G E Dolman

Immune Tolerant Chronic Hepatitis B: The Unrecognized Risks

Chronic infection with hepatitis B virus (HBV) progresses through multiple phases, including immune tolerant, immune active, immune control, and, in a subset of patients who achieve immune control, reactivation. The first, the immune tolerant phase, is considered to be prolonged in duration but essentially benign in nature, lacking long-term consequences, and thus not recommended for antiviral therapy. This review challenges the notion that the immune tolerant phase is truly benign and considers the possibility that events during this phase may contribute significantly to cirrhosis, hepatocellular carcinoma (HCC), and the premature death of 25% of HBV carriers worldwide. Thus, earlier treatment than recommended by current guidelines should be considered. Low therapeutic coverage exacerbated by restrictive treatment guidelines may facilitate disease progression in many patients but also increase the risk of neonatal and horizontal transmission from untreated mothers to their children. While a prophylactic vaccine exists, there are many areas worldwide where the treatment of adults and the delivery of an effective vaccination course to newborns present difficult challenges.

Statistical colour models: an automated digital image analysis method for quantification of histological biomarkers

BackgroundColour is the most important feature used in quantitative immunohistochemistry (IHC) image analysis; IHC is used to provide information relating to aetiology and to confirm malignancy.MethodsStatistical modelling is a technique widely used for colour detection in computer vision. We have developed a statistical model of colour detection applicable to detection of stain colour in digital IHC images. Model was first trained by massive colour pixels collected semi-automatically. To speed up the training and detection processes, we removed luminance channel, Y channel of YCbCr colour space and chose 128 histogram bins which is the optimal number. A maximum likelihood classifier is used to classify pixels in digital slides into positively or negatively stained pixels automatically. The model-based tool was developed within ImageJ to quantify targets identified using IHC and histochemistry.ResultsThe purpose of evaluation was to compare the computer model with human evaluation. Several large datasets were prepared and obtained from human oesophageal cancer, colon cancer and liver cirrhosis with different colour stains. Experimental results have demonstrated the model-based tool achieves more accurate results than colour deconvolution and CMYK model in the detection of brown colour, and is comparable to colour deconvolution in the detection of pink colour. We have also demostrated the proposed model has little inter-dataset variations.ConclusionsA robust and effective statistical model is introduced in this paper. The model-based interactive tool in ImageJ, which can create a visual representation of the statistical model and detect a specified colour automatically, is easy to use and available freely at http://rsb.info.nih.gov/ij/plugins/ihc-toolbox/index.html. Testing to the tool by different users showed only minor inter-observer variations in results.

Should the Pap smear be repeated at the first colposcopy visit

Aim:  To determine whether there is any benefit in repeating the Pap smear at the time of colposcopy in women referred to a teaching hospital dysplasia clinic.

Evaluation of area-based collagen scoring by nonlinear microscopy in chronic hepatitis C-induced liver fibrosis.

In this paper we analyze a fibrosis scoring method based on measurement of the fibrillar collagen area from second harmonic generation (SHG) microscopy images of unstained histological slices from human liver biopsies. The study is conducted on a cohort of one hundred chronic hepatitis C patients with intermediate to strong Metavir and Ishak stages of liver fibrosis. We highlight a key parameter of our scoring method to discriminate between high and low fibrosis stages. Moreover, according to the intensity histograms of the SHG images and simple mathematical arguments, we show that our area-based method is equivalent to an intensity-based method, despite saturation of the images. Finally we propose an improvement of our scoring method using very simple image processing tools.

SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis

Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis.

The performance of transient elastography compared to clinical acumen and routine tests – what is the incremental diagnostic value?

There is substantial evidence suggesting transient elastography (TE) is a useful tool in assessing liver fibrosis. We aimed to determine whether TE has incremental diagnostic value over clinical acumen and routinely available tests.

PTH-081 Enhanced Liver Fibrosis (elf) Test Performs Better Than Histological Parameters In Predicting Clinical Outcomes In Patients With Advanced Fibrosis Due To Chronic Hepatitis C Infection

Introduction Fibrosis progression in chronic hepatitis C infection is variable. We need tools to identify those patients who will progress rapidly to offer individualised patient management. We aimed to determine the predictors of progression in an unselected cohort of patients with advanced fibrosis. Methods The study cohort was derived from one centre of the Trent Study of Patients with Hepatitis C Virus Infection, a prospective natural history study commenced in 1991. Inclusion criteria were: a) liver biopsy before 2011 demonstrating advanced fibrosis (Ishak stage ≥3); b) no clinical outcome prior to biopsy; and c) patient did not achieve sustained viral response during follow-up. Sera collected within 6 months of the index biopsy were analysed for ELF. Biopsies were restaged using the Ishak system by one pathologist. Collagen quantification with image analysis was performed on biopsies stained with picrosirius red. A clinical outcome was defined as the first event of: ascites, encephalopathy, variceal haemorrhage, hepatocellular carcinoma, transplant or liver-related death. Abstract PTH-081 Figure 1 Results 136 patients were identified and 87 had sera available for ELF. 29 (33.3%) patients progressed to a clinical outcome (median follow-up 7.2 years). ELF was significantly associated with progression to clinical outcomes in univariate analysis (HR 2.07 [95% CI: 1.54–2.76]; p < 0.001). In a multivariate model including liver function tests, Ishak stage and collagen quantification, only ALP and ELF remained statistically significant (ALP: HR 1.004 [95% CI: 1.001–1.007; p = 0.016], ELF: HR 1.968 [95% CI: 1.454–2.663; p < 0.001]. Conclusion Our data suggest that ELF could be used to stratify risk of subsequent progression to clinical outcomes in advanced fibrosis secondary to hepatitis C infection. Disclosure of Interest None Declared.

Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease

The aim of this study was to determine if elastin content in needle core native liver biopsies was predictive of clinical outcome in patients with chronic hepatitis C virus‐related chronic liver disease.

PTU-006 Gastroenterology Trainees Express An Interest To Learn To Perform Ultrasound-assisted Liver Biopsies: Results Of A National Survey (uk)

Introduction Liver biopsy for the assessment of parenchymal liver disease is increasingly performed under direct ultrasound guidance by radiologists. As such, it is no longer a mandatory requirement for hepatology trainees in the UK to achieve competence in this procedure. Methods We aimed to determine whether trainees are receiving training to perform ultrasound-assisted liver biopsies; and whether they would be interested in doing so if not. Trainees anonymously responded to a 10 question, web based survey using a combination of pre-defined answers in drop down boxes and free text answers. Results Surveys were sent to approximately 800 trainees. 226 surveys were returned. Respondents represented all training grades (ST3-ST7). 75 respondents (33%) intend to pursue subspecialty accreditation in hepatology. 103 respondents (46%) have completed a period of training in a tertiary/transplant centre. 105 respondents (47%) have worked in a centre where physicians perform liver biopsies. 52 (23%) have been offered the opportunity to learn how to perform ultrasound assisted liver biopsy and 38 (17%) have been assessed and deemed competent in the procedure. Three respondents commented that they are trained in unguided liver biopsy; one trainee has used the Sonosite probe and one commented that he/she has performed liver biopsy after an appropriate site was marked by the radiologist 137 (61%) of trainees who responded to the survey would be interested in learning how to perform this procedure and a further 29 (13%) may be interested. 138 (61%) of respondents would be interested in attending a hands-on course to learn this procedure and 30 (13%) may be interested. Of the 75 respondents who intend to pursue subspecialty hepatology accreditation, 72 said they would be interested in learning how to perform ultrasound assisted liver biopsy. Trainees who participated in this survey reported that opportunities to learn this procedure were currently hit and miss. There were concerns about the practicality of maintaining competence during training and as a consultant and some respondents felt that it was safer for the procedure to be performed by radiologists. We cannot report the views of trainees who did not complete the survey and therefore our results may not be representative. However even if we make the assumption that all non-responders are not interested in learning this procedure, there is still an estimated 15–20% of trainees that would be interested (137/~ 800). Conclusion Trainees participating in this survey are interested in learning to perform ultrasound-assisted liver biopsies, but the infrastructure to offer this training is not currently well established. Discussion between trainees and training bodies should be considered to explore this issue further. Disclosure of Interest None Declared.

To feed or what to feed in cirrhosis

We congratulate Berzigotti et al. for performing an excellent study that raises more questions, just as many post hoc analyses of observational studies do. It is intriguing that obesity may predict future decompensation in patients with compensated cirrhosis and portal hypertension. The potential mechanism is unexplained. The presence of a proinflammatory and proangiogenic state driven by extrahepatic adipose tissue may accelerate existing liver disease. Furthermore, hemodynamic changes linked to metabolic syndrome may affect the development of portal hypertension. Age is another well-recognized determinant of outcomes for patients with liver disease. Obesity and smoking have been shown to accelerate the biological aging process. Therefore, it would be interesting to determine whether smoking was also associated with accelerated decompensation in this cohort. Finally, the presence of a dual hepatic pathology must be considered as an explanation for the reported association. Hence, a review of biopsy findings for cirrhosis and earlier stages of fibrosis (where available) could further clarify the current findings. The translation of the findings of this study into an effective intervention could be challenging. The prognosis of patients with cirrhosis is influenced by different macronutrient intake patterns and is worsened by protein-energy malnutrition. In addition, weight-loss targets have been difficult to achieve in the setting of nonalcoholic fatty liver disease without cirrhosis, even with motivated patients and intensive community support. In comparison with calorie-matched daytime supplementation, nocturnal nutritional supplements improve total body protein, and this suggests that prolonged fasting is probably detrimental for patients with cirrhosis. Very low-calorie diets and carbohydrate restriction may pose risks to patients with cirrhosis by inducing hepatic stressors (i.e., an increased demand for endogenous gluconeogenesis and an increased requirement for catabolizing ketone bodies). We have limited data about a cirrhotic liver’s ability to cope with such insults. Increased exercise is ordinarily an attractive weight-loss strategy, but impaired endogenous gluconeogenesis in patients with cirrhosis results in the potential risk of exercise-induced hypoglycemia during aerobic exercise. Therefore, caution needs to be applied when weight loss is being recommended as an intervention for these patients. We reinforce the authors’ comment that dedicated studies on the effects of obesity and weight loss on the prognosis of patients with compensated cirrhosis are needed. These studies should be performed in parallel with studies evaluating the methods, safety, and efficacy of lifestyle interventions.