Normal Serum ALT Research Articles

Rate and determinants of antiviral treatment initiation for patients with HBeAg-negative chronic hepatitis B.

Most clinic attenders with chronic hepatitis B (CHB) are serum HBeAg-negative, and a minority will require suppressive antiviral treatment. Expert guidelines propose schedules for the monitoring of untreated patients, but the recommended frequency of patient review does not reflect recognised demographic determinants of HBeAg-negative chronic hepatitis. Also, the impact of patient ethnicity on risk has not been defined. The aim of our study was to determine the rates and determinants of antiviral treatment initiation in a large multi-ethnic cohort of CHB patients attending a single centre. We undertook a retrospective study using entirely electronic sources of patient information. Treatment initiation dates were identified from electronic pharmacy records. Crude and time-dependent statistical analyses were undertaken to identify rate and risk factors for treatment initiation. Treatment was initiated for 232/1256 (18.5%) patients with rates of 23.2% and 33.2% at 5 and 10 years. An increased risk of treatment was associated with male sex (RR 1.803), older age at presentation (RR 1.027 per year increase) and with non-Black ethnicity (RR 1.654). Patient sex, baseline age and ethnicity also determined risk for treatment in the subset of patients with normal serum ALT and low HBV DNA at baseline, though overall treatment rate in this group was low (only 2% per annum). Thus, patient demographics permit risk stratification for treatment initiation and could determine to a significant extent the frequency of review required for untreated HBeAg-negative patients. Black ethnicity is associated with a significant reduction in risk of treatment initiation.

Abstract 296: Antigen-independent delivery of 4-1BB agonist to the tumor microenvironment improves immune response while reducing hepatotoxicity

Abstract Background: Clinical progress of α4-1BB has been impeded by hepatotoxicity. Current research is focused on improving targeted delivery of α4-1BB to the tumor using tumor-specific markers. However, targeted delivery of 4-1BB agonists to tumors faces challenges due to a lack of tumor biomarkers and effector T cells within tumors. To overcome these challenges, we developed antigen-independent targeting approach based on unnatural sugar-mediated metabolic glycoengineering and bio-orthogonal click chemistry to deliver α4-1BB to tumors. We utilized nanoparticles that can deliver a sugar analogue containing click-chemistry moiety to the tumor microenvironment. Method: The Ac4ManNAz was loaded in mPEG-PLGA nanoparticles (MazNP), and the loading efficiency was determined by HPLC. DBCO-functionalized α4-1BB (DBCO-α4-1BB) was synthesized via amine-NHS coupling reaction. The tumor inhibition efficiency was assessed on mice bearing different tumor models. Mice were either inoculated subcutaneously on the left flank (75,000 B16F10 cells) or injected on the left fourth mammary fat pad (100,000 4T1 cells). Mice were given MazNPs (IV) on day 5, 6, 10, and 11, and DBCO-α4-1BB (IV) and αPD-1 (IP) on day 8 and 13. T lymphocytes were analyzed by fluorescent IF staining. Serum liver enzyme was examined to evaluate hepatotoxicity of treatments. Liver pathology was assessed by H&E and CD8+ IHC staining. Results: The αPD1 plus DBCO-α4-1BB with MazNPs showed a 36.4% cure rate, compared to 0% of αPD1 plus DBCO-α4-1BB or αPD1 plus DBCO-α4-1BB with free Ac4ManNAz in B16F10 melanoma model. We then re-challenged the cured mice with 200,000 B16F10 cells and 50% of cured mice survived without any further treatment. In 4T1 breast cancer model, the survival data analyzed using the log-rank test showed that the median survival of αPD1 plus DBCO-α4-1BB with MazNP was increased by 71%, compared to the PBS, and 26% αPD1 plus α4-1BB or αPD1 plus DBCO-α4-1BB with free Ac4ManNAz. We showed that the involvement of NK and CD8+ T cells in the antitumor efficacy of αPD1 plus DBCO-α4-1BB with MazNP. Notably, a massive CD8+ T cell infiltration in the liver was observed in both αPD1 plus α4-1BB (29.8 ± 18.2%) and αPD1 plus DBCO-α4-1BB with Ac4ManNAz (22.1 ± 10.9), significantly higher than PBS control (0.9 ± 0.6%), while the percentage of CD8+ T cells in the MazNP treatment (5.4 ± 5.8%) was five times lower. Hepatotoxicity was further confirmed by serum liver enzyme analysis that ALT and AST levels were substantially elevated by αPD1 plus α4-1BB or αPD1 plus DBCO-α4-1BB with free Ac4ManNAz, as compared to PBS control group, while the MazNP-treated mice had normal serum ALT and AST levels except for one. Conclusion: Our findings demonstrated that antigen-independent targeted delivery of α4-1BB can improve anti-tumor immune responses while reducing hepatotoxicity. Citation Format: Hyesun Hyun, Bo Sun, Stephanie A. Montgomery, Teresa Griffin, Juanzhu Yan, Albert Wielgus, Yue Wang, Tian Zhang, Jianjun Cheng, Andrew Z. Wang. Antigen-independent delivery of 4-1BB agonist to the tumor microenvironment improves immune response while reducing hepatotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 296.

Association between serum sphingolipids and necroinflammation of liver tissue pathology in chronic hepatitis B

Background & Aims: Accurately identifying liver necroinflammation was essential for the timely implementation of antiviral therapy in chronic hepatitis B(CHB) patients. The sphingolipids were involved in various chronic inflammatory processes. This study aimed to evaluate the association between serum sphingolipids and liver necroinflammation in CHB patients. Methods: The study prospectively enrolled patients with a diagnosis of chronic hepatitis B who were subsequently treated with nucleos(t)ide analogs (NAs). Liver biopsy was performed at baseline and 5-year follow-up, and serum sphingolipid levels were measured by ultra-high-performance liquid chromatography tandem mass spectrometry. Results: A total of 70 CHB patients were enrolled with baseline liver necroinflammation of 27(38.6%) G1, 23(32.9%) G2, and 20(28.6%) G ≥ 3, respectively. A total of 126 liver biopsies were performed on the study population over a 5-year period, of which 80 (63.5%) G<2 and 46 (36.5%) G≥2. Serum ALT, ALP, SM d16:0/16:1, SM d16:0/17:1, SM d18:0/17:0 and Cer d18:2/22:0 showed significant differences between two groups (P<0.01). Multivariate analysis showed that serum ALT (OR 1.006, 95% CI: 1.000-1.011), SM d16:0/16:1 (OR 1.552, 95% CI: 1.150-2.093), Cer d18:2/22:0 (OR 0.003, 95% CI: 0.000-0.173) were associated with G ≥ 2. In the subgroup of patients with normal serum ALT, serum Cer d18:2/22:0 was lower in patients with G ≥ 2 than that with G < 2. After 5 years, alleviated inflammation was accompanied by decreased serum SM d16:0/16:1 and increased serum Cer d18:2/22:0 in patients with baseline G ≥ 2. Conclusions: Lower serum Cer d18:2/22:0 could reflect hepatic necroinflammation (G ≥ 2) in CHB patients including those with normal serum ALT, and its elevation predicts the inflammation improvement after NAs treatment.

Efficacy of 24-week Administration of Tenofovir Disoproxil Fumarate in the Management of Naïve Chronic Hepatitis B

&#x0D; BACKGROUND: Chronic hepatitis B (CHB) is becoming a common liver abnormality worldwide. Thus, a series of good management is needed to prevent the progression and complications of hepatitis B infection. Tenofovir disoproxil fumarate (TDF) is one of the drugs of choice that’s used for CHB management.&#x0D; AIM: Limited studies were found regarding the efficacy of tenofovir in dealing with CHB. Hence, the aim of this study is to determine the efficacy of TDF administration for 24 weeks in subjects with naïve CHB in Medan, Indonesia.&#x0D; METHODS: Retrospective study was conducted in Haji Adam Malik Hospital Medan, Indonesia, between January and December 2019. Subjects were CHB patients aged 18 years or older and were treated TDF for 24 weeks. Demographic, clinical, and CHB disease progression parameters (serum alanine aminotransferase [ALT], hepatitis B envelope antigen [HBeAg], and hepatitis B virus deoxyribonucleic acid [HBV DNA]) data were obtained.&#x0D; RESULTS: One hundred and twenty subjects were obtained and divided into 2 groups: HBeAg positive and HBeAg negative. Mean age of subjects was 46.5 ± 10.36 years in HBeAg positive group and 48.6 ± 10.67 years HBeAg negative group, with predominant males’ subjects in both groups (58.3% vs. 61.7%, respectively). Serum ALT normalization and undetectable serum HBV DNA were observed in more than 70% and 65% of subjects in both groups, respectively (both p &lt; 0.001). Serum HBeAg loss was achieved in 10.8% subjects (p &lt; 0.001). No subject showed serum HbsAg loss.&#x0D; CONCLUSION: Our results are consonant with current clinical guidelines and other evidence literature. For both HBeAg-positive and HBeAg-negative populations, TDF administration for 24 weeks has good efficacy in naïve CHB patients.

Prevalence of liver fibrosis in an unselected general population with high prevalence of obesity and diabetes mellitus. Time for screening?

IntroductionCirrhosis and liver cancer are currently common causes of death worldwide. The global epidemic of obesity has increased the incidence of nonalcoholic fatty liver disease (NAFLD) and cirrhosis in recent years. Advanced fibrosis increases the morbimortality rate in NAFLD. The Mexican population has one of the highest prevalence of obesity and diabetes mellitus (DM) worldwide. AimTo determine the prevalence of advanced liver fibrosis in Mexican general population. MethodsAdult individuals, without a history of liver disease nor heavy alcohol consumption were randomly sampled from 20,919 participants of a health and nutrition survey applied to the general population. Clinical and laboratory evaluations were performed to calculate the NAFLD fibrosis score (NFS) (an extensively validated non-invasive method). Two cut-off points were used. Advanced fibrosis was defined as a result >0.676. ResultsIn total 695 individuals were included. The mean age was 47.8±16.4. The majority were between 20 and 50 years (59%), 70.2% were female, 35.5% showed obesity and 15.8% DM. The 93% had normal serum ALT. Based on the NFS results, 56 individuals (8.1%) had a high probability of fibrosis. Most patients from this subgroup showed normal serum ALT (92.9%), 89.3% were >45yr. old, 52% were obese and 27% suffered from DM. ConclusionsBased on these results, 8.1% of Mexican general population without a history of liver disease is at high risk of having advanced liver fibrosis and complications and death derived from cardiovascular disease and cirrhosis. Most of them showed normal ALT serum levels.

The Role of Traditional Chinese Medicines (TCM) and Other Complementary and Alternative Medicines (CAM) in the Management of Chronic Hepatitis B

To provide a review and update of complementary and alternative medicine (CAM) approaches to the management of chronic hepatitis B, with particular emphasis upon traditional Chinese medicines (TCM). The major findings are as follows: (1) TCMs were better than interferons [IFN] in lowering serum HBeAg and normalizing serum ALT, and equivalent to IFN in clearing serum HBV DNA; (2) TCMs were equivalent to lamivudine [LAM] in lowering serum HBeAg, normalizing serum ALT, and clearing serum HBV DNA; (3) TCMs along with IFN or LAM significantly lowered serum HBeAg and improved the clearance of serum HBV DNA and the normalization of serum ALT, compared with IFN or LAM alone; (4) no serious adverse reactions of TCM were reported in all cited clinical trials. Although the composition of traditional medicines in the TCMs varied among RCTs, about 60% of the used herbs were homologous. Our major overarching conclusion was that TCMs seem effective as alternative remedies for patients with CHB. Other CAM approaches also are widely used, especially in east Asian countries, and there is limited evidence of benefit for some. CHB continues to be a major health problem worldwide. Although nucleosides such as tenofovir and entecavir are highly effective at suppression of HBV replication, they are expensive and often beyond reach of patients, especially in resource-limited nations and regions. Many such patients will continue to rely upon CAM and TCM for management of their chronic hepatitis B infections. Additional carefully done, placebo-controlled prospective randomized trials of CAM and TCM in chronic hepatitis B should be performed.

ASSESSMENT OF LIVER FUNCTION TESTS IN DENGUE FEVER

Background: The prevalence of dengue viral infection has tended to rise globally in the recent decades. In India the burden and prevalence of dengue viral infection is increasing as trends reported globally. Hence, along with global pandemic concern dengue has become major public health concern in India. Dengue is an emerging epidemic disease and several outbreaks among every state of India is being reported from time to time.&#x0D; Material &amp; Methods: The present cross-sectional study includes 50 Patients who had dengue IgM antibody positive were enrolled from outdoor and from ward by simple random sampling. Clearance from Institutional Ethics Committee was taken before start of study. Written informed consent was taken from each study participant.&#x0D; Results: 10 (20%) patients had normal serum ALT levels, 13 (26%) patients had serum ALT levels raised less than Two-folds, 12 (24%) patients had serum ALT levels raised more than Two-folds, 11 (22%) patients had serum ALT levels raised more than four-folds and 04 (8%) patients had serum ALT levels raised more than ten folds. Among the total study participants 7 (14%) had normal serum AST levels, 14 (28%) patients had serum AST levels raised less than Two-folds, 14 (28%) patients had serum AST levels raised more than Two-folds, 12 (24%) patients had serum AST levels raised more than four-folds and 03 (6%) patients had serum AST levels raised more than ten folds.&#x0D; Conclusion: Liver function deterioration in dengue fever was varied from normal range of biochemical markers to raised liver function markers. AST elevation was more statistically significant than ALT. Hyperbilirubinemia and raised alkaline phosphatase levels were reported. Low serum albumin levels were associated with critical phase of the liver disease.&#x0D; Key words: Dengue fever, Hyperbilirubinemia, AST, ALT.

Morphopathological and Biochemical Changes Induced by Cisplatin as Anticancer Drug and The Protective Role of Moringa Leaf Ethanolic Extract and L-Carnitine in Rat

Cisplatin is a potent, highly effective, broad spectrum chemotherapeutic agent, its clinical application is limited due to its adverse effects on normal tissues Since the pathogenesis of cisplatin-induced toxicities mainly involve free radical and lipid peroxidation, this study was designed to evaluate the protective efficacy of Moringa leaf ethanolic extract and L-carnitine against cisplatin-nephrotoxicity and hepatotoxicity in rats. 72 male albino rats were divided into 6 groups GI- control received no treatment, GII- cisplatin (7mg/kg for 4 days), GIII- Prophylaxis by Moringa (500mg/kg for 10 days) then cisplatin as in G2, GIV- Prophylaxis by L-Carnitine (200 mg/kg for 10 days) then cisplatin as in G2, GV- treatment by Moringa received cisplatin as group II plus Moringa extract for 14 days. VI- treatment by L-Carnitine received cisplatin as group II plus L-Carnitine for 14 days. The results indicate that cisplatin induced significant increase in serum ALT, AST, Urea, Creatinine and kidney MDA level, also significant decrease in kidney GSH and CAT levels and histopathological alteration in kidney tissues as cloudy swelling, necrobiotic changes of tubular epithelium, congestion of glomerular tuft, also hepatic lesions as congestion of the central and portal vein with necrosis of its lining intimal cells, formation of newly formed bile duct with lymphocytic cell infiltrations in portal area and coagulative necrosis of some hepatocytes and another hepatocytes showed hydropic degeneration. Both moringa leaf ethanolic extract and L-carnitine ameliorated these toxicities as evidenced by restoring normal serum ALT, AST, Urea, Creatinine and histopathological architecture of kidney and liver.

Predicting copper toxicosis: relationship between the ATP7A and ATP7B gene mutations and hepatic copper quantification in dogs.

This preliminary study summarizes the genotypes of 42 Labrador Retrievers and Labrador Retriever-Golden Retriever crosses and phenotypes a subset of ten of these dogs that are homozygous mutant, heterozygous, or homozygous normal for mutations in the ATP7A and ATP7B genes that have been associated with the development of copper toxicosis in Labrador Retrievers. The purpose of this study is to evaluate whether there is a correlation between ATP7A and ATP7B genotypes and clinical evidence of hepatic pathology in young, asymptomatic Labrador Retrievers. We evaluated serum ALT levels, hepatic copper concentrations, and hepatic histopathology from ten offspring where both parents had a least one copy of the ATP7B mutation. Five were homozygous mutant, four were heterozygous, and one was homozygous normal for comparison. None had increased serum ALT activity. All dogs homozygous for the ATP7B mutation had elevated hepatic copper concentrations compared to dogs heterozygous for the ATP7B mutation regardless of sex or presence of an ATP7A mutation with the mean hepatic copper concentration being 1464ppm (reference range 100-330ppm). Mean hepatic copper concentration in homozygous normal and heterozygous dogs was 328ppm. In this preliminary analysis, we found that dogs that carry two copies of the ATP7B mutation have abnormally elevated hepatic copper levels despite having normal serum ALT activity. Our findings support the hypothesis that the ATP7B DNA test can predict defects in hepatic copper metabolism. Veterinarians can test for the ATP7B gene mutation to identify Labrador Retrievers at risk for copper toxicosis so that they can take steps to prevent development of copper-associated chronic hepatitis in their patients.

Resveratrol and Montelukast Alleviate Paraquat-Induced Hepatic Injury in Mice: Modulation of Oxidative Stress, Inflammation, and Apoptosis.

Paraquat (PQ) is one of the most used herbicide worldwide. Its cytotoxicity is attributed to reactive radical generation. Resveratrol (Res) and montelukast (MK) have anti-inflammatory and antioxidant properties. The protective effects of Res, MK, or their combination against PQ-induced acute liver injury have not been investigated before. Therefore, we explored the protective potential of Res and/or MK against PQ hepatic toxicity in a mouse model. Mice were randomly assigned to five groups: group I served as the normal control and group II received a single dose of PQ (50 mg/kg, i.p.). Groups III, IV, and V received PQ plus oral Res (5 mg/kg/day), MK (10 mg/kg/day), and Res/MK combination, respectively. Res and/or MK reduced PQ-induced liver injury, evidenced by normalization of serum total protein, ALT, and AST. Res and/or MK significantly reversed PQ-induced oxidative stress markers glutathione and malondialdehyde. Res and/or MK significantly reduced PQ-induced inflammation reflected in TNF-α levels. Furthermore, Res and/or MK reversed PQ-induced apoptosis assessed by differential expression of p53, Bax, and Bcl-2. Histopathologic examination supported the biochemical findings. Although Res and MK displayed antioxidative, anti-inflammatory, and antiapoptotic activities, their combination was not always synergistic.

Ten-year follow-up analysis of chronic hepatitis C patients after getting sustained virological response to pegylated interferon-α and ribavirin therapy.

There is little data on the long-term follow-up outcomes of chronic hepatitis C patients achieving sustained virological response (SVR) after treatment with peglylated interferon-α plus ribavirin. We prospectively investigated the overall clinical, biochemical, virological and histological outcomes in a ten-year cohort study of 325 patients with chronic hepatitis C achieving SVR to pegylated interferon-α and ribavirin therapy. Patients underwent consistent clinical, biochemical and virological evaluation every six months, and patients with pretherapy Ishak fibrosis score ≥2 were invited to accept a second liver biopsy at the last follow-up. Liver biopsy specimens were evaluated using Ishak's scoring system. At the end of follow-up, five patients developed decompensated liver cirrhosis. One patient (0.3%) with pretherapy cirrhosis was diagnosed with hepatocellular carcinoma (HCC). A total of 305 patients (94%) had normal serum ALT and AST levels during the entire period of follow-up. Twenty-seven patients (8%) had conclusive evidence of virological relapse. Among the 117 patients with paired pretherapy and long-term follow-up biopsies, 96 (82%) had a decreased fibrosis score. Ninety-nine (79%) had a decrease in combined inflammation score. Thirty-seven (32%) had normal or nearly normal livers on long-term follow-up biopsy. SVR achieved with PEG-IFN-α and RBV combination therapy is durable, while late virological relapse may still occur in some patients. Clinical outcomes for patients who obtain SVR are excellent, although the patients with cirrhosis are still at a low risk of hepatocellular carcinoma.

PTH-101 Accuracy of Transient Elastography in Predicting Histological Fibrosis Severity in Treated Autoimmune Hepatitis?: Abstract PTH-101 Table 1

Introduction The role of transient elastography (TE) or Fibroscan in assessing severity of liver fibrosis has been validated against liver biopsy in chronic hepatitis B and C and in NAFLD. There are few studies assessing its role in autoimmune hepatitis (AIH). Four preliminary studies have reported data on the role of Fibroscan in AIH. In these, most patients had recently started treatment and thus, still had active disease. Minimal data on transaminases was provided. We aimed to assess the accuracy of Fibroscan in predicting histological fibrosis severity in patients who had achieved biochemical remission (normal transaminases) and were undergoing follow-up liver biopsy to confirm histological remission as per our Unit’s clinical policy. Methods Between 1/12/13 and 31/12/15 36 same-day Fibroscan and liver biopsy were performed in 32 patients with AIH (1999 International Group criteria; 25 female, age 56 (17–78) years who had achieved biochemical remission (normal serum ALT and globulins) after 2.7 (2.1–24.9) years treatments. No patient had ascites, extrahepatic cholestasis or congestive cardiac failure based on clinical and laboratory evaluation. Fibroscan was performed in fasted patients using the Echosens machine (M or XL probe used as needed) by trained operators. We assessed how accurately the liver stiffness evaluation (LSE) score on Fibroscan could predict Ishak fibrosis stage on biopsy (assessed independently by AKD). Results The ALT was 21 (9–99), normal value Conclusion In this study, Fibroscan showed good accuracy in excluding, but lower accuracy in predicting Ishak fibrosis stage of 4 or more. Accuracy was improved if a valid scan was obtained. Fibroscan was less accurate in predicting lower fibrosis stages. A combination of methods of assessing liver fibrosis may be necessary in some patients. Disclosure of Interest None Declared

PTU-083 Long-Term Follow-Up of Patients with Autoimmune Hepatitis after Withdrawal of Immunosuppressant Therapy

Introduction If immunosuppressant therapy (IST) is withdrawn in patients with autoimmune hepatitis (AIH) when remission is achieved, 50–70% will have a disease relapse within 12 months. Thus, many patients receive long-term maintenance IST. However, IST has potential side effects, including an increased cancer risk. Recent studies suggest a lower AIH relapse rate if IST is withdrawn at a later stage in the disease. Data are lacking in regard to long-term outcome following IST withdrawal. Methods Retrospective audit of long-term outcome of AIH following withdrawal of IST. A total of 282 patients with definite or probable AIH by International AIH Group criteria, had presented to our Unit between 1971–2015 and had achieved normalisation of serum ALT within 12 months of starting IST (prednisolone plus azathioprine, or mycophenolate if azathioprine intolerant). From these, we found 25 patients in whom all IST was subsequently discontinued. We assessed outcome in these patients, in comparison to those who continued IST. Follow-up was until last serum ALT for calculating relapse rate and until death or last known to be alive for calculating survival rates. Results The 25 patients (21 female, age at diagnosis 50 (8–68) years) had been on IST before withdrawal for 3.9 (0.1–22.4) years. Five had cirrhosis at presentation. All patients had normal serum ALT and globulins at time of withdrawal except one patient with acute pancreatitis. Reasons for IS withdrawal were: cancer (6), infections (3), side effects (4), frailty (6) patient choice (6), doubt about diagnosis (subsequently resolved) (1). Relapses occurred in 7 patients (28%) after 1.6 (0.5–9.6) years. Relapse rates were 15%, 20% and 28% after 2, 5 and 10 years respectively. All patients achieved re-normalisation of serum ALT within 3 months of re-starting therapy (prednisolone 10–40 mg/day) plus (in 5 patients) azathioprine or mycophenolate, subsequently continued as maintenance therapy. Over follow up (from IST withdrawal) of 4.2 (1.2–25.1 years), no patient developed liver decompensation, variceal bleeding or hepatocellular carcinoma. Six patients died after 4 (3.3–15.9) years; none due to liver disease or following AIH relapse. Patients stopping IST (n = 25) had, compared to those who continued IST (n = 257) higher 10- and 20 year survival (99±4% and 79±9% respectively vs 78±3% and 48±4% p = 0.021). Conclusion In patients with AIH who achieve remission a trial of withdrawal of IS therapy is associated with (a) a lower disease relapse rate than previously reported, (b) no liver adverse events and (c) no reduction in long-term survival compared with patients who continue on long-term IS therapy. Disclosure of Interest None Declared

Standard Treatment in Adults: Which Steroid? Or without Steroids?

Key Messages: (1) Standard treatment of autoimmune hepatitis in adults should be steroid based. In early trials, prednisolone +/- azathioprine was superior to the azathioprine mono-therapy (which was not significantly better than placebo). Prednisolone plus azathioprine has similar efficacy to, but is better tolerated than a higher-dose of prednisolone alone and therefore has become standard therapy. (2) In most treated patients, serum transaminases and globulin/IgG fall, but percentage attaining normal values within 6 months varies between 10 and 90%. Patients failing to do so have a worse longer-term outcome. (3) A higher initial prednisolone dose (1 mg/kg/day) plus azathioprine achieved 76% serum transaminase normalisation after 6 months but needs longer-term evaluation. (4) Histological remission (minimal hepatitis on re-biopsy) lags behind transaminase normalisation by 6-12 months and is achieved in 55-70% of patients after 24-36 months prednisolone. This lag and the inefficacy of azathioprine mono-therapy justifies continuing prednisolone (5-10 mg/day), even after transaminase normalisation, for a total of >2 years. (5) Repeat biopsy should be considered because 40-60% of patients still have (usually mild) persisting inflammation, despite normal serum transaminases and IgG. In such patients, fibrosis is less likely to regress and long-term mortality is higher. (6) In a large trial, non-cirrhotic treatment-naïve patients given budesonide (9 mg/day) plus azathioprine were more likely to achieve normal serum ALT after 6 months than those receiving prednisolone plus azathioprine and had less side effects. This trial was short term in nature and lacked follow-up histology. Budesonide is recommended in non-cirrhotic patients who develop prednisolone-related side effects. In an open study of mycophenolate plus prednisolone, 88% of treatment-naïve patients achieved normal serum transaminases. However, half relapsed during or after steroid withdrawal and only one of eight re-biopsied patients achieved histological remission. Mycophenolate is teratogenic, limiting its use in younger women. Conclusion: Despite its limitations, no regime has yet been shown clearly to be better than prednisolone and azathioprine-based therapy.

PWE-122 Autoimmune hepatitis (aih): assessment of usefulness of diagnosic liver biopsy and of “simplified” diagnostic scoring system

Introduction Although recommended in published guidelines, only 62% of UK Gastroenterologists routinely recommend diagnostic liver biopsy in patients with suspected AIH (Dhaliwal Gut 2012:62). Also, the relative usefulness of the International AIH Group diagnostic criteria (full 1999 or simplified 2008) is not established. Our aim was to assess the relationships between histological and immunological diagnostic features and response to treatment in patients meeting the 1999 IAIHG criteria, which we also assessed against the 2008 simplified criteria. Method 90 patients were identified; 79% women, with median age 61 yrs (14–85) presenting since 2006 with suspected AIH and underwent diagnostic liver biopsy. Histology was assessed using the Ishak system by one liver Histopathologist (AKD) without reference to other results. Results Interface hepatitis was found in 87(97%) of biopsies, mainly plasma cell infiltrate in 74(83%), rosettes in 68(76%) and emperipolesis in 100% (of 48 patients assessed). Biliary changes were seen in 14% and mild steatosis in 24%. Prior to biopsy, patients had 13(7–19) diagnostic points by IAIHG criteria, with 11 of the 90 patients not having the required 10 points. Biopsy contributed an additional 5(0–6) points and all patients then met the 1999 IAIHG criteria (61 definite, 29 probable) with 17(12–22) points. In 49 patients, with a pre biopsy score of >13, biopsy contributed 4(0–5) points and was not needed for diagnosis of AIH but detected biliary changes in 10 patients (3 AMA -ve,1 weak +ve subsequently diagnosed as PBC and started on treatment, 2 PSC overlap and 4 not overlap) and also detected cirrhosis in 9. Histological features did not differ between: patients with (n = 68) and without (n = 22) serum autoantibodies (nuclear, smooth muscle or LKM-1); between those with (n = 72) and without (n = 10) raised serum IgG; or between treated patients who did (n = 75) and did not (n = 8) achieve normal serum ALT within 6 months. Eighteen patients (20%) did not meet the 2008 simplified diagnostic criteria for AIH (6 points). In these, necro-inflammatory score was 9(2–15), fibrosis score was 3(0–5) and 13 of 14 treated patients achieved normal serum ALT by 6 months. Conclusion Liver biopsy is important for diagnosis of AIH in those with lower, but less so in those with higher pre-biopsy IAIHG (1999) diagnostic scores. It may also detect cirrhosis or indicate additional unsuspected biliary disease. Histological features are not associated with immunological features or response to treatment. The 2008 simplified diagnostic criteria will “miss” 20% of patients with AIH by 1999 criteria. Most of these patients have significant disease and respond to treatment. Disclosure of interest None Declared.

Kushenin Combined with Nucleos(t)ide Analogues for Chronic Hepatitis B: A Systematic Review and Meta-Analysis.

Objective. To evaluate the efficacy and safety of Kushenin (KS) combined with nucleoside analogues (NAs) for chronic hepatitis B (CHB). Methods. Randomized controlled trials (RCTs) of KS combined with NAs for CHB were identified through 7 databases. Frequencies of loss of serum HBeAg, HBeAg seroconversion, undetectable serum HBV-DNA, ALT normalization, and adverse events at 48 weeks were abstracted by two reviewers. The Cochrane software was performed to assess the risk of bias in the included trials. Data were analyzed with Review Manager 5.3 software. Results. 18 RCTs involving 1684 subjects with CHB were included in the analysis. KS combined with NAs including lamivudine (LAM), entecavir (ETV), adefovir dipivoxil (ADV), and telbivudine (TLV) showed different degree of improvement in CHB indices. KS combined with NAs increased the frequency of loss of serum HBeAg, HBeAg seroconversion, undetectable HBV-DNA levels, and ALT normalization compared with single agents. It also decreased serum ALT and AST level after one-year treatment. However, KS combined with TLV did not show a significant difference in CHB indices. The side-effects of KS combined with NAs were light and of low frequency. Conclusion. KS combined with NAs improves the efficacy of NAs in CHB.

TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess

Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation using mice with the genetic deletion of TR. TR knockout (TR(-/-)) mice and their littermate wild-type (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow. Metabolic phenotyping, liver injury, and liver and adipose tissue inflammation were assessed. Chemotaxis and activation of mouse bone marrow-derived macrophages (BMDMϕ) was measured. Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR(-/-) mice suppressed steatohepatitis, with essentially normal serum ALT, hepatocyte apoptosis and liver triglyceride accumulation. Gene array data implicated inhibition of macrophage-associated hepatic inflammation in the absence of the TR. In keeping with this, there was diminished accumulation and activation of inflammatory macrophages in liver and adipose tissue. TR(-/-) BMDMϕ manifest reduced chemotaxis and diminished activation of nuclear factor-κ B signaling upon activation by palmitate and lipopolysaccharide. These data advance the concept that macrophage-associated hepatic and adipose tissue inflammation of nutrient excess requires TR signaling.

Entecavir plus adefovir combination therapy versus lamivudine add-on adefovir for lamivudine-resistant chronic hepatitis B: A meta-analysis.

To determine whether adefovir (ADV) in combination with entecavir (ETV) is more effective than with lamivudine (LAM) in patients with lamivudine-resistant chronic HBV infection, electronic databases were searched through May 10th, 2013 to obtain relevant trials which met the inclusion criteria. Meta-analysis was performed on randomized controlled trials (RCTs) and non-randomized studies. Four trials containing a total of 323 patients were included. Serum HBV DNA reductions after 3 and 6 months of treatment in the ETV + ADV group were greater than that of LAM + ADV group (mean difference (MD) = 0.90, 95% confidence interval (CI): 0.74-1.07, P < 0.00001; MD = 0.81, 95% CI: 0.57-1.06, P < 0.00001). The rate of 6 months HBV DNA undetectability with ETV and ADV was higher than that of LAM and ADV (relative risk (RR) = 1.63, 95% CI: 1.14-2.34, P < 0.007). There were higher rates of serum ALT normalization than those in LAM + ADV group after 6 months of treatment (RR = 1.40, 95% CI: 1.11-1.77, P < 0.005). The ETV + ADV group had lower viral breakthrough and genotypic mutation rates than LAM + ADV group after 12 months of treatment (RR = 0.24, 95% CI: 0.10-0.58, P = 0.002). The combination of ETV plus ADV is a more effective rescue therapy than LAM add-on ADV in patients with LAM-resistant HBV.

P160 Prevalence of IBD among celiacs in our celiac centre

years 1995 and 2011. Each patient was questioned by clinical, labarotory and imaging examinations and finally pathology records for the existence of PSC and any hepatopancreatobiliary tumor and NET. Results: 59 UC patients with IPAA had full records for further evaluations. All of the patients, except one, had normal serum ast, alt, alp, and ggt levels and abdominal ultrasound examination before the operation. We found 4 patients with PSC. Only one was diagnosed before the operation (44 years old). The rest, 3 patients, were diagnosed after the IPAA operation. Interestingly, approximately 12 months later, these patients developed either liver enzyme abnormalities or pruritis and further examination showed PSC. In one (31 years-old, female), mrcp was normal at the beginning, psc was then diagnosed by liver biopsy. 24 months following the IPAA, MRCP and ERCP showed dominant stricture, no cholangiocancer during the follow-up. The other one (35 years old) developed serum alp/ggt abnormalities, then MRCP showed PSC. The last case had UC complicated with rectum cancer, operated and 1 year later (53 years old) developed enzyme abnormalities and psc with dominant stricture diagnosed by both MRCP and ERCP. Only 2 pateints were dead due to complications of IPAA operation during the follow-up. We also evaluated whether hepatopancreatobiliary cancers and NET was increased in this study. Nobody developed HCC, cholangio or gallblader and pancreas cancer or NET. In addition to the case above mentioned, we found 3 patients with colon cancer on the pathologic examination. According to the our IBD registration, of the 2200 patients with IBD in our IBD center, 41 patients (1.6%) had PSC and DS was diagnosed in 34%. Conclusions: Our results showed that the prevalence of PSC was increased by the existence of proctocolectomy-IPAA procedure in patients with UC, in a short period like 12 months. Of the 3 patients developed PSC after the operation, 2 had dominant stricture that was developed in a short period like 24 months. This experience suggests that proctocolectomyIPAA procedure can be formed in UC patients after the careful monitoring for the hepatobiliary conditions, even by liver biopsy in risky patients.

Clinical significance of serum hepatocyte growth factor (HGF) levels in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. This study was conducted to investigate the serum levels of hepatocyte growth factor (HGF)in HCC patients and the relationship with tumor progression and known prognostic parameters. Fifty-four patients with HCC were investigated. Pretreatment HGF levels were employed the quantitative sandwich enzyme immunoassay technique (ELISA). Age and sex matched 20 healthy controls were included in the analysis. The median age of the patients was 60 years (range 36-77 years); where males consistituted of majority of the group (88.8%). All of patients had cirrhotic history. Fourty-six percent (n = 25) of patients had Child-Pugh Score A, 30% (n = 16) had Score B or C. All of the patients were treated with local therapies but none of them received sorafenib. The baseline serum HGF levels were significantly higher in patients with HCC than in the control group (p < 0.001). Male patients had higher serum HGF levels compared with female patients (p = 0.01). Serum HGF levels were significantly higher in the patients with elevated serum ALT levels than others with normal serum ALT levels (p = 0.05). Poor performance status (p < 0.001), viral etiology of cirrhosis (p = 0.03), larger tumor size (p = 0.01), lower serum hemogloblin levels (p = 0.03), and not be treated for HCC (p = 0.001) related to worse survival. However, serum HGF did not have significantly adverse effect on survival (p = 0.58). Despite serum HGF levels were found diagnostic value, serum HGF levels had no prognostic value in patients with HCC.