technique is effective for PD compared with the classical Whipple's technique. It allows fast, safe and virtually bloodless dissection for exposure of the superior mesenteric and portal veins during early steps of PD. PD is normally a difficult and tedious procedure carrying a remote risk of major venous injury leading to substantial blood loss.

BACKGROUND: KRAS mutation plays an important role in the pathogenesis of pancreatic cancer. However, the role of wild-type KRAS in the progression of pancreatic cancer remains unknown. The present study was to investigate the expression of the Ras GTPase activating protein (DAB2IP) in pancreatic cancer and its clinical significance.
METHODS:  The expression of DAB2IP in pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was analyzed by Western blotting and real-time quantitative reverse transcription-PCR (qRT-PCR). The KRAS mutational types of pancreatic cancer tissues obtained from pancreatic cancer patients (n=20) were also analyzed. Subsequently, DAB2IP expression was detected in pancreatic cancer tissues, adjacent and normal pancreatic tissues (n=2) by immunohis-tochemistry, and the relationship between DAB2IP expression and the clinical characteristics of patients was evaluated.
RESULTS: Western blotting and qRT-PCR results showed that DAB2IP expression in pancreatic cancer cells with wild-type KRAS was lower than that in those with mutation-type KRAS and normal human pancreatic ductal epithelial cells (P<0.05). Immunohistochemistry showed that DAB2IP expression was lower in pancreatic cancer tissues than that in adjacent and normal pancreatic tissues (Z=-4.000, P=0.000). DAB2IP expression was lower in pancreatic cancer patients with the wild-type KRAS gene than that in those with KRAS mutations (WilcoxonW=35.000, P=0.042). Furthermore, DAB2IP expression in patients with perineurial invasion was lower than that in those without invasion (WilcoxonW=71.500, P=0.028). DAB2IP expression was lower in patients with more advanced stage than that in those with early clinical stage (WilcoxonW=54.000, P=0.002).
CONCLUSIONS: DAB2IP expression was reduced in patients with pancreatic cancer compared with those with no cancer. DAB2IP expression was correlated with the KRAS gene, perineurial invasion and clinical stage of the disease. Our data indicated that DAP2IP expression can be used as a potential prognostic indicator and a promising molecular target for therapeutic intervention in patients with pancreatic cancer.

A standard hepaticojejunostomy technique might be difficult to perform, especially when the bile duct is small and located deep in the liver hilum. Herein we present a new procedure, the Hand-Fan technique, that was used to enhance the exposure and ease the performance of these challenging anastomoses. Thirty-one patients who had had hepaticojejunostomy with this technique for bile duct injury and other benign biliary pathologies from July 2004 to June 2011 were included into the study. Median postoperative hospital stay was 7 days (6-25 days) and median follow-up time was 33 months (2-84 months). Liver function tests revealed that the blood bilirubin levels of the patients were normalized after hepaticojejunostomy. Follow-up showed that there were no signs of clinical recurrence or impaired bile flow. The Hand-Fan technique considerably facilitates challenging hepaticojejunostomies. Surgeon's comfort is exceptional and the clinical results are satisfactory.

Systematic study of risk factors for biliary stone post-liver transplantation is rarely performed. To investigate the risk factor of choledocholithiasis formation after liver transplantation, we c onducted a case-control study. Fourteen patients were selected into a study group. The stones of the bile duct of the patients were confirmed and treated successfully by endoscopic retrograde cholangiopancreatography. For univariate analysis, we selected carefully some potential risk factors such as cold ischemia time, warm ischemia time, and biliary stricture. The results revealed that cold ischemia time and biliary stenosis were significant predictors. But multivariate analysis revealed that only biliary stenosis was a significant risk factor. In conclusion, biliary stenosis is a risk factor of bile duct stones formation after liver transplantation. Endoscopic retrograde cholangiopancreatography is effective and safe in the diagnosis or treatment of bile duct stones after liver transplantation.

BACKGROUND: Choledochal cysts are congenital cystic dilatations of the extrahepatic or intrahepatic portion of the biliary tree. Complete excision of choledochal cysts is currently regarded as the gold standard treatment, while less extensive procedures including cystoduodenostomy have become obsolete due to the potential for malignant change in the remnant cyst. For type-1 choledochal cysts, which sometimes extend to the main pancreatic duct closely, some surgeons may adopt a less aggressive approach in order to avoid damage to the main pancreatic duct as such damage can lead to serious consequences. However, incomplete excision of choledochal cysts may also cause problems.
METHOD: Here we report on a reoperation treating incomplete excision of a choledochal cyst with focus on the technical aspect.
RESULTS: In the reoperation, meticulous dissection of the liver hilum which had been previously operated on was performed. The hepaticojejunostomy was left intact. With the assistance of intraoperative cholangiography, the residual pancreatic portion of the choledochal cyst was completely excised. The pancreatic opening and the lower end of the common bile duct were reconstructed. Whipple operation was avoided.
CONCLUSION: Careful planning with the aid of precise imaging before and during the operation largely enhanced the accuracy of the excision of the choledochal cyst.