MAFLD burden on the Spanish National Health System. A call to action.

We have read the editorial by Crespo et al on the metabolic associated liver disease (MAFLD) foreseeable burden on the Spanish National Health System over the next years. Between 0.35-0.4% of Spanish population has cirrhosis and more than one million people has significant fibrosis, assessed by ET ≥ 9 kPa. Compared with general population, patients with cirrhosis have more comorbidities and use healthcare resources more frequently. Recent data show a decrease of 24% in hospitalization due to cirrhosis during the period 2005-2014 in our country. These data predate the availability of direct antiviral agents against HCV. A 20% reduction of cirrhosis-related mortality during the period 2006-2018 was observed, as with other Southern European countries. This decline reflects a reduction of alcohol consumption in the last decades. More recently, 90% of patients with significant liver fibrosis were negative for HCV or HBV, did not consume harmful amounts of alcohol and showed components of metabolic syndrome thereby suggesting that MAFLD is the current leading cause of liver fibrosis in Spain. Some studies found that disadvantaged areas in the Community of Madrid had higher liver-related mortality, highlighting that lower income is another socioeconomic determinant of chronic liver disease.

Coordinated assistance plan for the elimination of hepatitis C virus at the centro de ayuda integral al drogodependiente (CAID (Comprehensive Care Centre for Drug Addicts)). / Plan asistencial coordinado para la eliminación del virus de la hepatitis C en el centro de ayuda integral al drogodependiente (CAID).

INTRODUCTION: The drug-injecting population has a high prevalence of hepatitis C virus (HCV) and high risk of transmission. It is a priority to establish an agile diagnostic and treatment plan. OBJECTIVES: 1) Assess the effectiveness of a new coordinated care plan of referral from the Comprehensive Care Centre for Drug Addicts (CAID) to specialised care and 2) Determine the prevalence of HCV, clinical characteristics, effectiveness and safety of treatment in this population. METHODS: 1,300 serologies requested by the CAID between 1998 and 2018 were retrospectively analysed, the seroprevalence of HCV was calculated and the efficiency of the traditional CAID-specialised care referral system was evaluated. A care plan was designed and coordinated among specialists involved in diagnosis and treatment. Since October 2018, 11 patients have been included in the new plan and the performance of both referral systems was compared. RESULTS: With the traditional system, 48.2% (83/172) of the patients were lost. 14.5% (172/1,300) presented positive HCV serology, compared to the general population OR = 19; 95% CI 14.3-25. The prevalence of active infection was 80.3% (90/112). The prevalence of active infection was 80.3% (90/112). Of the 11 patients referred by the new plan, 76.9% (8/11) had active infection and 100% (8/8) were treated with Direct Antiviral Agents successfully. CONCLUSIONS: The new coordinated CAID-specialised care plan presents high effectiveness in comparison with the traditional referral system. The seroprevalence and prevalence of active infection in the CAID population is very high. Treatments with Direct Antiviral Agents are effective and safe.

The contribution of telemedicine to hepatitis C elimination in a correctional facility.

BACKGROUND: micro-elimination has been recently proposed as an efficient strategy to achieve global hepatitis C virus (HCV) elimination. The Spanish Health Ministry Strategic Plan for hepatitis C infection highlighted intervention in prisons as a priority action. However, there are important barriers associated with the specialized care provision to the penitentiary population. AIMS: to assess the contribution of telemedicine for HCV elimination in a correctional facility in Spain. METHODS: an open label program of HCV elimination via telemedicine was started on February 3rd, 2015 in a large penitentiary of 1,200 inmates, as an alternative to referring patients to specialists. An anonymous satisfaction survey was performed among a random sample of inmates and all participating doctors. RESULTS: the prevalence of HCV viremia prior to program initiation was 12.4%. One hundred and thirty-one patients received DAA HCV treatment during the period 2015-2018; 42.74% had a HCV-HIV co-infection. Overall, 97% achieved a sustained virological response (SVR). A second regime of DAA successfully rescued non-responder patients and the HCV prevalence was zero at the end of the program. Satisfaction was high or very high according to 67% of inmates and all participating doctors. CONCLUSION: telemedicine is an effective tool for HCV elimination in penitentiary correctional facilities where referral to specialists is difficult. The extensive use of this technology should be recommended in this setting in order to facilitate equitable access to specialized care.

Higher levels of serum uric acid influences hepatic damage in patients with non-alcoholic fatty liver disease (NAFLD).

BACKGROUND: recent evidence suggests a causal link between serum uric acid and the metabolic syndrome, diabetes mellitus, arterial hypertension, and renal and cardiac disease. Uric acid is an endogenous danger signal and activator of the inflammasome, and has been independently associated with an increased risk of cirrhosis. AIM AND METHODS: six hundred and thirty-four patients from the nation-wide HEPAMET registry with biopsy-proven NAFLD (53% NASH) were analyzed to determine whether hyperuricemia is related with advanced liver damage in patients with non-alcoholic fatty liver disease (NAFLD). Patients were divided into three groups according to the tertile levels of serum uric acid and gender. RESULTS: the cohort was composed of 50% females, with a mean age of 49 years (range 19-80). Patients in the top third of serum uric acid levels were older (p = 0.017); they had a higher body mass index (p < 0.01), arterial blood pressure (p = 0.05), triglyceridemia (p = 0.012), serum creatinine (p < 0.001) and total cholesterol (p = 0.016) and lower HDL-cholesterol (p = 0.004). According to the univariate analysis, the variables associated with patients in the top third were more advanced steatosis (p = 0.02), liver fibrosis (F2-F4 vs F0-1; p = 0.011), NASH (p = 0.002) and NAS score (p = 0.05). According to the multivariate logistic regression analysis, the top third of uric acid level was independently associated with steatosis (adjusted hazard ratio 1.7; CI 95%: 1.05-2.8) and NASH (adjusted hazard ratio 1.8; CI 95%: 1.08-3.0) but not with advanced fibrosis (F2-F4) (adjusted hazard ratio 1.09; CI 95%: 0.63-1.87). CONCLUSION: higher levels of serum uric acid were independently associated with hepatocellular steatosis and NASH in a cohort of patients with NAFLD. Serum uric acid levels warrants further evaluation as a component of the current non-invasive NAFLD scores of histopathological damage.

Hepatitis B virus in patients with chronic hepatitis C treated with direct antiviral agents.

INTRODUCTION: cases of hepatitis B virus (HBV) reactivation have been reported in patients with hepatitis C virus (HCV) treated with direct antiviral agents (DAA). OBJECTIVES AND METHODS: the main objectives of the present study are: a) to determine the prevalence of HBV/HCV coinfection in HCV patients treated with DAAs in the Autonomous Community of Madrid (CM) and also to determine the incidence and clinical relevance of HBV reactivation; and b) to determine the HBV screening rates in HCV patients in our region. For that purpose, 1,337 HCV patients were consecutively treated with DAAs in two hospitals located in South CM between January 2015 and June 2017. RESULTS: nine of the 1,337 (0.67%) participants were HBsAg positive and 356 (26.6%) had previous HBV infection markers. Two of the four (50%) HBsAg positive patients with untreated HBV developed a virological reactivation, but not a biochemical reaction. Of the 356 patients with previous HBV infection markers, all had normal transaminases at the end of treatment and during follow-up. The HBV screening rate amounted to 92.9% of the cohort. CONCLUSIONS: the prevalence of HBV (HBsAg positive) infection in patients with chronic hepatitis C in the southern area of the CM is low. HBV reactivation in HBsAg positive patients treated with DAAs is common, although without clinical relevance. In our region, there is a high rate of HBV screening in patients with HCV that are likely treated with DAAs.

Comparison of the effectiveness and renal safety of tenofovir versus entecavir in patients with chronic hepatitis B.

OBJECTIVE: To compare the effectiveness and renal safety of treatment with tenofovir versus entecavir in patients with chronic hepatitis-B. METHODS: Retrospective study in hepatitis-B patients who initiated treatment with tenofovir or entecavir since January 1998 until 2013. The primary effectiveness variable was defined as viral DNA < 20 UI/ml (HBV-DNA) and the variable for renal safety was variations in glomerular filtration rate (eGFR) after 48 weeks of treatment. RESULTS: The analysis was conducted in 64 patients (1:1), with similar characteristics except for the prevalence of naive patients (p=0.036), comorbidities (p=0.077) and nephrotoxic drugs (p=0.088) in the entecavi arm, while the tenofovir arm presented a prevalence of patients with HBV-DNA < 20 UI/ml (p=0.032) and HBeAg-positive (p=0.050). Statistical univariate analysis and adjustment for confounding variables was conducted through the Propensity Score (PS). The outcomes for the primary effectiveness variable showed tenofovir superiority after PS adjustment, with an ORadj=6.7 (95% CI:1.2-35.3; p=0.028). Three patients on tenofovir experienced seroconversion (p=0.148). The outcomes for the primary safety variable (eGFR < 60 ml/min/1.73m2) showed no difference between both arms after adjustment, achieving an ORadj=0.6 (95% CI:0.1-2.8; p=0.521). The tenofovir arm registered two cases of treatment interruption due to renal toxicity, with subsequent recovery, including one Fanconi Syndrome. CONCLUSIONS: In our study, there are significant differences between both treatments regarding effectiveness, with tenofovir demonstrating superiority. In terms of renal safety, we have not found any significant differences, but two cases of treatment interruption due to renal toxicity with tenofovir lead us to the conclusion that treatment decision in patients with renal function alteration should include an individualized assessment of each case.

Objetivo: Comparar la efectividad y seguridad renal del tratamiento con tenofovir frente al entecavir en pacientes con hepatitis B cronica. Métodos: Estudio retrospectivo en pacientes con hepatitis B que iniciaron tratamiento con tenofovir o entecavir entre enero 1998-2013. La variable principal de la efectividad fue definida como DNA viral < 20 UI/ml (HBV-DNA) y la de la seguridad renal como variaciones en el filtrado glomerular (eGFR) tras 48 semanas de tratamiento. Resultados: Se analizaron un total de 64 pacientes (1:1), con caracteristicas semejantes excepto por el predominio de pacientes sin tratamiento previo (p=0,036), comorbilidades (p=0,077) y farmacos nefrotoxicos (p=0,088) en el grupo-entecavir, y de pacientes con HBV-DNA < 20 UI/ml (p=0,032) y HBeAg-positivo (p=0,050) en el grupo-tenofovir. Se realizaron analisis estadisticos univariantes y se ajustaron las variables confusoras mediante Propensity score (PS). Los resultados para la variable principal de efectividad (HBV-DNA < 20 UI/ml) denotan una superioridad del tenofovir tras el ajuste por PS con una ORadj= 6,7 (IC95%: 1,2-35,3; p=0,028). Tres pacientes con tenofovir sufrieron seroconversion (p=0,148). Los resultados para la variable principal de seguridad (eGFR < 60ml/min/1.73m2) no mostraron diferencias entre ambas ramas tras el ajuste, obteniendo una ORadj= 0,6 (IC95%: 0,1-2,8; p=0,521). El grupo-tenofovir registro dos casos de suspension por toxicidad renal, con posterior recuperacion, entre ellos un sindrome de Fanconi. Conclusiones: En nuestro estudio existen diferencias significativas entre ambos tratamientos respecto a su efectividad, mostrandose el tenofovir superior. En cuanto a la seguridad renal, no hemos encontrado diferencias significativas, pero dos casos de suspension de tratamiento por toxicidad renal con tenofovir nos llevan a concluir que la decision de tratamiento en los pacientes con alteraciones en la funcion renal deberia incluir un analisis individualizado de cada caso.

Hepatitis C seroprevalence in an at-risk population in the southwest Madrid region of Spain. / Seroprevalencia de hepatitis C en población con factores de riesgo del suroeste de la Comunidad de Madrid.

INTRODUCTION: The estimated seroprevalence of hepatitis C virus (HCV) in Spain is 1.7%, but is much higher in the at-risk population. The most efficient national screening strategy is unclear. AIMS: To estimate the prevalence of HCV among the at-risk population seen in primary care (PC), and to determine their epidemiological profile. MATERIALS AND METHODS: Cross-sectional descriptive prevalence study that included adult patients with risk factors for HCV infection seen in PC in the southwest Madrid region between 2010 and 2012. RESULTS: A total of 158 patients (men=51.3%), mean age 46 years (SD=16.6), were included. The most common risk factors were hypertransaminasaemia (44.3%) and major surgery (13.3%). Immigration, unsafe sexual practices, and tattoos or body piercing were more prevalent in patients younger than 45 years of age. Fifteen patients (9.5%) were positive for anti-HCV; 9 of these (5.7%) were HCV-ARN positive. Of the positive patients, 4 (44.4%) had significant fibrosis at diagnosis (F3-F4). Male patients had a higher rate of positive anti-HCV results (13.8 vs. 5.3%; P=.072), as did patients older than 45 years of age (12.8 vs. 6.3%; P=.167). Intravenous and intranasal drug use were associated with a higher rate of positive anti-HCV results (50 vs. 8.5%; P=.005 and 66.7 vs. 8.4%; P=.001, respectively). CONCLUSIONS: Patients with risk factors for HCV infection have high seroprevalence. Screening programmes must therefore be implemented to detect HCV infection in this population in PC.

Factores de riesgo de la enfermedad hepática grasa no alcohólica / Risk factors for non-alcoholic fatty liver disease

Prevalence of non-alcoholic fatty liver disease (NAFLD) may be 10%-15% worldwide, and these figures are even higher in obese and in type 2 diabetes mellitus patients. The most important risk factor is metabolic syndrome, especially central obesity. Even though the majority of patients with macrovesicular steatohepatitis will not progress to advanced liver disease, a subgroup of patients will evolve to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Independent risk factors associated with NASH are older age, type 2 diabetes mellitus and obesity. Patients with significant hepatocellular lesion, such as hepatocyte ballooning, Mallory hyalline or fibrosis, have a higher risk of cirrhosis and are more likely to have a high liver-related mortality, although higher global mortality has not been demonstrated. Although NASH related cirrhosis may have better prognosis compared to hepatitis C cirrhosis, recent series suggest that it may be the third cause of liver transplantation. Steatosis, NASH and cirrhosis recurrence post-liver transplantation is common. The risk of hepatocellular carcinoma (HCC) is increased in patients with NAFLD, and all patients with cryptogenic cirrhosis should be screened for HCC

La enfermedad hepática grasa no alcohólica puede afectar al 15%-25% de la población, con cifras mayores en pacientes obesos y con diabetes mellitus tipo 2. El principal factor de riesgo es el síndrome metabólico, especialmente la obesidad central. Aunque la mayoría de los pacientes con esteatosis macrovacuolar simple no presentan progresión de su enfermedad, existe un subgrupo que progresa a esteatohepatitis no alcohólica, y aunque se desconocen los factores de riesgo para esta progresión, la mayoría de los estudios reconocen la edad, la presencia de diabetes mellitas tipo 2 y la obesidad como predictores de riesgo independientes de EHNA. La presencia de lesión hepatocelular significativa, como el abalonamiento hepatocitario o la hialina de Mallory y la fibrosis, incrementan significativamente el riesgo de cirrosis. Los pacientes que tienen esta lesión histopatológica presentan una mortalidad de causa hepática superior, si bien no se ha demostrado una mortalidad global aumentada. Aunque la cirrosis secundaria a esteatohepatitis no alcohólica parece tener un pronóstico ligeramente mejor que la secundaria a hepatitis C, en muchas series es la tercera causa de trasplante ortotópico de hígado. La recurrencia postrasplante de la esteatosis, de la esteatohepatitis no alcohólica y de la cirrosis es frecuente. Existe un aumento del riesgo de hepatocarcinoma en pacientes con enfermedad hepática grasa no alcohólica. En la actualidad se recomienda el seguimiento para la detección precoz de este tumor en todos los pacientes con cirrosis criptogénica

Acute-on-chronic liver failure: Pathogenesis, prognostic factors and management.

Acute-on-chronic liver failure (ACLF) is increasingly recognized as a complex syndrome that is reversible in many cases. It is characterized by an acute deterioration of liver function in the background of a pre-existing chronic liver disease often associated with a high short-term mortality rate. Organ failure (OF) is always associated, and plays a key role in determining the course, and the outcome of the disease. The definition of ACLF remains controversial due to its overall ambiguity, with several disparate criteria among various associations dedicated to the study of liver diseases. Although the precise pathogenesis needs to be clarified, it appears that an altered host response to injury might be a contributing factor caused by immune dysfunction, ultimately leading to a pro-inflammatory status, and eventually to OF. The PIRO concept (Predisposition, Insult, Response and Organ Failure) has been proposed to better approach the underlying mechanisms. It is accepted that ACLF is a different and specific form of liver failure, where a precipitating event is always involved, even though it cannot always be ascertained. According to several studies, infections and active alcoholism often trigger ACLF. Viral hepatitis, gastrointestinal haemorrhage, or drug induced liver injury, which can also provoke the syndrome. This review mainly focuses on the physiopathology and prognostic aspects. We believe these features are essential to further understanding and providing the rationale for improveddisease management strategies.

[Hepatitis B virus reactivation in rituximab-treated patients: incidence and risk factors]. / Reactivación del virus de la hepatitis B en pacientes tratados con rituximab: incidencia y factores de riesgo.

Hepatitis B virus (HBV) reactivation after chemotherapy regimens is a well-known complication. The incidence and risk factors for HBV reactivation remain to be elucidated. We aimed to determine the incidence and risk factors for HBV reactivation in patients receiving rituximab, and the potential role of the cumulative rituximab dose in HBV reactivation. We retrospectively reviewed 320 patients receiving rituximab in our hospital. Of these, 42 (13.12%) had serological markers of hepatitis B. During follow-up, 21% (9/42) had HBV reactivation. Risk factors for reactivation were HBsAg positivity (p < 0.05), isolated anti-HBc positivity (p < 0.05), marginal zone lymphoma, and Mantle cell lymphoma (p < 0.05). The median rituximab dose tended to be higher in patients with reactivation (p = 0.06).

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B.

Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma (HCC). Globally, over half a million people each year are diagnosed with HCC, with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus (HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC, the molecular basis for this association has not been fully elucidated. In addition, a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis, recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agents in achieving profound and durable suppression of HBV DNA levels while improving liver function and histology, robust evidence of other long-term clinical outcomes, such as prevention of HCC, are limited.

[Impact of antiviral therapy on the natural history of hepatitis C virus]. / Impacto del tratamiento antiviral en la historia natural del virus de la hepatitis C.

Chronic hepatitis C virus infection affects around 150 million persons, and 350,000 persons worldwide die of this disease each year. Although the data on its natural history are incomplete, after the acute infection, most patients develop chronic forms of hepatitis C with variable stages of fibrosis. In these patients, continual inflammatory activity can cause significant fibrosis, cirrhosis, decompensation of the liver disease, or hepatocarcinoma. In the next few years, it is expected that hepatitis C virus infection and its complications will significantly increase, as will the incidence of hepatocarcinoma in Spain. This review presents the data on the natural history of hepatitis C virus infection and discusses the potential impact of antiviral therapy on the distinct stages of the disease.

Prevalence of occult hepatitis B virus infection.

Occult hepatitis B virus (HBV) infection (OBI) is characterized by the persistence of HBV DNA in the liver tissue in individuals negative for the HBV surface antigen. The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world, the different assays utilized in the studies, and the different populations studied. Many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals. The studies show that OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without liver disease.