Tenofovir Disoproxil Fumarate Reduces the Severity of COVID-19 in Patients with Chronic Hepatitis B.

BACKGROUND AND AIMS: HIV-positive patients on tenofovir hydroxyl fumarate (TDF)/emtricitabine have a lower risk of COVID-19 and hospitalization than those given other treatments. Our aim was to analyze the severity of COVID-19 in patients with chronic hepatitis B (CHB) on TDF or entecavir (ETV). METHODS: Spanish hospital databases (n = 28) including information regarding adult CHB patients on TDF or ETV for the period February 1st to November 30th 2020 were searched for COVID-19, defined as a positive SARS-CoV-2 polymerase chain reaction, and for severe COVID-19. RESULTS: Of 4736 patients, 117 had COVID-19 (2.5%), 67 on TDF and 50 on ETV. Compared to patients on TDF, those on ETV showed (p < 0.05) greater rates of obesity, diabetes, ischemic cardiopathy, and hypertension. COVID-19 incidence was similar in both groups (2.3 vs. 2.6%). Compared to TDF, patients on ETV more often (p < 0.01) had severe COVID-19 (36 vs. 6%), required intensive care unit (ICU) (10% vs. 0) or ventilatory support (20 vs. 3%), were hospitalized for longer (10.8 ± 19 vs. 3.1 ± 7 days) or died (10 vs. 1.5%, p = 0.08). In an IPTW propensity score analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage, TDF was associated with a sixfold reduction in severe COVID-19 risk (adjusted-IPTW-OR 0.17, 95%CI 0.04-0.67, p = 0.01). CONCLUSION: Compared to ETV, TDF seems to play a protective role in CHB patients with SARS-CoV-2 whereby the risk of severe COVID-19 is lowered.

Implementation and impact of an antibiotic control program and multidrug-resistant bacterial colonization in a liver transplant unit.

INTRODUCTION: infections by multidrug-resistant bacteria are a major cause of morbidity and mortality in transplant patients. OBJECTIVE: a retrospective single-center study was performed to evaluate the implementation of an Antimicrobial Treatment Optimization Program (PROA) on multidrug-resistant bacteria colonization and infection after liver transplant (LT). METHODS: colonization by multidrug-resistant bacteria and infections during the first year after a liver transplant were analyzed in a group of 76 transplanted patients in two stages, before and after PROA (2016-2019). Clinical variables related to infection, readmissions and survival one year after the liver transplant were analyzed. RESULTS: there was good adherence to the PROA. Infection was the most frequent cause for readmission during the first year after the liver transplant. Incidence of infections was similar during both periods (mean of 1.25 and 1.5 episodes of bacterial infection per patient/year, respectively) with 19 bacterial infectious episodes, six by hospital-acquired multidrug-resistant and extensively drug-resistant (MDR-XDR) bacteria in the pre-PROA stage, and 18 bacterial infectious episodes, five by MDR-XDR in the post-PROA stage. A 37 % decrease of post-TH of rectal colonization by MDR-XDR after liver transplant was observed during 2019. CONCLUSIONS: epidemiological surveillance policies and antibiotic optimization are key to control the increase of colonization and infection by multidrug-resistant bacteria in liver transplant units. Long-term studies are needed to better evaluate the impact of these programs.

Implantación e impacto de un programa de control antibiótico y colonización por bacterias multirresistentes en una unidad de trasplante hepático / Implementation and impact of an antibiotic control program and multidrug-resistant bacterial colonization in a liver transplant unit

Introducción: las infecciones por bacterias multirresistentes constituyen una importante causa de morbimortalidad pre coz en los pacientes trasplantados.Propósito: se presenta un estudio unicéntrico, retrospectivo, con objetivo de evaluar la implantación de un programa de optimización del uso de antibióticos y de control epidemio lógico (PROA) en la colonización e infección por bacterias multirresistentes tras el trasplante hepático (TH).Métodos: se analizaron la colonización por bacterias multi rresistentes y las infecciones en el primer año postrasplante hepático (post-TH) en un grupo de 76 pacientes trasplanta dos en dos etapas, anterior y posterior al PROA, entre los años 2016 y 2019. Se analizaron variables clínicas relacio nadas con infección, reingresos y supervivencia a un año.Resultados: se produjo una buena adherencia al PROA. Las infecciones en el primer año post-TH fueron la causa más fre cuente de reingreso. La incidencia de infecciones fue similar en ambos periodos, con una media de 1,25 y 1,5 episodios de infección bacteriana por paciente/año con 19 episodios infecciosos bacterianos, seis por bacterias multirresistentes y de resistencia extendida (MDR-XDR) en la etapa pre-PROA y 18 episodios infecciosos bacterianos, cinco por MDR-XDR. en la etapa posterior. Se objetivó un descenso del 37 % post TH de colonización rectal por MDR-XDR durante el año 2019.Conclusión: las políticas de vigilancia epidemiológica y optimización de antibióticos son necesarias como estrategia de control del incremento de colonización e infección por bac terias multirresistentes en unidades de trasplante hepático. Son necesarios estudios a largo plazo para evaluar mejor el impacto de estos programas (AU)

Early predictors of corticosteroid response in acute severe autoimmune hepatitis: a nationwide multicenter study.

BACKGROUND AND AIMS: To assess whether corticosteroids improve prognosis in patients with AS-AIH, and to identify factors at therapy initiation and during therapy predictive of the response to corticosteroids. METHODS: This was a retrospective cohort study including all patients with AS-AIH admitted to 13 tertiary centres from January 2002 to January 2019. The composite primary outcome was death or liver transplantation within 90 days of admission. Kaplan-Meier and Cox regression methods were used for data analysis. RESULTS: Of 242 consecutive patients enrolled (mean age [SD] 49.7 [16.8] years), 203 received corticosteroids. Overall 90-day transplant-free survival was 61.6% (95% confidence interval [CI] 55.4-67.7). Corticosteroids reduced the risk of a poor outcome (adjusted hazard ratio [HR] 0.25; 95% CI 0.2-0.4), but this treatment failed in 30.5%. An internally validated nomogram composed of older age, MELD, encephalopathy and ascites at the initiation of corticosteroids accurately predicted the response (C-index 0.82; [95% CI 0.8-0.9]). In responders, MELD significantly improved from days 3 to 14 but remained unchanged in non-responders. MELD on day 7 with a cut-off of 25 (sensitivity 62.5%[95% CI: 47.0-75.8]; specificity 95.2% [95% CI: 89.9-97.8]) was the best univariate predictor of the response. Prolonging corticosteroids did not increase the overall infection risk (adjusted HR 0.75; 95% CI 0.3-2.1). CONCLUSION: Older patients with high MELD, encephalopathy or ascites at steroid therapy initiation and during treatment are unlikely to show a favourable response and so prolonged therapy in these patients, especially if they are transplantation candidates, should be avoided.

Noninvasive Prediction of Outcomes in Autoimmune Hepatitis-Related Cirrhosis.

The value of noninvasive tools in the diagnosis of autoimmune hepatitis (AIH)-related cirrhosis and the prediction of clinical outcomes is largely unknown. We sought to evaluate (1) the utility of liver stiffness measurement (LSM) in the diagnosis of cirrhosis and (2) the performance of the Sixth Baveno Consensus on Portal Hypertension (Baveno VI), expanded Baveno VI, and the ANTICIPATE models in predicting the absence of varices needing treatment (VNT). A multicenter cohort of 132 patients with AIH-related cirrhosis was retrospectively analyzed. LSM and endoscopies performed at the time of cirrhosis diagnosis were recorded. Most of the patients were female (66%), with a median age of 54 years. Only 33%-49% of patients had a LSM above the cutoff points described for the diagnosis of AIH-related cirrhosis (12.5, 14, and 16 kPa). Patients with portal hypertension (PHT) had significantly higher LSM than those without PHT (15.7 vs. 11.7 kPa; P = 0.001), but 39%-52% of patients with PHT still had LSM below these limits. The time since AIH diagnosis negatively correlated with LSM, with longer time being significantly associated with a lower proportion of patients with LSM above these cutoffs. VNT was present in 12 endoscopies. The use of the Baveno VI, expanded Baveno VI criteria, and the ANTICIPATE model would have saved 46%-63% of endoscopies, but the latter underpredicted the risk of VNT. Conclusions: LSM cutoff points do not have a good discriminative capacity for the diagnosis of AIH-related cirrhosis, especially long-term after treatment initiation. Noninvasive tools are helpful to triage patients for endoscopy.

Decreased Long-Term Severe Acute Respiratory Syndrome Coronavirus 2-Specific Humoral Immunity in Liver Transplantation Recipients 12 Months After Coronavirus Disease 2019.

Long-term humoral immunity and its protective role in liver transplantation (LT) patients have not been elucidated. We performed a prospective multicenter study to assess the persistence of immunoglobulin G (IgG) antibodies in LT recipients 12 months after coronavirus disease 2019 (COVID-19). A total of 65 LT recipients were matched with 65 nontransplanted patients by a propensity score including variables with recognized impact on COVID-19. LT recipients showed a lower prevalence of anti-nucleocapsid (27.7% versus 49.2%; P = 0.02) and anti-spike IgG antibodies (88.2% versus 100.0%; P = 0.02) at 12 months. Lower index values of anti-nucleocapsid IgG antibodies were also observed in transplantation patients 1 year after COVID-19 (median, 0.49 [interquartile range, 0.15-1.40] versus 1.36 [interquartile range, 0.53-2.91]; P < 0.001). Vaccinated LT recipients showed higher antibody levels compared with unvaccinated patients (P < 0.001); antibody levels reached after vaccination were comparable to those observed in nontransplanted individuals (P = 0.70). In LT patients, a longer interval since transplantation (odds ratio, 1.10; 95% confidence interval, 1.01-1.20) was independently associated with persistence of anti-nucleocapsid IgG antibodies 1 year after infection. In conclusion, compared with nontransplanted patients, LT recipients show a lower long-term persistence of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, SARS-CoV-2 vaccination after COVID-19 in LT patients achieves a significant increase in antibody levels, comparable to that of nontransplanted patients.

HCV eradication in recurrent hepatitis C after liver transplantation normalizes enhanced endothelial activation.

The increased risk of cardiovascular disease (CVD) conferred by hepatitis C virus (HCV) is especially relevant after liver transplantation (LT), but its mechanism is still not well defined. This study aimed to evaluate the influence of HCV eradication in inflammatory and endothelial activation markers after LT. We evaluated inflammatory (TNF-alfa, IL-6, IL-8, and MCP-1) and endothelial activation (E-selectin, ICAM-1, VCAM-1, and MMP-9) markers before and after eradication in 45 LT recipients with HCV infection (LT+/HCV+) and 44 non-transplanted HCV-infected patients (LT-/HCV+). We also considered an additional group of 40 LT recipients without HCV infection (LT+/HCV-). LT+/HCV+ patients presented a higher endothelial activation status before eradication compared with LT+/HCV- patients. However, levels of E-selectin, ICAM-1, VCAM-1, and MMP-9 were comparable between LT+/HCV+ and LT-/HCV+ patients before eradication. HCV eradication decreased ICAM-1 (5466.55 pg/ml vs. 3354.88 pg/ml, P < 0.001) and VCAM-1 (10456.52 pg/ml vs. 6658.85 pg/ml, P < 0.001) levels in LT+/HCV+ and LT-/HCV+ patients. Remarkably, HCV eradication restored levels of endothelial activation markers of LT+/HCV+ patients compared with that of LT+/HCV- patients. HCV plays a major role in endothelial dysfunction after LT. Furthermore, HCV eradication restores endothelial activation despite the exposure to immunosuppressive therapy.

COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes - an ELITA/ELTR multicentre cohort study.

OBJECTIVE: Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course. DESIGN: Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed. RESULTS: From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10-30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15-19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44-102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31-170). CONCLUSIONS: Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity. AIMS: To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients. METHODS: Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG. RESULTS: A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496). CONCLUSION: Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.

Long-term outcomes and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation: a prospective study in a pilot cohort.

INTRODUCTION: the presence of donor-specific antibodies (DSA) is thought to affect survival of the allograft and patient after liver transplantation (LT). However, their significance is not well understood. PATIENTS AND METHODS: a prospective study was performed of 32 adult patients who underwent LT in 2011 to analyze the existence of DSA, associated risk factors and medium-term impact. Immunological determinations were performed immediately before LT and at three, six, 12 months and five years after LT. RESULTS: eight patients (24.2 %) presented pre-formed DSA. However, titers were negative in all patients five years after LT and there were no associated events. Eight out of 24 patients (33.3 %) developed de novo DSA. After five years, only two remained positive; both were class II with high mean fluorescence intensity (MFI) values at diagnosis (over 15,000). No association was found between the development of DSA and the risk of rejection, graft loss or death. However, an increase in liver stiffness values was observed in patients with persistent DSA, and focal sinusoidal deposition of C4d and moderate liver fibrosis were reported. CONCLUSION: the incidence of DSA is high after LT. In addition, the persistence of de novo DSA could be associated with silent liver fibrosis with a potential impact on graft outcomes.

Protective Role of Tacrolimus, Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study.

BACKGROUND AND AIMS: Despite concerns that liver transplant (LT) recipients may be at increased risk of unfavorable outcomes from COVID-19 due the high prevalence of co-morbidities, immunosuppression and ageing, a detailed analysis of their effects in large studies is lacking. METHODS: Data from adult LT recipients with laboratory confirmed SARS-CoV2 infection were collected across Europe. All consecutive patients with symptoms were included in the analysis. RESULTS: Between March 1 and June 27, 2020, data from 243 adult symptomatic cases from 36 centers and 9 countries were collected. Thirty-nine (16%) were managed as outpatients while 204 (84%) required hospitalization including admission to the ICU (39 of 204, 19.1%). Forty-nine (20.2%) patients died after a median of 13.5 (10-23) days, respiratory failure was the major cause. After multivariable Cox regression analysis, age >70 (HR, 4.16; 95% CI, 1.78-9.73) had a negative effect and tacrolimus (TAC) use (HR, 0.55; 95% CI, 0.31-0.99) had a positive independent effect on survival. The role of co-morbidities was strongly influenced by the dominant effect of age where comorbidities increased with the increasing age of the recipients. In a second model excluding age, both diabetes (HR, 1.95; 95% CI, 1.06-3.58) and chronic kidney disease (HR, 1.97; 95% CI, 1.05-3.67) emerged as associated with death CONCLUSIONS: Twenty-five percent of patients requiring hospitalization for COVID-19 died, the risk being higher in patients older than 70 and with medical co-morbidities, such as impaired renal function and diabetes. Conversely, the use of TAC was associated with a better survival thus encouraging clinicians to keep TAC at the usual dose.

Chronic Budd-Chiari syndrome in Behçet's disease successfully managed with transjugular intrahepatic portosystemic shunt: a case report and literature review.

Budd-Chiari syndrome (BCS) is characterized by an obstruction of hepatic venous outflow from small hepatic veins to inferior vena cava, caused by acute thrombosis or its fibrous sequellae. An underlying myeloproliferative neoplasm is present in 50% of cases. Clinical manifestations are widely variable, from asymptomatic to fulminant episodes. Long-term complications range from cirrhosis to hepatocellular carcinoma. Behçet's disease (BD) is a rare recurrent inflammatory multisystemic disorder characterized by recurrent skin-mucosa lesions and systemic involvement. Vascular involvement is observed in up to 40% of the patients with BD, and it is one of the major causes of mortality and morbidity. BCS is a rare complication of BD with a frequency of < 5% among patients with vascular involvement. Immunosuppressive treatment is the cornerstone for the management of vascular involvement in BD, while anticoagulant therapy has been an issue of debate. Transjugular intrahepatic portosystemic shunt (TIPS) in severe cases of BCS-of all causes- improves survival. However, there is scarce evidence about the role of TIPS in the setting of BCS in BD. We present a case of a vascular Behçet's disease associated with chronic Budd-Chiari syndrome with progression of thrombosis despite adequate anticoagulant and immunosuppressive treatment, successfully managed with TIPS.

Clinical Utility of a Risk-Adapted Protocol for the Evaluation of Coronary Artery Disease in Liver Transplant Recipients.

The prevalence and management of coronary artery disease (CAD) in liver transplantation (LT) candidates are not well characterized. The aims of this study were to evaluate the impact on clinical outcomes of a specifically designed protocol for the management of asymptomatic CAD in LT candidates and to investigate noninvasive risk profiles for obstructive and nonobstructive CAD for 202 LT candidates. Those with high baseline cardiovascular risk (CVR; defined by the presence of classic CVR factors and/or decreased ejection fraction) received coronary angiography and significant arterial stenosis and were treated with percutaneous stents. Patients were followed up after LT until death or coronary event (CE). There were 78 patients who received coronary evaluation (62 direct angiography, 14 computed tomography coronary angiography, and 2 both). Of them, 39 (50%) patients had CAD of any severity, and 6 (7.7%) had significant lesions (5 were amenable to be treated with stents, whereas 1 patient had diffuse lesions which contraindicated the LT). Insulin-dependent diabetes was the only factor related to CAD of any severity (odds ratio, 3.44; 95% confidence interval [CI], 1.00-11.97). A total of 69 patients (46 with coronary evaluation) received LT. The incidence of CEs and overall survival after LT were similar between patients with and without coronary evaluation. Furthermore, no differences occurred between these groups in a multivariate competing risk model (subhazard ratio, 0.84; 95% CI, 0.27-2.61; P = 0.76). In conclusion, the application of an angiographic screening protocol of CAD in a selected high-risk Mediterranean population is safe and effective. The short- and medium-term incidence rates of CEs and death after LT in this population are similar to that observed in low-risk patients.

Refractory hepatic encephalopathy in a patient with hypothyroidism: Another element in ammonia metabolism.

Hepatic encephalopathy (HE) remains a diagnosis of exclusion due to the lack of specific signs and symptoms. Refractory HE is an uncommon but serious condition that requires the search of hidden precipitating events (i.e., portosystemic shunt) and alternative diagnosis. Hypothyroidism shares clinical manifestations with HE and is usually considered within the differential diagnosis of HE. Here, we describe a patient with refractory HE who presented a large portosystemic shunt and post-ablative hypothyroidism. Her cognitive impairment, hyperammonaemia, electroencephalograph alterations, impaired neuropsychological performance, and magnetic resonance imaging and spectroscopy disturbances were highly suggestive of HE, paralleled the course of hypothyroidism and normalized after thyroid hormone replacement. There was no need for intervention over the portosystemic shunt. The case findings support that hypothyroidism may precipitate HE in cirrhotic patients by inducing hyperammonaemia and/or enhancing ammonia brain toxicity. This case led us to consider hypothyroidism not only in the differential diagnosis but also as a precipitating factor of HE.

Safety and Efficacy of Anti-TNFα Treatment in Crohn's Disease Patients with Abdominal Abscesses.

BACKGROUND/AIMS: It is estimated that up to 30% of CD patients develop abdominal abscesses; the management of active luminal CD in such patients represents a clinical challenge. The aim of this study is to assess the safety of biologics in patients with Crohn's disease and abdominal abscesses treated with percutaneous drainage and/or broad-spectrum antibiotics. METHODOLOGY: We performed a retrospective review of the clinical charts of consecutive Crohn's disease patients with abdominal abscesses treated with anti-TNFα therapy attended in our institution. RESULTS: 12 patients were finally included in the study. All were treated with broad-spectrum antibiotic and biological therapy (anti-TNF); indication of anti-TNFα therapy was moderate to severe activity of CD in all of them. Percutaneous drainage of the abscess was performed in 7 of the 12 patients. No complications were observed during a mean follow-up of 37,8 (16-71) months, including abscess volume increase, enterocutaneous fistula, soft tissue infections, bacteraemia, or need for emergency surgery. CONCLUSIONS: In addition to conventional treatment, the use of anti-TNFα therapy in Crohn's disease patients with abdominal abscesses seems to be safe. Usefulness of this approach has to be validated in larger cohorts.

Tuberculosis pancreática: presentación en forma de pancreatitis con desarrollo de hipertensión portal / Pancreatic tuberculosis: Presentation in the form of pancreatitis with portal hypertension

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Pseudomelanosis gástrica y duodenal: a propósito de dos casos / Gastric and duodenal pseudomelanosis: a propos of two cases

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