Grand round: anticoagulation in chronic liver disease

In this Grand Round, we first present a case of a man with decompensated liver disease who subsequently developed a fatal pulmonary embolism, having not been prescribed prophylactic anticoagulation to prevent venous thromboembolic disease. We go on to discuss the burden of thrombotic disease in those with chronic liver disease, before a more detailed discussion regarding the current evidence, safety data, and clinical dilemmas regarding the use of anticoagulation in patients with chronic liver disease, as well as discussing potential future directions within this field

Antinuclear antibodies (ANA) in chronic hepatitis C virus infection: correlates of positivity and clinical relevance.

We examined correlates of antinuclear antibody (ANA) positivity (ANA+) in individuals with chronic hepatitis C virus (HCV) infection and the effect of positivity on clinical outcome of HCV. Pretreatment sera from 645 patients from three centres in Sweden (n = 225), the UK (n = 207) and Italy (n = 213) were evaluated by indirect immunofluorescence on Hep-2 cells for ANA pattern and titre by a single laboratory. Liver biopsies were all scored by one pathologist. A total of 258 patients were subsequently treated with interferon monotherapy. There was a significant difference in the prevalence of ANA (1:40) by geographic location: Lund 4.4%, London 8.7%, Padova 10.3% [odds ratio (OR) = 0.66; 95% CI: 0.46-0.94; P = 0.023]. Duration of HCV infection, age at infection, current age, route of infection, viral genotype, alcohol consumption, fibrosis stage and inflammatory score were not correlated with ANA+ or ANA pattern. Female gender was correlated with ANA+ and this association persisted in multivariable analyses (OR = 3.0; P = 0.002). Increased plasma cells were observed in the liver biopsies of ANA-positive individuals compared with ANA-negative individuals, while a trend towards decreased lymphoid aggregates was observed [hazard ratio (HR) = 9.0, P = 0.037; HR = 0.291, P = 0.118, respectively]. No correlations were observed between ANA positivity and nonresponse to therapy (OR = 1.4; P = 0.513), although ANA+ was correlated with faster rates of liver fibrosis, this was not statistically significant (OR = 1.8; P = 0.1452). Low titre ANA+ should not be a contraindication for interferon treatment. Our observation of increased plasma cells in ANA+ biopsies might suggest B-cell polyclonal activity with a secondary clinical manifestation of increased serum immunoglobulins

Hepatitis B testing and treatment in HIV patients in The Gambia - compliance with international guidelines and clinical outcomes

Background Compliance with WHO guidelines on HBV screening and treatment in HIV-coinfected patients is often challenging in resource limited countries and has been poorly assessed in sub-Saharan Africa. Methods Between 2015 and 2016, we assessed physician’s compliance with WHO guidelines on HIV-HBV coinfection in the largest HIV clinic in The Gambia, and the hepatic outcomes in HIV-HBV coinfected patients as compared to randomly selected HIV-monoinfected controls. Results 870 HIV-infected patients regularly seen in this clinic agreed to participate in our study. Only 187 (21.5%, 95% CI 18.8–24.3) had previously been screened for HBsAg, 23 (12.3%, 95% CI 8.0–17.9) were positive of whom none had liver assessment and only 6 (26.1%) had received Tenofovir. Our HBV testing intervention was accepted by all participants and found 94/870 (10.8%, 95% CI 8.8–13.1) positive, 78 of whom underwent full liver assessment along with 40 HBsAg-negative controls. At the time of liver assessment, 61/78 (78.2%) HIV-HBV coinfected patients received ART with 7 (11.5%) on Tenofovir and 54 (88.5%) on Lamivudine alone. HIV-HBV coinfected patients had higher APRI score compared to controls (0.58 vs 0.42, p = 0.002). HBV DNA was detectable in 52/53 (98.1%) coinfected patients with 14/53 (26.4%) having HBV DNA >20,000 IU/L. 10/12 (83.3%) had at least one detectable 3TC-associated HBV resistance, which tended to be associated with increase in liver fibrosis after adjusting for age and sex (p = 0.05). Conclusions Compliance with HBV testing and treatment guidelines is poor in this Gambian HIV programme putting coinfected patients at risk of liver complications. However, the excellent uptake of HBV screening and linkage to care in our study suggests feasible improvements

Impact and cost-effectiveness of hepatitis B virus prophylaxis in pregnancy: a dynamic simulation modelling study

BACKGROUND: In 2020, WHO recommended the addition of peripartum antiviral prophylaxis (PAP) to hepatitis B birth dose vaccination (HepB-BD) and hepatitis B infant vaccination (HepB3) to reduce mother-to-child transmission of hepatitis B virus (HBV) infection in pregnant women who have a marker of high infectivity (ie, HBV DNA ≥200 000 international units per mL or HBeAg-positive). We aimed to evaluate the impact and cost-effectiveness of this recommendation and of a theoretical simplified strategy whereby PAP is given to all pregnant women who are HBsAg-positive without risk stratification. METHODS: This modelling study used a dynamic simulation model of the HBV epidemic in 110 countries in all WHO regions, structured by age, sex, and country. We assessed three strategies of scaling up PAP for pregnant women: PAP for those with high viral load (PAP-VL); PAP for those who are HBeAg-positive (PAP-HBeAg); and PAP for all pregnant women who are HBsAg-positive (PAP-universal), in comparison with neonatal vaccination alone (HepB-BD). We investigated how different diagnostic and antiviral drug costs affected the cost-effectiveness of the strategies evaluated. Using a health-care provider perspective, we calculated incremental cost-effectiveness ratios in cost (US$) per disability-adjusted life-year (DALY) averted in each country's population and compared these with country-specific cost-effectiveness thresholds. We also calculated new neonatal infections averted for each of the strategies. FINDINGS: Adding PAP-VL to HepB-BD could avert around 1·1 million (95% uncertainty interval 1·0 million-1·2 million) new neonatal infections by 2030 and around 3·2 million (95% uncertainty interval 3·0 million-3·4 million) new neonatal infections and approximately 8·8 million (7·8 million-9·7 million) DALYs by 2100 across all the countries modelled. This strategy would probably be cost-effective up to 2100 in 28 (26%) of 106 countries analysed (which included some of the countries that have the greatest HBV burden) if costs are as currently expected to be, and in 74 (70%) countries if diagnostic and monitoring costs were lowered (by about 60-75%). The relative cost-effectiveness of PAP-VL and PAP-HBeAg was finely balanced and depended on the respective diagnostic and monitoring costs. The PAP-universal strategy could be more cost-effective than either of these strategies in most countries, but the use of antiviral treatment could be five times as high than with PAP-VL. INTERPRETATION: PAP can provide substantial health benefits, and, although the current approach might already be cost-effective in some high-burden settings, decreased diagnostic costs would probably be needed for PAP to be cost-effective in most countries. Therefore, careful consideration needs to be given about how such a strategy is implemented, and securing reduced costs for diagnostics should be a priority. The theoretical strategy of offering PAP to all women who are HBsAg-positive (eg, if diagnostic tests to identify mothers at risk of transmission are not available) could be a cost-effective alternative, depending on prevailing costs of diagnostics and antiviral therapy. FUNDING: UK Medical Research Council, UK National Institute for Health and Care Research, and the Vaccine Impact Modelling Consortium

CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.

OBJECTIVE: Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. DESIGN: Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. RESULTS: Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. CONCLUSION: Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent

The clinical role of circulating free tumor DNA in gastrointestinal malignancy

Circulating cell-free DNA (cfDNA) is DNA released from necrotic or apoptotic cells into the bloodstream. While both healthy cells and cancer cells release cfDNA, tumors are associated with higher levels of tumor-derived circulating cell-free DNA (ctDNA) detectable in blood. Absolute levels of ctDNA and its genetic mutations and epigenetic changes show promise as potentially useful biomarkers of tumor biology, progression, and response to therapy. Moreover, studies have demonstrated the discriminative accuracy of ctDNA levels for diagnosis of gastrointestinal cancer compared with benign inflammatory diseases. Therefore, ctDNA detected in blood offers a minimally invasive and easily repeated “liquid biopsy” of cancer, facilitating real-time dynamic analysis of tumor behavior that could revolutionize both clinical and research practices in oncology. In this review, we provide a critical summary of the evidence for the utility of ctDNA as a diagnostic and prognostic biomarker in gastrointestinal malignancies

Global metabolic changes induced by plant-derived pyrrolizidine alkaloids following a human poisoning outbreak and in a mouse model

Several hundred cases of Hirmi Valley Liver Disease (HVLD), an often fatal liver injury, occurred from 2001 to 2011 in a cluster of rural villages in Tigray, Ethiopia. HVLD is principally caused by contamination of the food supply with plant derived pyrrolizidine alkaloids (PAs), with high exposure to the pesticide DDT among villagers increasing their susceptibility. In an untargeted global approach we aimed to identify metabolic changes induced by PA exposure through 1H NMR spectroscopic based metabolic profiling. We analysed spectra acquired from urine collected from HVLD cases and controls and a murine model of PA exposure and PA/DDT co-exposure, using multivariate partial least squares discriminant analysis. In the human models we identified changes in urinary concentrations of tyrosine, pyruvate, bile acids, N-acetylglycoproteins, N-methylnicotinamide and formate, hippurate, p-cresol sulphate, p-hydroxybenzoate and 3-(3-hydroxyphenyl) propionic acid. Tyrosine and p-cresol sulphate were associated with both exposure and disease. Similar changes to tyrosine, one-carbon intermediates and microbial associated metabolites were observed in the mouse model, with tyrosine correlated with the extent of liver damage. These results provide mechanistic insight and implicate the gut microflora in the human response to challenge with toxins. Pathways identified here may be useful in translational research and as “exposome” signals