The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis.

BACKGROUND: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. OBJECTIVE: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. METHODS: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2-5; (c) cholestatic pattern(C), < 2. OUTCOMES: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. RESULTS: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69-0.79) vs. 0.83 (95% CI 0.80-0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69-0.85) vs. 0.84 (95% CI 0.80-0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12-5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. CONCLUSIONS: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.

Predictive factors for decompensating events in patients with cirrhosis with primary biliary cholangitis under different lines of therapy.

BACKGROUND AND AIMS: The landscape in primary biliary cholangitis (PBC) has changed with the advent of second-line treatments. However, the use of obeticholic acid (OCA) and fibrates in PBC-related cirrhosis is challenging. We assessed the impact of receiving a second-line therapy as a risk factor for decompensated cirrhosis in a real-world population with cirrhosis and PBC, and identify the predictive factors for decompensated cirrhosis in these patients. APPROACH AND RESULTS: Multicenter study enrolling 388 patients with PBC-cirrhosis from the Spanish ColHai registry. Biopsy (20%), ultrasound (59%), or transient elastography (21%) defined cirrhosis, and the presence of varices and splenomegaly defined clinically significant portal hypertension (CSPH). Paris-II and PBC OCA international study of efficacy criteria determined the response to ursodeoxycholic acid (UDCA), fibrates (n=93), and OCA (n=104). The incidence of decompensated cirrhosis decreased for UDCA versus OCA or fibrates in the real-world population, but they were similar considering the propensity score-matched cohort (UDCA 3.77 vs. second-line therapy 4.5 100 persons-year, respectively), as patients on second-line therapy exhibited advanced liver disease. Consequently, GGT, albumin, platelets, clinically significant portal hypertension, and UDCA response were associated with a decompensating event. OCA response (achieved in 52% of patients) was associated with bilirubin (OR 0.21 [95% CI: 0.06-0.73]) and AST (OR 0.97 [95% CI: 0.95-0.99]), while fibrate response (achieved in 55% of patients) with AST [OR 0.96 (95% CI: 0.95-0.98]). In patients treated with OCA, drug response (sHR 0.23 [95% CI: 0.08-0.64]), diabetes (sHR 5.62 [95% CI: 2.02-15.68]), albumin (sHR 0.34 [95% CI: 0.13-0.89]), and platelets (sHR 0.99 [95% CI: 0.98-1.00]) were related to decompensation. In patients treated with fibrate, drug response (sHR 0.36 (95% CI: 0.14-0.95]), albumin (sHR 0.36 (95% CI: 0.16-0.81]), and clinically significant portal hypertension (sHR 3.70 (95% CI: 1.17-11.70]) were associated with decompensated cirrhosis. CONCLUSIONS: Advanced PBC, rather than OCA and fibrates, was found to be associated with decompensating events. Therefore, biochemical and clinical variables should be considered when making decisions about the management of these drugs. Moreover, a positive response to OCA and fibrates reduced the risk of decompensation.

Impacto de la docencia online en el rendimiento académico de estudiantes españoles de medicina / The impact of online teaching on the academic performance of spanish medical students

Introducción: El confinamiento derivado de la situación sanitaria a finales del primer trimestre de 2020 en España obligó a que la segunda parte del curso 2019-2020 de todos los niveles educativos pasara a formato online de una manera forzada e imprevista. Objetivo: Identificar el impacto de la docencia online en el rendimiento académico de los estudiantes de medicina en el curso 2019-2020. Métodos: El estudio fue de tipo transversal y utilizó datos públicos anonimizados sobre rendimiento académico de estudiantes de medicina en universidades españolas. A partir de la información pública de los sistemas de garantía interna de calidad de estas universidades, se analizaron los valores medios de las tasas de rendimiento y éxito de los cuatro cursos comprendidos entre 2015 y 2019 en 17 universidades españolas. Estos se compararon mediante una prueba t de Student con los obtenidos en el curso 2019-2020. Resultados: Las tasas de rendimiento y éxito fueron superiores en el curso 2019-2020 en comparación con la media de los cuatro cursos anteriores. Conclusiones: La situación de confinamiento y de cambio forzado a docencia online parece haber producido una mejora en el ya de por sí elevado rendimiento académico de los estudiantes de medicina, lo que sugiere niveles elevados de resiliencia y una buena capacidad de adaptación a una situación adversa como la experimentada en la segunda parte del curso 2019-2020 (AU)

Introduction: The lockdown derived from the health situation at the end of the first quarter of 2020 in Spain forced the second part of the 2019-2020 academic course of all educational levels to be move to the online modality in a compulsory and unforeseen way. Objective: To identify the impact of online teaching on the academic performance of medical students in the 2019-2020 academic year. Methods: The study was cross-sectional and used anonymized public data on the academic performance of medical students in Spanish universities. Based on public information from the internal quality assurance systems of these universities, the mean values of performance and success rates were analyzed for the four academic years between 2015 and 2019 in seventeen Spanish universities. Using a Student's t test, these were compared with those obtained in the 2019-2020 academic year. Results: The performance and success rates were higher in the 2019-2020 academic year compared to the average of the four previous academic years. Conclusions: The situation of lockdown and forced change to online teaching seems to have produced an improvement in the already high academic performance of medical students, being this suggestive of high levels of resilience and a good capacity to adapt to an adverse situation such as the one experienced in the second part of the 2019-2020 academic year(AU)

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia.

BACKGROUND AND AIMS: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3α,7α,12α-trihydroxy-5ß-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. METHODS AND RESULTS: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. CONCLUSIONS: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.

Hepatocellular carcinoma risk in hepatitis C stage-3 fibrosis after sustained virological response with direct-acting antivirals.

BACKGROUND & AIMS: Patients with chronic hepatitis C and stage 3 fibrosis are thought to remain at risk of hepatocellular carcinoma after sustained virological response. We investigated this risk in a large cohort of patients with well-defined stage 3 fibrosis. METHODS: We performed a multicentre, ambispective, observational study of chronic hepatitis C patients with sustained virological response after treatment with direct-acting antivirals started between January and December 2015. Baseline stage 3 was defined in a two-step procedure: we selected patients with transient elastography values of 9.5-14.5 kPa and subsequently excluded those with nodular liver surface, splenomegaly, ascites or collaterals on imaging, thrombopenia or esophago-gastric varices. Patients were screened twice-yearly using ultrasound. RESULTS: The final sample comprised 506 patients (median age, 57.4 years; males, 59.9%; diabetes, 17.2%; overweight, 44.1%; genotype 3, 8.9%; HIV coinfection, 18.4%; altered liver values, 15.2%). Median follow-up was 33.7 (22.1-39.1) months. Five hepatocellular carcinomas and 1 cholangiocarcinoma were detected after a median of 29.4 months (95% CI: 26.8-39.3), with an incidence of 0.47/100 patients/year (95% CI: 0.17-1.01). In the multivariate analysis, only males older than 55 years had a significant higher risk (hazard ratio 7.2 [95% CI: 1.2-41.7; P = .029]) with an incidence of 1.1/100 patients/year (95% CI: 0.3-2.8). CONCLUSIONS: In a large, well-defined cohort of patients with baseline hepatitis C stage-3 fibrosis, the incidence of primary liver tumours was low after sustained virological response and far from the threshold for cost-effectiveness of screening, except in males older than 55 years.

Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.

BACKGROUND AND AIM: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD). METHODS: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years). RESULTS: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. CONCLUSIONS: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.

A Model Based on Noninvasive Markers Predicts Very Low Hepatocellular Carcinoma Risk After Viral Response in Hepatitis C Virus-Advanced Fibrosis.

BACKGROUND AND AIMS: Patients with hepatitis C virus (HCV) and advanced fibrosis remain at risk of hepatocellular carcinoma (HCC) after sustained viral response (SVR) and need lifelong surveillance. Because HCC risk is not homogenous and may decrease with fibrosis regression, we aimed to identify patients with low HCC risk based on the prediction of noninvasive markers and its changes after SVR. APPROACH AND RESULTS: This is a multicenter cohort study, including patients with HCV and compensated advanced fibrosis that achieved SVR after direct antivirals. Clinical and transient elastography (TE) data were registered at baseline, 1 year, and 3 years after the end of treatment (EOT). All patients underwent liver ultrasound scan every 6 months. Patients with clinical evaluation 1 year after EOT were eligible. Univariate and multivariate Cox regression analysis were performed, and predictive models were constructed. HCC occurrence rates were evaluated by Kaplan-Meier. Nine hundred and ninety-three patients were eligible (56% male; 44% female; median age 62 years), 35 developed HCC (3.9%), and the median follow-up was 45 months (range 13-53). Baseline liver stiffness measurement (LSM) (HR 1.040; 95% CI 1.017-1.064), serum albumin (HR 0.400; 95% CI 0.174-0.923), 1-year DeltaLSM (HR 0.993; 95% CI 0.987-0.998), and 1-year FIB-4 score (HR 1.095; 95% CI 1.046-1.146) were independent factors associated with HCC. The TE-based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤ 17.3 kPa, albumin >4.2 g/dL, and 1-year DeltaLSM > 25.5%) versus 5.2% in patients with score 1-3 (Harrell's C 0.779; log-rank 0.002). An alternative model with FIB-4 similarly predicted HCC risk. CONCLUSIONS: A combination of baseline and dynamic changes in noninvasive markers may help to identify patients with a very low risk of HCC development after SVR.

Reflex testing. A key tool for the elimination of hepatitis C.

Hepatitis C is a major cause of liver cirrhosis and hepatocellular carcinoma, as well as the primary indication for liver transplant in Europe. The highly effective direct-acting antivirals currently available make it possible to achieve the hepatitis C elimination targets set by the World Health Organization. For this, population screening and reflect testing are fundamental strategies.

Significant fibrosis predicts new-onset diabetes mellitus and arterial hypertension in patients with NASH.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) could play a catalytic role in the development of metabolic comorbidities, although the magnitude of this effect in metabolically healthy patients with NAFLD remains unclear. We assessed the role of biopsy-proven NAFLD on the risk of developing type 2 diabetes mellitus (T2DM) and other metabolic comorbidities (arterial hypertension [AHT], and dyslipidemia) in metabolically healthy patients. METHODS: We included 178 metabolically healthy-defined by the absence of baseline T2DM, AHT, dyslipidemia-patients with biopsy-proven NAFLD from the HEPAmet Registry (N = 1,030). Hepamet fibrosis score (HFS), NAFLD fibrosis score, and Fibrosis-4 were calculated. Follow-up was computed from biopsy to the diagnosis of T2DM, AHT, or dyslipidemia. RESULTS: During a follow-up of 5.6 ± 4.4 years, T2DM occurred in 9% (16/178), AHT in 8.4% (15/178), low HDL in 9.6% (17/178), and hypertriglyceridemia in 23.6% (42/178) of patients. In multivariate analysis, significant fibrosis predicted T2DM and AHT. Independent variables related to T2DM appearance were significant fibrosis (HR 2.95; 95% CI 1.19-7.31; p = 0.019), glucose levels (p = 0.008), age (p = 0.007) and BMI (p = 0.039). AHT was independently linked to significant fibrosis (HR 2.39; 95% CI 1.14-5.10; p = 0.028), age (p = 0.0001), BMI (p = 0.006), glucose (p = 0.021) and platelets (p = 0.050). The annual incidence rate of T2DM was higher in patients with significant fibrosis (4.4 vs. 1.2 cases per 100 person-years), and increased in the presence of obesity, similar to AHT (4.6 vs. 1.1 cases per 100 person-years). HFS >0.12 predicted the risk of T2DM (25% [4/16] vs. HFS <0.12 4.5% [4/88]; logRank 6.658, p = 0.010). CONCLUSION: Metabolically healthy patients with NAFLD-related significant fibrosis were at greater risk of developing T2DM and AHT. HFS >0.12, but not NAFLD fibrosis score or Fibrosis-4, predicted the occurrence of T2DM. LAY SUMMARY: Patients with biopsy-proven non-alcoholic fatty liver disease and significant fibrosis were at risk of developing type 2 diabetes mellitus and arterial hypertension. The risk of metabolic outcomes in patients with significant fibrosis was increased in the presence of obesity. In addition to liver biopsy, patients at intermediate-to-high risk of significant fibrosis by Hepamet fibrosis score were at risk of type 2 diabetes mellitus.

Digestive units in the National Health System of the 21st century. Organizational and management standards for a patient-centered service.

The Spanish Society of Digestive Pathology has set a consensus document on the standards and recommendations for gastroenterology units (GU). These standards are considered as relevant in the organization and management of the unit to develop their activities with efficiency and quality. Four key groups of processes have been identified: a) care for the acutely ill adult patient; b) outpatient digestive endoscopy; c) in-hospital support to other services and outpatient clinics; and d) management of patients with chronic complex digestive pathology. Standards for organization and management of the unit were classified within the group of support processes, and training and research as strategic processes. Standards have also been developed for some functional and monographic units such as endoscopy, hepatology and inflammatory bowel disease; as well as for certain procedures including endoscopic retrograde cholangiopancreatography, colonoscopy and gastroscopy. The standards will be set for other units and procedures as they are developed. The standards developed must be reviewed within a maximum period of five years.

Clinical Outcome Event Adjudication in a 10-Year Prospective Study of Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B.

Background and Aims: In the REALM (Randomized, Observational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Patients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progression events, and deaths. An external event adjudication committee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize potential adverse effects of the large cohort, interdisciplinary outcome assessments, geographic scope, and long duration. Methods: The EAC comprised an international group of hepatologists and oncologists with expertise in diagnosis of targeted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria captured in the EAC charter. Operational processes, including data collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%; hepatocellular carcinoma (HCC), 83.3%; non-HCC malignancies, 88.0%; non-HCC HBV disease progression, 68.2%. Reasons for lack of concordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consistency; EAC performance was facilitated by well-defined diagnostic criteria, effective data capture, and efficient operational processes. Trial registration: ClinicalTrials.gov NCT00388674.

Alcohol-related liver disease. Clinical practice guidelines. Consensus document sponsored by AEEH. / Enfermedad hepática por alcohol. Guías de práctica clínica. Documento de consenso auspiciado por la AEEH.

Alcohol-related liver disease (ARLD) is the most prevalent cause of advanced liver disease and liver cirrhosis in Europe, including Spain. According to the World Health Organization the fraction of liver cirrhosis attributable to alcohol use in Spain is 73.8% among men and 56.3% among women. ARLD includes various stages such as steatohepatitis, cirrhosis and hepatocellular cancer. In addition, patients with underlying ARLD and heavy alcohol intake may develop alcoholic hepatitis, which is associated with high mortality. To date, the only effective treatment to treat ARLD is prolonged withdrawal. There are no specific treatments, and the only treatment that increases life expectancy in alcoholic hepatitis is prednisolone. For patients with alcoholic hepatitis who do not respond to treatment, some centres offer the possibility of an early transplant. These clinical practice guidelines aim to propose recommendations on ARLD taking into account their relevance as a cause of advanced chronic liver disease and liver cirrhosis in our setting. This paper aims to answer the key questions for the clinical practice of Gastroenterology, Hepatology, as well as Internal Medicine and Primary Health Centres, making the most up-to-date information regarding the management and treatment of ARLD available to health professionals. These guidelines provide evidence-based recommendations for the clinical management of this disease.

Elimination of hepatitis C. Positioning document of the Spanish Association for the Study of the Liver (AEEH).

The Spanish Association for the Study of the Liver (AEEH) is convinced that the elimination of hepatitis C virus (HCV) in Spain is possible as long as we are able to use the resources and tools necessary for it. This document reflects the position of the AEEH regarding the elimination of HCV, establishing a wide range of recommendations that can be grouped into five categories: 1) Screening of HCV according to age, of the existence of classic acquisition risk factors of infection, active search of previously diagnosed patients and development of microelimination strategies in vulnerable populations; 2) Simplification of HCV diagnosis (one-step diagnosis and diagnosis at the point of patient care); 3) Simplification of patient treatment and improvement of care circuits; 4) Health policy measures, and, finally, 5) Establishment of HCV elimination indicators.

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.

Comparative study of overweight and obese patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in the western world. Although NAFLD prevalence is higher in patients with a BMI > 25 kg /m2, it is unclear if there are differences between overweight and obese patients. The associated biochemical, dietary and genetic parameters were compared between overweight and obese patients with NAFLD. METHODS: patients with biopsy-proven NAFLD (n = 203) were enrolled in a cross-sectional study. The MEDAS questionnaire was used to assess adherence to the Mediterranean diet. Biochemical, anthropometrical parameters and the I148M variant (rs738409) of the PNPLA3 gene and rs180069 of the TNF-α gene were evaluated. RESULTS: overweight patients had higher serum adiponectin levels (22.5 ± 21.9 vs 11.2 ± 18.1 ng/ml; p < 0.05) and lower resistin (3.3 ± 1.7 vs 8.1 ± 8 ng/ml; p < 0.001) and leptin concentrations (22.9 ± 21.9 vs 55.8 ± 45 ng/ml; p < 0.001) than obese patients. Non-alcoholic steatohepatitis (NASH) was more frequent in the obese group (59.3% vs 41.3%; p = 0.02). The multivariate analysis showed adherence to the Mediterranean diet to be an independent protective factor for NASH and liver fibrosis in overweight patients (OR 0.7, 95% CI 0.5-0.8). CONCLUSIONS: NASH was more prevalent in obese patients than in overweight subjects. HOMA-IR and adherence to the Mediterranean diet provided protection against fibrosis in overweight patients. Adherence to the Mediterranean diet was the only independent factor associated with NASH in these patients.

The effects of metabolic status on non-alcoholic fatty liver disease-related outcomes, beyond the presence of obesity.

BACKGROUND: Metabolically healthy obesity (MHO) shows a reduced risk compared with obese patients with adverse metabolic conditions. Lean people suffering some metabolic derangements also have non-alcoholic fatty liver disease (NAFLD)-related outcomes compared with non-obese subjects with a few metabolic risks. AIM: To define the impact of the metabolic status on the NAFLD-related outcomes, beyond the presence of obesity. METHODS: We designed a multicentre cross-sectional study, including 1058 biopsy-proven NAFLD patients. Metabolically healthy status was strictly defined by the lack of metabolic risk factors (diabetes mellitus, low HDL, hypertriglyceridemia, arterial hypertension). Non-alcoholic steatohepatitis (NASH) and significant fibrosis (F2-F4) were identified by liver biopsy. Chronic kidney disease epidemiology collaboration equation was calculated for kidney function and the atherogenic index of plasma (AIP) for cardiovascular risk. RESULTS: Metabolically healthy (OR 1.88; P = 0.050) and unhealthy obesity (OR 3.47: P < 0.0001), and unhealthy non-obesity (OR 3.70; P < 0.0001) were independently associated with NASH together with homeostatic model assessment (HOMA), ALT, and platelets. Significant fibrosis was more frequently observed in the presence of adverse metabolic conditions in obese (OR 3.89; P = 0.003) and non-obese patients (OR 3.92; P = 0.002), and independently associated with platelets, albumin, ALT, HOMA, and age. The number of metabolic factors determined the risk of NASH and significant fibrosis. Glomerular filtration rate was lower in unhealthy (91.7 ± 18) than healthy metabolism (95.6 ± 17) (P = 0.007). AIP was higher in adverse metabolic conditions (P = 0.0001). Metabolically unhealthy non-obesity showed higher liver damage (NASH 55.8% vs 42.4%; P < 0.05; significant fibrosis 31.7% vs 11.4%; P < 0.0001) and cardiovascular risk (P < 0.0001) than healthy obesity. CONCLUSIONS: Metabolic unhealthy status showed a greater impact on NASH, significant fibrosis, kidney dysfunction, and atherogenic profile than obesity. However, metabolically healthy obesity was not a full healthy condition. We should focus our messages especially on patients with adverse metabolic conditions.

Consensus document. Management of non-alcoholic fatty liver disease (NAFLD). Clinical practice guideline. / Documento de consenso. Manejo de la enfermedad hepática grasa no alcohólica (EHGNA). Guía de práctica clínica.

Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville.

Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon?

BACKGROUND: Hepatitis B virus (HBV) chronic infection affects up to 240 million people in the world and it is a common cause of cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) plays an essential role in HBV persistence and replication. Current pharmacological treatment with nucleos(t)ide analogues (NA) may suppress HBV replication with little or no impact on cccDNA, hence lifelong treatment is required in the vast majority of patients. Clearances of intrahepatic cccDNA and/or HBsAg are critical endpoints for future antiviral therapy in chronic HBV. Recent promising developments targeting different molecular HBV life cycle steps are being pre-clinically tested or have moved forward in early clinical trials. METHODS: We review the current state of the art of these pharmacological developments, mainly focusing on efficacy and safety results, which are expected to lay the ground for future HBV eradication. An inclusive literature search on new treatments of HBV using the following electronic databases: Pubmed/MEDLINE, AMED, CINAHL and the Cochrane Central Register of Controlled Trials. Full-text manuscripts and abstracts published over the last 12 years, from 2005 to March 2011 were reviewed for relevance and reference lists were crosschecked for additional applicable studies regarding new HBV antiviral treatment. RESULTS: HBV entry inhibitors, HBV core inhibitors, HBV cccDNA transcripts RNA interference, HBV cell apoptosis inducers, HBV RNA, viral proteins and DNA knock down agents, HBV release inhibitors, anti-sense nucleosides, exogenous interferon stimulation, interferon response stimulation and HBV therapeutic vaccines were reviewed. CONCLUSION: This review will provide readers with an updated vision of current and foreseeable therapeutic developments in chronic hepatitis B.

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

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.