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We present a case patient in her second trimester of pregnancy who developed acute liver failure from metastatic neuroendocrine tumor (NET). Although she underwent prompt induction of a non-viable fetus due to initial concerns of hemolysis, elevated liver enzymes, and low platelet count syndrome, her liver function continued to deteriorate postpartum. She was subsequently transferred to our institution in order to undergo further evaluation that included a transjugular liver biopsy and subsequent diagnosis of high-grade NET. She was given salvage carboplatin-based chemotherapy, as she was not a liver transplant candidate. Unfortunately, the patient expired from cardiovascular collapse as a component of multiorgan failure.

Hepatocellular carcinoma (HCC) is the second most common lethal cancer, and there is a need for effective therapies. Selective internal radiation therapy (SIRT) has been increasingly used, but is not supported by guidelines due to a lack of solid evidence. Determine the efficacy and safety of SIRT in HCC across the Barcelona Clinic Liver Cancer (BCLC) stages A, B, and C. Consecutive patients that received SIRT between 2006 and 2016 at two centers in Canada were evaluated. We analyzed 132 patients, 12 (9%), 62 (47%), and 58 (44%) belonged to BCLC stages A, B, and C; mean age was 61.2 (SD ± 9.2), and 89% were male. Median survival was 12.4 months (95% CI 9.6–16.6), and it was different across the stages: 59.7 (95% CI NA), 12.8 (95% CI 10.2–17.5), and 9.3 months (95% CI 5.9–11.8) in BCLC A, B, and C, respectively (p = 0.009). Independent factors associated with survival were previous HCC treatment (HR 2.01, 95% CI 1.23–3.27, p = 0.005), bi-lobar disease (HR 2.25, 95% CI 1.30–3.89, p = 0.003), ascites (HR 1.77, 95% CI 0.99–3.13, p = 0.05), neutrophil-to-lymphocyte ratio (HR 1.11, 95% CI 1.02–1.20, p = 0.01), Albumin–Bilirubin (ALBI) grade-3 (HR 2.69, 95% CI 1.22–5.92, p = 0.01), tumor thrombus (HR 2.95, 95% CI 1.65–5.24, p

Currently there is no consensus on the optimal management of small-for-size syndrome following liver transplantation. Here we describe a technique to alleviate portal hypertension and improve the hepatocyte reperfusion in small-for-size liver transplantation in a Lewis rat model. The rats underwent trans-portal vein intra-hepatic portosystemic shunt using a self-developed porous conical tube (TPIPSS: Fig. 1) on small-for-size liver transplants (SFS) with right lobe graft. The treatment effect was evaluated by comparing hemodynamic parameters, morphological changes, serum parameters, ET-1 and eNOS expression, hepatocyte proliferation and apoptosis, CYP3A2 levels, postoperative complications, and survival between the two groups with SFS liver transplants. Porous conical prosthesis prolonged the filling time of small-for-size grafts. Moreover, grafts with TPIPSS showed a lower portal vein pressure, improved microcirculatory flow, alleviated histological changes, decreased ET-1 and increased eNOS expressions, and significantly less damage to liver function comparing to grafts without TPIPSS. Mean survival and overall 30-day survival were significantly higher in the TPIPSS group. These results demonstrate that porous conical tube as trans-portal vein intra-hepatic portosystemic shunt device is an effective way to alleviate portal vein hypertension and improve hepatocyte reperfusion after small-for-size liver transplantation.

Postmenopausal women have a higher risk of nonalcoholic steatohepatitis (NASH) along with an increase in age, and vitamin D deficiency occurs in some patients with NASH. We performed ovariectomy (OVX) surgery on female mice to mimic menopause, fed them a choline-deficient high-fat (CDHF) diet to induce NASH, and then investigated the effects of treatment with 1,25(OH)2D3. Seven-week-old C57BL/6J female mice were separated into five experimental groups: SHAM, OVX, and OVX + intraperitoneal (i.p.) injection of 1,25(OH)2D3 (0.0008, 0.004, and 0.02 μg/kg). All groups were fed a CDHF diet for 8 weeks. Injections took place twice per week throughout the experimental period. Blood samples and liver tissue were collected for analyzing liver histological changes, serum biochemical indicators of hepatic function, and hepatic genes associated with fibrosis. Supplementation of 1,25(OH)2D3 in CDHF-diet mice showed decreased serum levels of ALT, AST, indicating the improvement in overall liver function, and suppressed histological NASH regarding fibrosis stage, lobular inflammation, and steatosis compared to the OVX group. Primary fibrotic markers of TGF-β, TIMP-1, α-SMA, and COL1A1 were significantly lower in the 1,25(OH)2D3 groups than in the OVX group. Furthermore, down-regulated levels of SMAD2 and SMAD3 were also observed in 1,25(OH)2D3 groups. Supplementation of 1,25(OH)2D3 may ameliorate liver fibrosis and improve liver function in OVX mice with NASH induced by a CDHF diet, suggesting the therapeutic effects on postmenopause with NASH.

Background Transarterial chemoembolization (TACE) is an important therapy for hepatocellular carcinoma (HCC) in cirrhosis. In particular in advanced cirrhosis, post-TACE hepatic failure liver (PTHF) failure may develop. Currently, there is no standardization for the periinterventional risk assessment. The liver maximum capacity (LiMAx) test assesses the functional liver capacity, but has not been investigated in this setting. Aims The aim of this study was to prospectively evaluate periinterventional LiMAx and CT volumetry measurements in patients with cirrhosis and HCC undergoing repetitive TACE. Methods From 06/2016 to 11/2017, eleven patients with HCC and cirrhosis undergoing TACE were included. LiMAx measurements (n = 42) were conducted before and after each TACE. Laboratory parameters were correlated with the volume–function data. Results The median LiMAx levels before (276 ± 166 µg/kg/h) were slightly reduced after TACE (251 ± 122 µg/kg/h; p = 0.08). This corresponded to a median drop of 7.1%. Notably, there was a significant correlation between LiMAx levels before TACE and bilirubin (but not albumin nor albumin–bilirubin [ALBI] score) increase after TACE (p = 0.02, k = 0.56). Furthermore, a significantly higher increase in bilirubin in patients with LiMAx ≤ 150 µg/kg/h was observed (p = 0.011). LiMAx levels at different time points in single patients were similar (p = 0.2). Conclusion In our prospective pilot study in patients with HCC and cirrhosis undergoing multiple TACE, robust and reliable LiMAx measurements were demonstrated. Lower LiMAx levels before TACE were associated with surrogate markers (bilirubin) of liver failure after TACE. Specific subgroups at high risk of PTHF should be investigated. This might facilitate the future development of strategies to prevent occurrence of PTHF.

Enoxaparin, a low molecular weight heparin, has been used to prevent thrombotic events during major surgery without increasing the rate of hemorrhage. On the other hand, it was reported to cause liver injury, but the details of liver injury induced by prophylactic enoxaparin after abdominal surgery remain unclear. This study aimed to clarify the relationship between prophylactic enoxaparin and liver injury after colorectal surgery, and characterize the injury profile. We retrospectively reviewed 732 Japanese patients who underwent elective resection of the colorectum, and compared their clinicopathological background, details of surgery, postoperative complications, including liver injury, and the type of liver injury according to prophylactic use of enoxaparin. Univariate and multivariate analyses were performed to identify risk factors for liver injury during the postoperative period. The rate of liver injury was 8.9% for patients treated by prophylactic enoxaparin and 1.4% for those who did not receive enoxaparin after colorectal surgery (p

Injecting MSCs via blood vessel is most commonly used method, which has a major drawback of safety. The aim of our study was to evaluate efficacy using scaffold-loaded MSCs in acute liver failure model. Acute liver failure was induced in mice using thioacetamide (TAA) (200 mg/kg, i.p) once a day for two consecutive days. The animals were divided in four acute liver failure groups: (1) TAA; (2) empty scaffold; (3) MSCs injected through tail vein; (4) MSC + Scaffold, scaffold loaded with MSCs, to evaluate the mortality and changes in liver function. Polylactic-co-glycolic acid scaffold alone and loaded with human MSCs was implanted on mice dorsum. TAA dose was titrated until one-third mortality rate was achieved. TAA (200 mg/kg) once daily for two consecutive days was injected to establish the acute liver failure model. The mortality of TAA and scaffold groups was 55.9% and 63.2%, respectively. Although, mortality of MSC-TV group decreased 14.7% as compared to TAA group (p = 0.200), MSC + Scaffold group had the lowest mortality (31.4%) (p = 0.013). Cells implanted in PLGA biomaterial were survived until 3 weeks, and their function was increased. Area of hepatic inflammation and necrosis was significantly reduced in MSC-TV and MSC + Scaffold groups; but there was no difference between the two groups. Gene expressions related to inflammation were significantly decreased in MSC-TV and MSC + Scaffold groups compared to TAA group. In MSC + Scaffold group, no migration of stem cells to liver tissue was observed. Although, not all cells in scaffold were stained, some of them were differentiated into hepatocyte-like cells which stained positive for PAS and CYP2E1 antibody. Scaffold loaded with MSCs showed protective effects via paracrine signaling on acute liver failure model.

MELD attempts to objectively predict the risk of mortality of patients with liver cirrhosis and is commonly used to prioritize organ allocation. Despite the usefulness of the MELD, updated metrics could further improve the accuracy of estimates of survival. To assess and compare the prognostic ability of an enzymatic 13C-based liver function test (LiMAx) and distinct markers of liver function to predict 3-month mortality of patients with chronic liver failure. We prospectively investigated liver function of 268 chronic liver failure patients without hepatocellular carcinoma. Primary study endpoint was liver-related death within 3 months of follow-up. Prognostic values were calculated using Cox proportional hazards and logistic regression analysis. The Cox proportional hazard model indicated that LiMAx (p

To compare the therapeutic effects of 125I versus non-125I combined with transcatheter arterial chemoembolization (TACE) for the treatment of unresectable hepatocellular carcinoma (HCC) with obstructive jaundice. A retrospective analysis was conducted using the records of 54 consecutive patients who were initially diagnosed with HCC with obstructive jaundice between May 2009 and July 2016. Twenty-one cases (group A) were treated with percutaneous transhepatic biliary drainage (PTBD) followed by 125I radioactive seed strip implantation through the PTBD tube. After the total serum bilirubin level was reduced to normal and the liver function recovered to Child–Pugh class A or early B, TACE was conducted. In 33 cases (group B) PTBD was performed in combination with TACE without applying the 125I radioactive seeds. The duration of biliary patency and survival were analyzed. The technical success rate in both groups was 100%. The median biliary patency time was 6.000 ± 0.315 months (95% CI 5.382–6.618 months) in group A and 4.000 ± 0.572 months (95% CI 2.879–5.121 months) in group B; the two groups were significantly different (P = 0.001). The median survival was 11.000 ± 0.864 months (95% CI 9.306–12.694 months) in group A and 9.000 ± 0.528 months (95% CI 7.965–10.035 months) in group B; the two groups were significantly different (P = 0.022). The combination of 125I with TACE was more effective than TACE without the radioactive seeds for treating patients with unresectable HCC with obstructive jaundice. Future prospective trials with larger samples will be required to validate these results.

To investigate the protective effects of helix B surface peptide (HBSP) on acute liver injury induced by carbon tetrachloride (CCl4). HBSP (8 nmol/kg) was intraperitoneally injected into C57 BL/6 mice 2 h after CCl4 administration. Serum and liver tissue samples were collected 24 h after injury. Liver function and histological injuries were evaluated. Inflammatory cell infiltration and cytokines were examined and hepatocytes apoptosis was measured. The human liver cell line LO2 and murine primary hepatocytes were stimulated by CCl4 with and without HBSP treatment and glutathione peroxidase activity, cell survival, and apoptosis were evaluated. In addition, we examined the PI3K/Akt/mTORC1 pathway to elucidate the mechanism underlying HBSP-mediated protection in acute liver injury. HBSP significantly decreased serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and pro-inflammatory cytokines in liver tissues after CCl4 injection compared with those in the control group. Immunohistochemical staining indicated that the number of CD3-, CD8-, and CD68-positive cells and the expression of cleaved caspase-3 were significantly decreased by HBSP treatment. Additionally, HBSP reduced apoptosis in vivo. In an in vitro study, the glutathione peroxidase activity and survival rate increased, while the total apoptotic rate was reduced in the HBSP-treated group compared with that in the control group after CCl4 treatment. HBSP activated the PI3K/Akt/mTORC1 pathway, which was confirmed by the PI3K inhibitor LY294002 both in vivo and in vitro. Furthermore, HBSP increased the survival of mice with acute liver injury, and this effect was abolished by LY294002. HBSP is a potential therapeutic agent against acute liver injury induced by CCl4.

Brachytherapy is a targeted type of radiotherapy utilized in the treatment of cancers. Elastin-like polypeptides are a unique class of genetically engineered peptide polymers that have several attractive properties for brachytherapy.To explore the feasibility and application of brachytherapy for VX2 liver tumor using elastin-like polypeptides with (131)I so as to provide reliable experimental evidence for a new promising treatment of liver cancer.Elastin-like polypeptide as carrier was labeled with (131)I using the iodogen method. Ten eligible rabbits with VX2 liver tumor were randomly divided into the treatment group (n = 5) and control group (n = 5). The treatment group received brachytherapy using elastin-like polypeptide with (131)I, and in the control group, elastin-like polypeptide was injected into the VX2 liver tumor as a control. Periodic biochemical and imaging surveillances were required to assess treatment efficacy.The stability of elastin-like polypeptide with (131)I in vitro was maintained at over 96.8 % for 96 h. Biochemistry and imaging indicated brachytherapy using elastin-like polypeptide with (131)I for liver tumor can improve liver function and inhibit tumor growth (P 0.05).Elastin-like polypeptide can be an ideal carrier of (131)I and have high labeling efficiency, radiochemical purity and stability. Brachytherapy using elastin-like polypeptide with (131)I for liver tumor is a useful therapy that possesses high antitumor efficacy advantages.

Unlike systemic chemotherapy for hematological malignancies with hepatitis B virus (HBV) infection, transarterial chemoembolization (TACE) for HBV-related hepatocellular carcinoma (HCC) has only recently been reported to cause HBV reactivation and subsequent hepatitis. Most patients with HBV-related HCC have an underlying disease with liver fibrosis or cirrhosis, and TACE may potentially induce HBV reactivation and liver decompensation. Currently, there are no clinical guidelines for managing TACE-caused HBV reactivation. In this review, we summarize the changes of HBV status and liver function after TACE and the effect of antiviral treatment before, during, or after TACE.

Malnutrition might affect survival and severity of complications in cirrhotic patients. However, adequate evaluation of the nutritional status is a difficult task since the common assessment tools are either inappropriate or too complicated. A simpler method could evaluate the patient’s risk for malnutrition instead of the nutritional status itself. This study evaluated the prediction of clinical deterioration and transplant-free survival in patients with chronic liver disease by two nutritional risk scores. In 84 cirrhotic patients, Nutritional Risk Screening (NRS), Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT), and the chronic liver disease questionnaire have been assessed. These patients were evaluated at a second time point after a median observation time of 500 days. Another cohort of 64 patients was collected to validate the findings. Of the included patients, 67.7 % were male with a median age of 57 years and a median Child score of 9. RFH-NPT classified 50.7 % of the patients as high-risk patients, and NRS assessed 44.6 % of the patients as moderate- to high-risk patients. RFH-NPT correlated with clinical deterioration, severity of disease (Child score, MELD score), and clinical complications such as ascites, hepatorenal syndrome, and episodes of hepatic encephalopathy. RFH-NPT was an independent predictor of clinical deterioration and transplant-free survival. Furthermore, improvement in RFH-NPT within 500 days was associated with improved survival. Assessing the patients’ risk for malnutrition by RFH-NPT may be a useful predictor of disease progression and outcome for patients with chronic liver disease.

For patients with hepatocellular carcinoma (HCC), gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) improved the diagnosis, migrated Barcelona Clinic Liver Cancer (BCLC) stage, and changed therapeutic decision in retrospective analysis. This prospective study was to evaluate the clinical impact of EOB-MRI on HCC management. From September 2012 to February 2014, consecutive patients with suspicion of HCC in BCLC early stage by multidetector computed tomography or dynamic MRI with non-specific gadolinium, well liver function reserve, and admitted for resection evaluation were enrolled prospectively. Additional EOB-MRI was performed. The HCC diagnosis, BCLC staging, and treatment decision were obtained in a liver cancer conference. EOB-MRI impact on HCC management was analyzed. One hundred and three patients including 68 with typical and 35 with atypical HCC nodules in dynamic imaging studies were enrolled. EOB-MRI characterized 3 (4.4 %) benign and 33 (94.3 %) HCC for patients with typical and atypical HCC nodules, respectively. For 90 HCC patients, additional EOB-MRI changed BCLC stage in 25 (27.8 %) and treatment decision in 17 (18.9 %) patients. There were 66 patients with 78 resected nodules including 65 HCCs, 4 intrahepatic cholangiocarcinomas, and 9 benign nodules. Dynamic study and EOB-MRI detected and characterized 69 and 77 nodules, respectively. The sensitivity and accuracy in HCC diagnosis were 98.5 and 85.7 % for EOB-MRI, which were better than those of dynamic study (p

Tension homology deleted on chromosome ten (PTEN) is important in liver fibrosis. The purpose of this study was to evaluate the PTEN gene effects and mechanism of action on hepatic stellate cells (HSCs). The rat primary HSCs and human LX-2 cells were transfected by an adenovirus containing cDNA constructs encoding the wild-type PTEN (Ad-PTEN), the PTEN mutant G129E gene (Ad-G129E) and RNA interference targeting the PTEN sequence PTEN short hairpin RNA (PTEN shRNA), to up-regulate and down-regulate PTEN expression, respectively. The HSCs were assayed with a fluorescent microscope, real time PCR, Western blot, MTT, flow cytometry and Terminal-deoxynucleoitidyl transferase mediated nick end labeling. In addition, the CCl4 induced rat hepatic fibrosis model was also established to check the in vivo effects of the recombinant adenovirus with various levels of PTEN expression. The data have shown that the over-expressed PTEN gene led to reduced HSCs activation and viability, caspase-3 activity and cell cycle arrest in the G0/G1 and G2/M phases, as well as negative regulation of the PI3K/Akt and FAK/ERK signaling pathways in vitro. The over-expressed PTEN gene improved liver function, inhibited proliferation and promoted apoptosis of HSCs both in vitro and in vivo. These data have shown that gene therapy using the recombinant adenovirus encoding wild-type PTEN inhibits proliferation and induces apoptosis of HSCs, which is a potential treatment option for hepatic fibrosis.

Soluble TGF-β1 type II receptor (sTβRII) via TGF-β1 inhibition could inhibit hepatic fibrosis, but over-dosage triggers autoimmune responses. To test whether the use of a TGF-β1-responsive collagen I promoter COL1A1, via generating a feedback loop to TGF-β1 level, could offer accurate control on sTβRII expression. Recombinant adenoviruses with COL1A1 (Ad-COL-sTβRII/Luc) or CMV promoter (Ad-CMV-sTβRII/Luc) were constructed and characterized. Inhibition of TGF-β activity was determined both in vitro and in vivo. Total and bioactive TGF-β, hepatic fibrosis scale, α-SMA, collagen levels, and liver function were determined. COL1A1, but not CMV, responded to TGF-β1 in vitro. Both in vitro and in vivo, Ad-COL-sTβRII could significantly, but not completely inhibit TGF-β1 activity while Ad-CMV-sTβRII almost completely inhibited TGF-β1 activity. As evidenced by fibrosis scale, α-SMA, and collagen levels in liver tissue, Ad-COL-sTβRII and Ad-CMV-sTβRII had comparable efficacies in treating hepatic fibrosis. Ad-COL-sTβRII was better than Ad-CMV-sTβRII in liver function restore. Ad-CMV-sTβRII, but not Ad-COL-sTβRII, induced high level of anti-dsDNA and anti-Sm antibodies in rats. COL1A1 can precisely control sTβRII expression to inhibit excessive bioactive TGF-β level and thus inhibit hepatic fibrosis but without inducing autoimmune responses.

Jejunal varices occur very rarely [1–5]. Moreover, unlike esophageal or gastric varices, they are difficult to treat with an endoscopic approach because of their anatomic location. While surgery is an option, it is invasive and risky, especially in patients with liver cirrhosis and poor hepatic function. Thus, endovascular intervention may be a better approach for jejunal varices. The endovascular treatments for gastric varices include balloon-occluded retrograde transvenous obliteration (BRTO), percutaneous transhepatic obliteration, and transjugular intrahepatic portosystemic shunt (TIPS). TIPS reduces portal pressure by diverting portal flow to a hepatic vein through an artificial shunt, thereby reducing variceal hypertension and risk of bleeding, but can worsen liver function and cause hepatic encephalopathy. In contrast, BRTO directly induces sclerosis of the varices. Therefore, hepatic encephalopathy is not associated with this procedure. BRTO also associates with a lower rate of variceal bleeding recurrence than TIPS [6, 7]. For these reasons, BRTO is currently considered to be the first endovascular treatment choice for gastric varices. BRTO is a minimal invasive radiologic procedure that gives the sclerosing agent while blocking the outflow by a balloon catheter [8]. This report describes a case of jejunal varices treated with BRTO.

Massive hepatectomy often leads to fatal liver failure because of a small remnant liver volume. The aim of this study was to investigate the potential mechanisms leading to liver failure. Sprague–Dawley rats had performed a sham operation, 85 % partial hepatectomy (PH) or 90 % PH, and all had free access to water with or without supplemented glucose. Liver function and survival were evaluated. Liver parenchymal injury was assessed by evaluating hepatic pathology, blood biochemistry, and apoptotic and necrotic alterations. The regeneration response was assessed by the weight gain of the remnant liver, hepatocyte proliferation markers, and regeneration-related molecules. The 90 % hepatectomy resulted in a significantly lower survival rate and impaired liver function; however, no significant more serious liver parenchymal injuries were detected. TNF-α, HGF, myc and IL-6 were either similarly expressed or overexpressed; however, the increase in remnant liver weight, mitotic index, and the presence of Ki-67 and PCNA were significantly lower in the 90 %-hepatectomized rats. mTOR, p70S6K and 4EBP1 were not activated in the remnant liver after a 90 % hepatectomy as obviously as those after an 85 % hepatectomy, which was concomitant with the higher expression of phospho-AMPK and a lower intrahepatic ATP level. Glucose treatment significantly improved the survival rate of 90 %-hepatectomized rats. Suppression of remnant liver regeneration was observed in the 90 % PH and contributed to fatal liver failure. This suppressed liver regenerative capacity was related to the inhibited activation of mTOR signaling.

Recent research shows that abnormal expression of microRNA plays an important role in the process of hepatic fibrosis . miR-370 has been reported to be involved in liver function and is suppressed during hepatic carcinogenesis. The aim of this study was to investigate the role of miR-370 in hepatic fibrosis. The expression levels of miR-370 in rat fibrotic livers and activated hepatic stellate cells (HSCs) were evaluated by quantitative real-time PCR. The effect of miR-370 on the activation of HSCs was analyzed by flow cytometric analyses, real-time PCR and Western blot. Adenovirus carrying miR-370 was injected through the tail vein to access the effect of miR-370 on hepatic fibrosis induced by CCl4 in rats. The downstream targets of miR-370 were predicted by the Target Scan database and verified by luciferase assays, real-time PCR and Western blot in HSCs and were further confirmed by immunohistochemistry in vivo. Real-time PCR showed that miR-370 expression was significantly reduced in rat fibrotic livers and TGFβ1-stimulated HSCs. Overexpression of miR-370 inhibited the proliferation of HSC-T6 cells via inducing cell apoptosis and suppressed the activation of HSCs. Upregulation of miR-370 obviously attenuated the CCl4-induced liver fibrosis in rats. miR-370 was directly bound to the 3′UTR of Smoothened (SMO) and suppressed the expression of SMO in HSCs and fibrotic livers. Our study demonstrated that miR-370 plays an inhibitory role in hepatic fibrogenesis by targeting SMO. Restoration of miR-370 may have beneficial effects on the treatment of liver fibrosis.

To date, major hepatectomy with obstructive jaundice is still a highly risky and difficult surgery because of the high rate of complications. An excessive inflammatory response may be the primary hindrance to postoperative recovery of liver function.Recent research has demonstrated that ulinastatin blocks the release of inflammatory factors and prevents the cytokine cascade reaction. This study was conducted to investigate the effect of ulinastatin on major hepatectomy after obstructive jaundice and to explore the potential mechanisms of this effect.Male Sprague-Dawley rats were divided into three groups: sham, control and treated groups. In the control and treated groups, obstructive jaundice was induced, and a 70 % major hepatectomy was performed with implementation of ulinastatin treatment in the treated group but not the control group. The rats were sacrificed after hepatectomy on day 1, day 3, day 5 and day 7. The survival time, liver function, inflammatory cytokine expression and the indices of proliferation activities were examined. Kupffer cells were isolated, and the mRNA and protein levels of CD14 and NF-κB P65 in the Kupffer cells were determined.Compared to the control group, the survival rates, postoperative liver function, and the indices of proliferation activities were better in the treated group; in the treated group serum TNF-α and IL-6 levels were lower whereas serum IL-10 levels were higher. The expression of CD14 and NF-κB P65 in Kupffer cells at both the mRNA and protein levels was significantly higher in the control group than in the treated group.Ulinastatin has a protective effect in major hepatectomy with obstructive jaundice by inhibiting Kupffer cell activation and modulating the hepatic cytokine response.

Interferon-free therapy has revolutionized the treatment of hepatitis C (HCV) in patients with cirrhosis, including those with decompensated disease. In December 2013, the Food and Drug Administration (FDA) approved simeprevir, a second-generation NS3/4A protease inhibitor, and sofosbuvir, the first-in-class nucleotide analogue NS5B polymerase inhibitor, providing the first opportunity for all oral therapy for HCV. Sofosbuvir with ribavirin was approved for use in patients of all viral genotypes wait-listed for liver transplantation, based upon results from a phase 2 study of patients with Child-Pugh (CP) class A cirrhosis and hepatocellular carcinoma. Simeprevir and sofosbuvir use, initially off-label, was based upon results from the phase 2 COSMOS study [1], where patients with genotype 1 with varying degrees of fibrosis, including compensated cirrhosis, were treated for 12 or 24 weeks. The frequency of sustained virologic response at week 12 (SVR12) reached 93 % (38/41) among those with compensated cirrhosis [1]. Recently, the FDA approved sofosbuvir and simeprevir for treatment of genotype 1 HCV, including cirrhotics. However, the safety information for this combination in patients with CP class B cirrhosis is limited. In this issue of Digestive Diseases and Sciences, Stine et al. [2] describe two patients with CP-B cirrhosis and elevated baseline total bilirubin concentrations (5.3 and 9.5 mg/dL) who developed worsening hepatic decompensation during treatment with sofosbuvir and simeprevir. Both patients developed significant elevations of total bilirubin (indirect fraction unknown), by week 4–5 in Case 1 and by week 2 in Case 2. The authors concluded that simeprevir was “probably” (Case 1) and “possibly” (Case 2) causative of these events, based on the Roussel Uclaf Causality Assessment Method (RUCAM), a system that assigns specific points for clinical, biochemical, serologic, and radiologic features of liver injury to yield a composite score that reflects the likelihood that the hepatic injury is due to a specific medication [3]. Essential aspects of these cases are not included, such as changes in renal function, the results of evaluations for infectious or other causes of acute hepatic decompensation, and if drug–drug interactions may have been contributory. Moreover, the validity of RUCAM criteria in patients with cirrhosis and marked elevations of bilirubin at baseline is questionable. Nonetheless, these two cases highlight the striking changes in clinical status that can occur during HCV treatment for patients with decompensated cirrhosis and the heightened concerns of clinicians regarding use of protease inhibitors in this setting. Treatment of patients with decompensated cirrhosis, of whom many have renal dysfunction, requires detailed knowledge of antiviral drug metabolism and excretion. Sofosbuvir is extensively metabolized in the liver to the pharmacologically active nucleoside triphosphate analog GS-461203 with eventual dephosphorylation to the inactive metabolite GS-331007 [4]. Relative to subjects with normal hepatic function, the sofosbuvir areas under the curves from 0 to 24 h (AUC0–24) were 130 and 140 % higher in patients with CP class B and C cirrhosis, whereas the GS-331007 AUC0–24 was only 18 and 9 % higher, respectively [4]. Further, no dose adjustments for sofosbuvir are recommended for patients with CP class B or C cirrhosis due to the lack of adverse effects with exposure to sofosbuvir and GS-331007 based on population pharmacokinetic analysis [4]. Instead, renal clearance is the major elimination pathway for sofosbuvir, via GS-331007. Compared to subjects with normal renal function, the sofosbuvir AUC0–∞ was 1.7-fold higher and the GS-331007 AUC0–∞ was 4.5-fold higher in those with eGFR

Assessment of liver function is essential for management of hepatocellular carcinoma (HCC). Recently, albumin–bilirubin (ALBI) grade has been reported as a useful tool for assessing hepatic reserve in patients with HCC. The objective of this study was to determine whether ALBI grade could be used to predict the overall survival of very early-stage HCC patients treated with radiofrequency ablation (RF ablation). A cohort of 368 patients with very early-stage HCC treated with RF ablation was retrospectively analyzed. The overall survival and recurrence-free survival were calculated in groups classified by ALBI grade and Child–Pugh score. Overall survival of patients with ALBI grade 1 was better than that of patients with ALBI grade 2 (5-year survival rate 88.5 vs. 73.8%, P

To evaluate the clinical value of tumor growth rate in hepatocellular carcinoma (HCC) patients, we investigated the growth rate of HCC by calculating the tumor volume doubling time (TVDT) and its impact on survival and recurrence.A retrospective cohort study of 269 HCC patients who underwent two or more pretreatment imaging studies of computed tomography or magnetic resonance imaging was performed. Tumor growth rate and TVDT were calculated by comparing tumor volumes between imaging studies. Clinical parameters independently related to a TVDT of 2 months were evaluated. After dividing patients into slow-growing (159 patients with TVDT 2 months) and rapid-growing (110 patients with TVDT 2 months) groups, we compared the groups in terms of their survival and recurrence outcomes. The response to transarterial chemoembolization (TACE) was evaluated according to TVDT.The median tumor growth rate and TVDT were 37.5%/month and 2.37 months, respectively. By logistic regression analyses, a high Child-Pugh score, small initial tumor diameter, gross vascular invasion, and tumor multiplicity were found to be independently associated with a TVDT of 2 months (P 0.05). Patients in the rapid-growing group had lower survival rates and higher recurrence rates (P 0.05). The response to TACE was worse in the rapid-growing group (P 0.05).A fast HCC growth rate is associated with poor liver function and aggressive tumor biology. HCC patients with shorter TVDTs exhibit poorer survival and recurrence outcomes as well as a poor response to TACE.

Transplantation centers have given much attention to donor availability. However, no reliable quantitative methods have been employed to accurately assess graft quality before transplantation. Here, we report that the indocyanine green (ICG) clearance test is a valuable index for liver grafts. We performed the ICG clearance test on 90 brain-dead donors within 6 h before organ procurement between March 2015 and November 2016. We also analyzed the relationship between graft liver function and early graft survival after liver transplantation (LT). Our results suggest that the ICG retention rate at 15 min (ICGR15) of donors before procurement was independently associated with 3-month graft survival after LT. The best donor ICGR15 cutoff value was 11.0%/min, and we observed a significant increase in 3-month graft failure among patients with a donor ICGR15 above this value. On the other hand, a donor ICGR15 value of ≤ 11.0%/min could be used as an early assessment index of graft quality because it provides additional information to the transplant surgeon or organ procurement organization members who must maintain or improve organ function to adapt the LT. An ICG clearance test before liver procurement might be an effective quantitative method to predict graft availability and improve early graft prognosis after LT.

Progressive lipoprotein impairment occurs in liver cirrhosis and is associated with increased morbidity and mortality. The present review aims to summarize the current evidence regarding the prognostic value of lipoprotein abnormalities in liver cirrhosis and to address the need of a better prognostic stratification of patients, including lipoprotein profile assessment. Low levels of lipoproteins are usual in cirrhosis. Much evidence supports the prognostic role of hypolipidemia in cirrhotic patients. In particular, hypocholesterolemia represents an independent predictor of survival in cirrhosis. In cirrhotic patients, lipoprotein impairment is associated with several complications: infections, malnutrition, adrenal function, and spur cell anemia. Alterations of liver function are associated with modifications of circulating lipids. Decreased levels of lipoproteins significantly impact the survival of cirrhotic patients and play an important role in the pathogenesis of some cirrhosis-related complications.

To assess the incidence, prognostic factors, and clinical outcomes of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) creation. In this single-institution retrospective study, 191 patients (m:f = 114:77, median age 54 years, median Model for End-Stage Liver Disease or MELD score 14) who underwent TIPS creation between 1999 and 2013 were studied. Medical record review was used to identify demographic characteristics, liver disease, procedure, and outcome data. Post-TIPS HE within 30 days was defined by new mental status changes and was graded according to the West Haven classification system. The influence of data parameters on HE occurrence and 90-day mortality was assessed using binary logistic regression. TIPS was successfully created with hemodynamic success in 99 % of cases. Median final PSG was 7 mmHg. HE incidence within 30 days was 42 % (81/191; 22 % de novo, 12 % stable, and 8 % worsening). Degrees of HE included grade 1 (46 %), grade 2 (29 %), grade 3 (18 %), and grade 4 (7 %). Medical therapy typically addressed HE, and shunt reduction was necessary in only three cases. MELD score (P = 0.020) and age (P = 0.009) were significantly associated with HE development on multivariate analysis. Occurrence of de novo HE post-TIPS did not associate with 90-day mortality (P = 0.400), in contrast to worsening HE (P

A 4-month-old female with a history of neonatal cholestasis was initially evaluated with jaundice, ascites, coagulopathy, and worsening aminotransferase levels. At 5 weeks of age, her parents had noticed ‘‘yellowing’’ of her eyes and skin accompanied by a slightly more pale appearance of her regularly yellow-colored stools. Initially, she was noted to have conjugated hyperbilirubinemia, with total bilirubin 6.5 and conjugated 4.5, aspartate aminotransferase (AST) 163, alanine aminotransferase (ALT) 103, and elevated alkaline phosphatase. Liver ultrasound was normal. A percutaneous liver biopsy, obtained due to her continued unexplained cholestasis, was reported as showing possible large duct obstruction and bile duct proliferation, suggestive of extrahepatic biliary atresia. A subsequent endoscopic retrograde cholangiopancreatography (ERCP) and intraoperative cholangiogram showed no anatomic abnormalities in the intrahepatic and extra hepatic biliary system, inconsistent with the diagnosis of biliary atresia (Fig. 1). During her hospital admission, a serum alpha-1 antitrypsin (A1AT) concentration was 34 mg/dl (normal 100–250 mg/dl), with A1AT MZ phenotype reported. Her conjugated hyperbilirubinemia improved slightly, and her liver numbers stabilized. She was discharged home with a close follow-up outpatient appointment in the pediatric gastroenterology clinic. The remainder of her evaluation for neonatal cholestasis, including an echocardiogram and ophthalmology examination for Alagille’s syndrome, was negative. Infectious studies were negative as well. Hepatosplenomegaly or ascites were not detected by physical examination, with reassuring and age-appropriate biometrics noted. Ongoing outpatient medical care revealed elevated cytomegalovirus (CMV) IgM titers (0.97). Due to persistent cholestasis, a repeat A1AT serum concentration was low level at 32 mg/dl, although a repeat ELISA was now reported as the Z phenotype consistent with the ZZ genotype. Due to conflicting tests of mutant serum A1AT proteins, her liver biopsy was re-analyzed with intrahepatic positive periodic acid–schiff stain (PAS) granules now reported, consistent with the diagnosis of A1AT deficiency (Fig. 2). Concomitantly, CMV viremia was confirmed with an elevated CMV polymerase chain reaction (PCR) assay of 12,800. In the clinic, she exhibited significantly increased abdominal distension and marked ascites. Her bilirubin (total 8.8 mg/dl; conjugated 5.3 mg/dl) and aminotransferases (AST/ALT 500/309 units/l) were elevated. Additionally, a significant coagulopathy was noted with an international normalized ratio (INR) of 2.2 and low fibrinogen of 88. Hyponatremia (119 mg/dl) and metabolic acidosis were also present. She did not have any changes in her mental status, and her venous ammonia concentration was mildly elevated to 68 lmol/l. She was admitted to Lucile Packard Children’s Hospital at Stanford for correction of her electrolyte abnormalities and coagulopathy. She was treated with ganciclovir for CMV viremia. During her first 48 h in the hospital, despite the use of IV phytonadione, her hepatic synthetic liver function deteriorated rapidly, with daily doses of fresh-frozen plasma required to treat her coagulopathy. Due to her P. Arias (&) J. Kerner M. Christofferson W. Berquist K. T. Park Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Lucile Packard Children’s Hospital, Stanford University Medical Center, 750 Welch Road, Suite 116, Palo Alto, CA 94304, USA e-mail: parias@stanford.edu

Acute liver failure (ALF) is an uncommon disorder that leads to jaundice, coagulopathy, and multisystem organ failure [1]. Malignancy is an uncommon cause of ALF, and diffuse parenchymal metastases are a pattern that is capable of causing liver failure. Hematological malignancies are recognized to be the most common cause of diffuse parenchymal metastases, but this metastatic pattern has also been identified in many primary neoplasms, such as breast cancer [1]. The prognosis is very poor [1–3]. Recently, in a literature review performed by Mogrovejo et al. [2], 32 cases were characterized (only 25 % were diagnosed premortem, but with a statistically significant trend of increasing premortem diagnosis since 2000: p = 0.001); common signs included jaundice, hepatomegaly, shifting dullness, and bilateral leg edema; mean serum level of AST was 296.4 ± 204.0 U/l, ALT was 183.2 ± 198.9 U/l, and total bilirubin was 8.6 ± 8.3 mg/ dl. Authors reported also a new case of ALF from breast cancer (mixed ductal and lobular carcinoma) with hepatic metastases (demonstrated by liver biopsy) that occurred 21 years after original breast primary. We report too the case of a 35-year-old women, without any pathological history. Four years ago, she underwent demolitive surgery for invasivemixed ductal and lobular left breast cancer, G3, ER = 90 %, PgR = 0 %, MIB-1 = 20–30 %, HER2/NEU = 3?, pT1bpN0M0. She was treated with adjuvant chemotherapy with docetaxel (75 mg/m), carboplatin (AUC 6), and trastuzumab (8 mg pro kg for the first dose and 6 mg pro kg for subsequent doses) (TCH) each 21 days for six cycles, followed by the administration of three weekly trastuzumab (6 mg pro kg) for 1 year; she also started hormone therapy with tamoxifen at the dose of 20 mg/daily following chemotherapy (for 5 years total treatment provided) and enantone 3.75 mg/month. After 3 years, she presented with asthenia and right upper quadrant pain. At physical examination, jaundice and hepatomegaly were found; Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 3. Abdominal ultrasonography revealed the presence of bone and liver metastases (several hypoechoic lesions in right and left hepatic lobe), ranging from 10 to 15 mm in maximum diameter as confirmed by the subsequent CT scan. Liver function test showed increased total and direct bilirubin of 5.0 and 2.5 mg/dl, respectively, AST (388 U/l), ALT (236 U/l), and cGT (449 U/l) serum levels (Table 1). Considering the young age and the bio-pathological features of the disease, we decided to start chemotherapy with weekly carboplatin (AUC 2), vinorelbine, and trastuzumab (2 mg pro kg). We have seen a progressive improvement in both the general condition of the patient (ECOG PS = 1) and the values of liver function. In particular, after 1 month of chemotherapy, values of liver function were nearly normalized: total bilirubin = 0.4 mg/dl, AST = 48 U/l, ALT = 60 U/l, and cGT = 88 U/l serum levels (Table 1). The CT scan revealed a partial remission (PR) of liver metastases. After 6 months of the onset, the patient was treated with nab-paclitaxel (80 mg/m, for hypersensitivity reaction to the second administration of weekly paclitaxel) and trastuzumab (2 mg pro kg) for liver progression of the disease (PD). We have seen a progressive deterioration of the general condition of the patient; the patient died about 9 months after the onset of the disease for PD. & Jacopo Giuliani giuliani.jacopo@alice.it

Many have advocated the preferential use of high risk allografts for hepatocellular carcinoma patients undergoing liver transplantation. Hepatocellular carcinoma (HCC) patients tend to have relatively preserved liver function, and their outcome is felt to be driven largely by tumor-related factors.The aim of this study was to compare the relative importance of donor versus recipient factors on post-orthotopic liver transplantation survival among HCC and non-HCC recipients.The study group included Scientific Registry of Transplant Recipients data on adult recipients of deceased donor liver transplants from February 2002 through December 2008. Recipients were classified as HCC based on MELD exception applications and were compared to all other recipients. Predictors of post-LT survival were identified by Cox regression. To test whether donor factors have less impact on survival in HCC patients, interaction terms were created between HCC diagnosis and donor factors.Of the 40,212 DDLTs during the study period, 29,020 (72 %) met study criteria. A total of 7,786 (27 %)were transplanted with a diagnosis of HCC. The mean donor risk index was 1.5 in both cohorts. The 1-/5-year survival was 88 %/68 % and 87 %/74 % among HCC and non-HCC recipients, respectively (p\0.0001). On multivariate analysis, there was no statistically significant interaction between HCC diagnosis and DRI (HR 0.94,p = 0.317). Likewise, no interaction was seen between HCC diagnosis and individual donor factors. In both groups, donor and recipient factors carried similar weight in determining post-LT survival.Contrary to previous assumptions, donor factors play a similar role in determining survival post-LT among HCC patients and non-HCC patients.

Previous studies have shown that betaine prevents alcohol-induced liver injury and improves liver function. The purpose of this study was to investigate the hepatoprotective effects of betaine on nonalcoholic fatty liver disease (NAFLD) and to observe changes of HMGB1/TLR4 signaling.Thirty rats were randomly divided into control, model, and betaine groups. The rats in the model and betaine groups were fed a high-fat diet for 12 weeks to induce an animal model of NAFLD. The rats in the betaine group were then intragastrically administered betaine solution at a dose of 400 mg/kg per day for four weeks. Liver histology was examined. Serum levels of ALT, AST, TC, TG, HDL-C, LDL-C, FFA, HMGB1, NF-κB, TLR4, and tHcy were determined and intrahepatic TC, TG, and Hcy levels were assayed. mRNA expression and protein levels of HMGB1, NF-κB, and TLR4 in liver tissue were also determined.Compared with the control group, rats in the model group developed severe liver injury, accompanied by significant increases in serum levels of ALT, AST, TC, TG, LDL-C, FFA, HMGB1, NF-κB, and TLR4, intrahepatic TC, TG, and Hcy content, histological scores for steatosis, inflammation, and necrosis, and mRNA expression and protein levels of HMGB1, NF-κB, and TLR4, and a significant decrease in serum HDL-C (P0.05). Compared with the model group, all these indicators were significantly improved by administration of betaine (P0.05).Betaine effectively protects against high-fat-diet-induced NAFLD and improves liver function; the mechanism is probably related to inhibition of HMGB1/TLR4 signaling pathways.

(13)C-Aminopyrine breath test ((13)C-ABT) is a non-invasive, dynamic, quantitative liver function test, and the model for end-stage liver disease (MELD) is a recognised biochemical score used to predict survival in patients with cirrhosis.The purpose of this study was to evaluate the relationship between the (13)C-ABT and MELD score in a cohort of cirrhotic patients and, moreover, to assess the prognostic value of (13)C-ABT results in the same group of patients.Forty-six patients with cirrhosis and without hepatocellular carcinoma who underwent (13)C-ABT and who had at least 1-year follow-up were prospectively included in this study. MELD score was calculated at entry into the study in all patients. End-points of the study were 1-year liver-related death or liver transplantation.(13)C-ABT %dose/h at 30 min (%dose/h30) results showed significant, inverse correlation with MELD scores (r = -0.414, P = 0.004). During 1-year follow-up nine patients died (19.6 %) and two were transplanted (4.3 %). Median (13)C-ABT %dose/h30 results (3.2 vs. 1.8) were significantly higher in patients who survived as compared to those who died or underwent transplantation (P = 0.04). Receiver operating characteristics curves showed that a (13)C-ABT %dose/h30 cut-off of 2.0 had the best accuracy (c-index = 0.717) in assessing 1-year prognosis.We observed a correlation between a flow-independent quantitative liver function test and the MELD score, and found that the (13)C-ABT may accurately provide long-term prognostic information in cirrhotic patients.

The purpose of this study was to examine the correlation between serum HBV DNA level and the severity of hepatic inflammation and fibrosis in patients with chronic hepatitis B. Liver function, serological markers of HBV and serum HBV DNA quantification were assayed in 215 CHB patients who also underwent liver biopsy. Liver pathology was regarded as the evaluation criteria to evaluate the correlation between serum HBV DNA level and the severity of liver inflammation and fibrosis. Of the 215 patients, 136 were HBeAg-positive and 79 were HBeAg-negative; 134 patients had mild hepatic inflammation and fibrosis and 81 had significant hepatic inflammation and fibrosis in pathological diagnosis. We found that positive correlation between the severity of hepatic inflammation and fibrosis and serum HBV DNA level was only present in HBeAg-negative patients but not HBeAg-positive patients (P

Although anatomical resection (AR) is considered better than non-anatomical resection (NAR) for the treatment for hepatocellular carcinoma (HCC), there is only limited evidence in support of this argument.The aim of this study was to investigate whether AR is superior to NAR regarding postoperative outcomes in patients with small solitary HCC and preserved liver function.The study subjects were 92 curatively-resected patients with adequate liver function reserve (indocyanine green retention rate at 15 min15%, prothrombin time70%, serum albumin3.5 g/dl) and macroscopically small (≤3.0 cm) solitary HCC without macroscopic vascular invasion; 30 patients underwent AR and 62 patients NAR. Postoperative short-term outcomes including mortality and morbidity and long-term outcomes were compared in the two groups.There was no significant difference in clinicopathological background in the two groups. Although resected liver volume was significantly larger in the AR group than the NAR group (p0.0001), no significant differences were detected in the incidence of mortality or morbidity. For long-term outcomes, there were no significant differences between the two groups in disease-free survival or overall survival. Multivariate analysis showed that the extent of surgical procedure was not a significant prognostic factor for disease-free or overall survival.AR of a solitary small HCC did not carry postoperative outcome advantages compared with NAR in patients with preserved liver function. We recommend NAR for hepatic resection of small solitary HCC in patients with preserved liver function.

Hepatocyte injury is a common pathological cause of various liver diseases. Due to a lack of an effective preventive treatment, gene therapy has become an interesting approach to prevent and alleviate liver injury.A protective effect of adenovirus-mediated dual gene expression of human interleukin-10 (hIL-10) and human hepatocyte growth factor (hHGF) was investigated against tetrachloromethane (CCl(4))-induced hepatocyte injury in rats.An adenoviral vector carrying the hIL-10 and hHGF genes was constructed, and its protective effect against rat hepatocyte injury was investigated both in vivo and in vitro.In the in vitro CCl(4)-induced cell injury model, simultaneous transfection of hIL-10 and hHGF genes via an adenoviral vector resulted in production of anti-hepatocyte biological factors by an autocrine mechanism, then significantly improved hepatocyte viability. In the in vivo rat model, synergistic effects of these two gene products protected hepatocytes from damage by reducing the CC1(4)-induced hepatocyte degeneration, hepatic fibrosis, and intrahepatic inflammatory cell infiltration, thereby preserving liver function.Adenovirus-mediated dual gene expression of hIL-10 and hHGF effectively protected against liver damage by likely regulating immune responses to reduce hepatocyte injury and by promoting hepatocyte regeneration. The hIL-10 and hHGF dual gene expression vector has significant potential in the field of liver disease therapeutics and constitutes one of the most promising current strategies for gene therapy.

Although treatment of acute liver failure has been improved significantly recently, the survival rate of acute liver failure is only 5–20%. Therefore, prevention and treatment of acute liver failure are still urgent issues in the field of liver disease. It has been demonstrated that ulinastatin could attenuate acute injury of internal organs from endotoxin. This study evaluates whether ulinastatin can prevent and/or attenuate acute liver failure induced by the combination of lipopolysaccharide and d-galactosamine (LPS/d-gal). Sprague–Dawley rats were employed to induce acute liver failure by injection of LPS/d-gal. The liver function, inflammatory factors, oxidative stress index, and hepatic histopathological alteration were examined in the rats with and without ulinastatin treatment. In rats treated with LPS/d-gal, there were increases in the levels of ALT and AST in the serum and levels of malondialdehyde and inducible nitric oxide synthase in liver tissues. Moreover, the levels of antioxidants such as superoxide dismutase and glutathione peroxidase were reduced in the liver. Furthermore, inflammatory factors (TNF-alpha and IL-6) and apoptotic enzyme (caspase-3) were increased in the respective serum and liver of rats treated with LPS/d-gal. However, pre-treatment of ulinastatin significantly reversed all of these parameters in the rats that received LPS/d-gal alone. The finding in this study suggests that ulinastatin could be a potential agent for prevention and treatment of acute liver injury induced by LPS/d-gal.

Progressive deterioration in liver function is a common cause of hepatic decompensation and indication for liver transplantation in patients with advanced liver disease. Previous studies in animal models of acute and chronic liver disease revealed that daily ciprofloxacin improves biochemical parameters of hepatic function. The primary objective of this study was to determine whether hepatic function improves in patients with advanced liver disease after 1 month of daily ciprofloxacin therapy. A secondary objective was to determine whether ciprofloxacin treatment for 1 or 3 months results in fewer hospitalizations for decompensated liver disease. Forty-four patients with advanced liver disease awaiting liver transplantation received oral ciprofloxacin (250 or 500 mg twice daily) or placebo for 1 (n = 22/group) or 3 (n = 10 ciprofloxacin, 14 placebo) months. Compared to placebo recipients, ciprofloxacin-treated patients had mild improvements in serum albumin levels (+1.5 versus −3.4%, p = 0.026) while bilirubin and international normalized ratios (INR) of prothrombin times remained unchanged. Overall, fewer hospitalizations occurred in ciprofloxacin-treated patients (1/22, 5% versus 7/22, 32%, respectively, p = 0.02) during the study period. Treatment was well tolerated and no resistant infections occurred in either cohort. The results of this study suggest that daily ciprofloxacin may result in fewer hospitalizations for patients with advanced liver diseases awaiting liver transplantation but not by enhancing hepatic function.

Hepatocellular carcinoma (HCC) is a heterogeneous disease, with many poorly-defined prognostic patient subsets. Identification of discrete subsets will aid rational patient and treatment selection. A database with 778 biopsy-proven, unresectable and untransplantable HCC patients who were followed from diagnosis till death was interrogated. Using a moving average algorithm, patients were ordered by survival and then survival cohorts were analyzed according to standard liver function and CT characteristic parameters. We found characteristic age clustering groupings by survival. In the older age patients, two survival sub-groups were identified, with 45–80 days in one and 330–1,250 days survival in the other group. The longer surviving group had the lowest serum bilirubin and AFP levels and the lowest tumor mass. Remarkably, the trends for both AFP and bilirubin were similar, suggesting that they were not independent variables. This idea was supported by the similar correlation of typical AFP with GGTP, ALKP and SGOT levels. A large HCC cohort showed significant age clustering characteristics for survival, especially in older patients. AFP, bilirubin and age were found to be inter-related factors for HCC severity and survival.

Hepatocellular carcinoma (HCC) is a common malignancy in Asians with hepatitis B virus infection. HCC patients often present with poor liver function and large tumors resulting in rapid mortality. The impact of HCC surveillance and subsequent therapy on patient survival remain controversial.We sought to determine if surveillance for HCC in a community-based clinic improve survival and, if so, identify factors that contribute to the benefit of early tumor detection.From 1991 to 2008, alpha-fetoprotein and abdominal ultrasound examination were used as surveillance tests for HCC. The survival of HCC patients detected by surveillance was compared to patients who presented to the clinic with HCC (no surveillance). An adjusted lead-time bias interval was added to the survival time of patients who presented with HCC.During this period, 26 patients with surveillance developed HCC while 52 patients presented with HCC. More surveillance patients had normal levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase (p0.05-0.0001) and had tumors that were within Milan and University of California San Francisco (UCSF) criteria (p = 0.02-0.0001). The 1-, 3-, and 5-year survival rates were higher in surveillance patients and in those who received surgical or loco-regional therapies (p = 0.007-0.0001). On multivariate analysis, baseline independent factors predicting survival were single tumors (Hazard ratio [HR] 0.25, p = 0.0005), UCSF criteria (HR 0.29, p = 0.006), Child-Turcotte-Pugh class A (HR 0.45, p = 0.03), platelet counts per log(10) increase (HR 0.315, p = 0.04) and aspartate aminotransferase per log(10) increase (HR 5.7, p = 0.01).Surveillance for HCC identified patients with smaller tumor burdens and more adequate liver function who were able to receive more definitive therapies. HCC surveillance improves survival and should be included as standard of care for patients with hepatitis B.

Severe acute hepatitis B is a rapid deterioration of liver function, which carries a high mortality rate. The aim of this study is to evaluate the efficacy of lamivudine in patients with severe acute hepatitis B. In this study, 80 patients with severe acute hepatitis B were randomly divided into lamivudine and the control group. For the two groups, we compared HBsAg, HBeAg seroconversion rates, serum HBV DNA-negative rate, biochemical indicators, the incidence of liver failure, and mortality. The influential factors on the mortality were studied by Cox proportional hazards model. The improvement in serum TBiL, INR, and HBV DNA levels of the lamivudine group was significantly greater than that of the control group. The mortality of lamivudine group (7.5%, 3/40) was significantly lower than that of the control group (25.0%, 10/40) (p = 0.034). The incidence of liver failure (8.7%, 2/23) of patients receiving lamivudine within a week was significantly lower than that (35.3%, 6/17) of those who received it after a week (p = 0.038). In multivariate Cox proportional hazards analyses, age (p = 0.043), ratio of total to direct bilirubin (p = 0.009), treatment method (p = 0.006), and the decline of HBV DNA load during therapy (p = 0.017) were independent predictors of mortality. The HBsAg seroconversion rates (62.5%, 25/40) and HBeAg seroconversion rates (63.6%, 21/33) of the lamivudine group were significantly lower than those (85.0%, 34/40), (87.5%, 28/32) of the control group (p = 0.022, 0.026). Early treatment with lamivudine leads to a greater decrease in HBV DNA level, better clinical improvement and mortality improvement in patients with severe acute hepatitis B, but with a lower seroconversion rate. A rapid decline of HBV DNA load is a good predictor for the treatment outcome.

We sought to determine the effect of statin therapy on serum AST and ALT levels in a cohort of HCV-infected veterans with well-characterized liver disease.We examined liver biopsy records of consecutive HCV-infected patients and identified 20 patients who were prescribed statins. We matched them on age, stage of fibrosis, and time between HCV diagnosis and statin start dates with up to four HCV-infected patients who did not use statins. ALT and AST values from up to four time points within 1 year of follow-up were abstracted from the medical record. We compared median ALT and AST levels using Wilcoxon-Mann-Whitney tests and assessed changes in ALT and AST over time between the statin and non-statin groups using a non-parametric repeated measures ANOVA model, adjusting for the matching factors, receipt of HCV treatment, BMI, and diabetes.Patients prescribed statins had higher median BMIs, were more likely to have diabetes, and had higher total cholesterol levels. Median baseline ALT levels were higher among those prescribed statins (P = 0.04) while median baseline AST levels were lower among statin users (P = 0.03). From baseline to follow-up, the median decreases in both ALT (-13.5 vs. -4.0) and AST (-4.5 vs. -0.5) were significantly larger among statin users compared to non-statin users (P = 0.03 and P = 0.0007, respectively) even after adjustment.Among HCV-infected patients AST and ALT levels for those prescribed statins decreased over a 6 to 12-month follow-up period compared to patients not taking statins.

We previously reported that both experimental and human studies have shown the importance of TIMP-1 and TIMP-2 in the development of liver fibrosis, a disease mostly caused by HBV and HCV infection in China. Inhibiting the expression of TIMP-1 by an antisense oligonucleotide (ASON) can prevent liver fibrosis through decreasing the deposition of collagen I and III. Whether blocking the expression of TIMP-2 has the same effect on liver fibrosis is not clear.To interfere with this potentially effective target, we designed and synthesized two different ASON targeting TIMP-2, then mixed and transfected them by hydrodynamic injection into the rat livers with immune-induced liver fibrosis. We isolated HSCs from the HSA-induced rat model with liver fibrosis, and transfected them with ASON or sense oligonucleotide in vitro.We observed that TIMP-2 ASON markedly reduced the expression of TIMP-2 by real-time PCR, Western blot, and enzyme linked immunosorbent assay. However, TIMP-2 ASON had little effect on alpha-SMA expression in vitro by Western blot. Inhibition of the expression of TIMP-2 by TIMP-2 ASON clearly decreased deposition of collagen I and IV, ameliorated liver pathology, and improved the liver function among the rats with immune-induced liver fibrosis.The results suggested that TIMP-2 ASON could prevent the progression of liver fibrosis in this rat model. It is possible that this could form the basis for exploration of new liver anti-fibrosis drugs at a genetic level.

Spontaneous bacterial peritonitis (SBP), a common complication of cirrhosis of liver, might result from translocation of bacteria from the small bowel. However, there is scanty data on frequency of small intestinal bacterial overgrowth (SIBO) in patients with cirrhosis of the liver. There are no data on SIBO in patients with extra-hepatic portal venous obstruction (EHPVO) in the literature. A total of 174 patients with cirrhosis of the liver, 28 with EHPVO and 51 healthy controls were studied for SIBO using glucose hydrogen breath test (GHBT). Persistent rise in breath hydrogen 12 ppm above basal (at least two readings) was considered diagnostic of SIBO. Of 174 patients (age 47.2 ± 11.9 years, 80.5% male) with cirrhosis due to various causes, 67 (38.5%) were in Child’s class A, 70 (40.2%) class B and 37 (21.7%) class C. Of the 174 patients with cirrhosis, 42 (24.14%) had SIBO as compared to 1 of 51 (1.9%) healthy controls (P < 0.0001). Patients with EHPVO had similar frequency of SIBO compared to healthy controls [2/28 (7.14%) vs 1/51 (1.97%), P = ns]. Frequency of SIBO in Child’s A, B and C was comparable [13 (18.6%) vs 16 (23.9%) and 13 (35.1%), respectively; P = ns]. Presence of SIBO were not related to ascites, etiology of cirrhosis, and degree of liver dysfunction. SIBO is common in patients with cirrhosis of the liver. Patients with EHPVO do not have higher frequency of SIBO than healthy subjects. SIBO in cirrhosis is not related to the degree of derangement in liver function or of portal hypertension.

Background It is difficult to differentiate early compensated cirrhosis from chronic hepatitis solely by clinical features. The aim of this study was to assess the usefulness of liver stiffness measurement (LSM) for detection of early compensated liver cirrhosis in chronic hepatitis B (CHB). Methods Ninety-one consecutive CHB patients who underwent liver biopsy (LB) and LSM were recruited. All patients did not fulfill the clinical criteria for cirrhosis. The cutoff of LSM for cirrhosis was 10.3 kPa. Results All patients were divided into either group A (cirrhosis) or group B (CHB) according to LB result. The median LSM values of groups A and B were 11.8 and 7.6 kPa, respectively (P < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of LSM in predicting cirrhosis were 0.59, 0.78, 0.68, and 0.72, respectively. The area under the receiver operating characteristics curve (AUROC) of LSM was 0.803, whereas the AUROCs of aspartate to alanine aminotransferase ratio (AAR) and aspartate aminotransferase to platelet ratio index (APRI) were 0.488 and 0.723, respectively. Conclusions LSM showed an acceptable diagnostic accuracy for detecting early compensated cirrhosis in CHB.

The aims of this study were to select the patients with a potential for progression to hepatic failure due to lamivudine-resistant HBV and to standardize the treatment for patients with lamivudine-resistant HBV. Patients (n = 47) with reactivated hepatitis due to lamivudine-resistant HBV were classified into two groups, with and without potential for progression to hepatic failure, according to the criteria using the data of serum bilirubin level and prothrombin activity after the reactivated hepatitis. Multivariate analysis showed that prothrombin activity at the initiation of lamivudine therapy was related to the deterioration of the liver function after the emergence of lamivudine-resistant HBV (P = 0.0025, 95%CI 0.8269-0.9601). We assume that earlier additional or substitutive treatment with other antiviral agent, such as adefovir dipivoxil, should be recommended when the lamivudine-resistant HBV is detected in patients with the history of decompensated liver disease before the administration of lamivudine, even when hepatitis has not been reactivated yet.