Patient-reported outcomes in NAFLD/NASH clinical trials: A blind spot that needs addressing

Health-related quality of life; Non-alcoholic steatohepatitis; Patient-reported outcomesCalidad de vida relacionada con la salud; Esteatohepatitis no alcohólica; Resultados informados por el pacienteQualitat de vida relacionada amb la salut; Esteatohepatitis no alcohòlica; Resultats informats pel pacien

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology

Hepatic fibrosis; Non-alcoholic steatohepatitis; Transient elastographyFibrosis hepática; Esteatohepatitis no alcohólica; Elastografía transitoriaFibrosi hepàtica; Esteatohepatitis no alcohòlica; Elastografia transitòriaBackground & Aims Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. Methods This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. Results From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13–8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29–5.98) and 0.70% (95% CI 0.10–4.95) respectively. Conclusions These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available

Liver steatosis induces portal hypertension regardless of fibrosis in patients with NAFLD: A proof of concept case report

Esteatosi hepàtica; Hipertensió portalLiver steatosis; Portal hypertensionEsteatosis hepática; Hipertensión portalNo financial support was received for data analysis or writing assistance. JRE is a PhD student at Universitat Autònoma de Barcelona, Spain. JMP reports having received consulting fees from Boehringer Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898 (PI22/01770). JG has received consulting fees from Boehringer Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. All other authors: nothing to disclose

When Sugar Reaches the Liver: Phenotypes of Patients with Diabetes and NAFLD

MODY diabetes; Liver fibrosis; Type 2 diabetesDiabetes MODY; Fibrosis hepática; Diabetes tipo 2Diabetis MODY; Fibrosi hepàtica; Diabetis tipus 2Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) have been traditionally linked to one another. Recent studies suggest that NAFLD may be increasingly common in other types of diabetes such as type 1 diabetes (T1DM) and less frequently ketone-prone and Maturity-onset Diabetes of the Young (MODY) diabetes. In this review, we address the relationship between hyperglycemia and insulin resistance and the onset and progression of NAFLD. In addition, despite the high rate of patients with T2DM and other diabetes phenotypes that can alter liver metabolism and consequently develop steatosis, fibrosis, and cirrhosis, NALFD screening is not still implemented in the daily care routine. Incorporating a clinical algorithm created around a simple, non-invasive, cost-effective model would identify high-risk patients. The principle behind managing these patients is to improve insulin resistance and hyperglycemia states with lifestyle changes, weight loss, and new drug therapies

Risk factors for persistent enterococcal bacteraemia: a multicentre retrospective study

Enterococcal bacteraemia; Enterococcus; Persistent bacteraemiaBacteriemia enterocócica, Enterococo; Bacteriemia persistenteBacterèmia enterocòccica; Enterococ; Bacterèmia persistentObjectives Conditions favouring persistent enterococcal bacteraemia (p-EB) have not been fully investigated yet. The aim of our study is to analyse risk factors for p-EB and its impact on mortality. Methods International two-centre retrospective study of all hospitalised adults with enterococcal bacteraemia managed with follow-up blood cultures (BCs) during the period 2011–2019. Exclusion criteria were: (1) death within 72 hours from index BCs and (2) polymicrobial bacteraemia. Primary endpoint was p-EB, defined as further isolation of the same species of Enterococcus spp. from BCs after at least 72 hours of appropriate antibiotic therapy. Multivariable logistic regression model was performed to assess risk factors for p-EB. The impact of p-EB on 30-day mortality was assessed by Kaplan-Meier survival curve and Cox regression multivariable model. Results During the study period, 244 enterococcal bacteraemia were diagnosed. P-EB were 13.5% (33/244). At multivariable analysis, factors independently associated with p-EB were hematologic malignancy (OR 4.60 [95% CI 1.32–16.00], P = 0.01), infective endocarditis (OR 7.99 [95% CI 2.20–28.9], P = 0.002), and use of daptomycin as initial treatment (OR 4.50 [95% CI 1.29–15.61], P = 0.018). Mortality rate was higher in the p-EB group (32% vs. 18%). Kaplan-Meier survival curve showed that patients with p-EB were less likely to survive at 30 days from index BCs (log-rank P = 0.002). Using a Cox regression model, independent predictors of 30-day mortality were hematologic malignancy (HR 2.30 [95% CI 1.02–4.11], P = 0.043), p-EB (HR 1.93 [95% CI 0.92–4.04], P = 0.08), and septic shock (HR 5.92 [95% CI 2.17–16.30], P = 0.001). Conclusion P-EB was diagnosed mainly in very fragile patients and in those receiving daptomycin as frontline therapy. P-EB may have an impact on mortality

Are Women’s Empowerment and Income Inequality Associated with Excess Weight in Latin American Cities?

Income inequality; Latin America; Women’s empowermentDesigualdad de ingresos; América Latina; Empoderamiento de la mujerDesigualtat d'ingressos; Amèrica Llatina; Empoderament de la donaWhile income gradients and gender inequalities in excess weight have been noted elsewhere, data from Latin American cities is lacking. We analyzed gender-specific associations between city-level women’s empowerment and income inequality with individual-level overweight/obesity, assessing how these associations vary by individual education or living conditions within cities in Latin America. Data came from national surveys and censuses, and was compiled by the SALURBAL project (Urban Health in Latin America). The sample included 79,422 individuals (58.0% women), living in 538 sub-cities, 187 cities, and 8 countries. We used gender-stratified Poisson multilevel models to estimate the Prevalence Rate Ratios (PRR) for overweight/obesity (body mass index ≥ 25 kg/m2) per a unit change in city-level women’s empowerment (proxied by a score that measures gender inequalities in employment and education) and income inequality (proxied by income-based Gini coefficient). We also tested whether individual education or sub-city living conditions modified such associations. Higher city labor women’s empowerment (in women) and higher city Gini coefficient (in men) were associated with a lower prevalence of overweight/obesity (PRR = 0.97 (95%CI 0.94, 0.99) and PRR = 0.94 (95%CI 0.90, 0.97), respectively). The associations varied by individual education and sub-city living conditions. For labor women’s empowerment, we observed weakened associations towards the null effect in women with lower education and in residents of sub-cities with worse living conditions (men and women). For the Gini coefficient, the association was stronger among men with primary education, and a negative association was observed in women with primary education. Our findings highlight the need for promoting equity-based policies and interventions to tackle the high prevalence of excess weight in Latin American cities.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature

Influence of Type 2 Diabetes in the Association of PNPLA3 rs738409 and TM6SF2 rs58542926 Polymorphisms in NASH Advanced Liver Fibrosis

Advanced fibrosis; Nonalcoholic steatohepatitis; Type 2 diabetesFibrosis avanzada; Esteatohepatitis no alcohólica; Diabetes tipo 2Fibrosi avançada; Esteatohepatitis no alcohòlica; Diabetis tipus 2Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d’Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13–10.20; p < 0.001), PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63–9.54; p = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03–77.35; p = 0.001 for PNPLA3 rs738409 and OR = 11.45; 95%CI 3.16–41.55; p < 0.001 for TM6SF2 rs58542926). In non-T2D patients, the IR (HOMA-IR ≥ 5.2, OR = 14.33; 95%CI 2.14–18.66; p = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71–650.84; p = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the PNPLA3 rs738409 and/or TM6SF2 rs58542926 polymorphisms, respectively

Fat: Quality, or Quantity? What Matters Most for the Progression of Metabolic Associated Fatty Liver Disease (MAFLD)

Fibrosi; Obesitat; Àcid palmític (AP)Fibrosis; Obesidad; Ácido palmítico (AP)Fibrosis; Obesity; Palmitic acid (PA)Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils); 2. HP-WD—high concentration of PA (main fat source—palm oil); 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.This work was supported by the MINECO Retos SAF2016-78711, SAF2017-87919-R, PID2020-117827RB-IOO, PID2020-117941RB-IOO, EXOHEP-CM S2017/BMD-3727, NanoLiver-CM Y2018/NMT-4949, AMMF 2018/117, COST Action CA17112 and UCM-25/2019, German Research Foundation (SFB/TRR57/P04, SFB 1382-403224013/A02). F.J.C. and Y.A.N. are Ramón y Cajal Researchers RYC-2014-15242 and RYC-2015-17438. F.J.C. is a Gilead Liver Research Scholar. The research group belongs to the validated Research Groups Ref. 970935 ¨Liver Pathophysiology¨, 920631 ¨Lymphocyte immunobiology¨, 920361 “Inmunogenética e6937 inmunología de las mucosas” and IBL-6 (imas12-associated). O.E.-V. is supported by Beca FPI (associated with MINECO SAF2017-87919R), C.-S.G. by Atracción de Talento 2019-T1/BMD-1331 and R.B.-U. by Contratos predoctorales de personal investigador en formación UCM-Banco Santander (CT63/19). F.G. is a Chinese Scholarship Council (CSC) fellow. T.B. is supported by the German Research Foundation SFB 1382-403224013/B07, and P.A. by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971-16) and MCIU/AEI/FEDER, UE (RTI2018-095134-B-100)

Non-Invasive Tests of Liver Fibrosis Help in Predicting the Development of Hepatocellular Carcinoma among Patients with NAFLD

Carcinoma hepatocelular; Elastografía transitoriaCarcinoma hepatocel·lular; Elastografia transitòriaHepatocellular carcinoma; Transient elastographyBackground: The potential role of non-invasive tests (NITs) for liver fibrosis for hepatocellular carcinoma (HCC) prediction remains poorly known. Methods: Retrospective analysis of a NAFLD cohort from a single university hospital in Barcelona, Spain. Incidence rates and cumulative incidence for the overall cohort, as well as cirrhotic and non-cirrhotic patients were calculated. Logistic regression analyses were carried out to investigate risk factors of HCC. Results: From the entire cohort of 1040 patients, 996 patients (95.8%) were analyzed, in whom 35 cases of HCC were detected, of which 26 (72.4%) HCC incident cases were newly diagnosed during a median follow-up of 2.5 (1.9–3.6) years. Two-hundred and thirty-one (23.2%) were cirrhotic at baseline. With the exception of 2 (7.7%) cases of HCC, the rest were diagnosed in cirrhotic patients. Overall HCC cumulative incidence was 9.49 (95% CI 6.4–13.9) per 1000 person-years. The incidence rate for cirrhotic patients was 41.2 (95% CI 27.6–61.6) per 1000 person-years and 0.93 (95% CI 0.23–3.7) per 1000 person-years for patients without cirrhosis. Overall mortality was significantly higher amongst patients with HCC (4.4% vs. 30.8%, p < 0.001). In patients with available liver biopsy (n = 249, 25%), advanced fibrosis (F3–F4) was significantly associated with higher HCC incidence, but not steatosis, lobular inflammation, nor ballooning. In the overall cohort, FIB-4 ≥1.3 (HR 8.46, 95% CI 1.06–67.4, p = 0.044) and older age (HR 1.06, 95% CI 1.01–1.11, p = 0.025) were associated with increasing risk of HCC over time, whereas in cirrhotic patients predictors of HCC included decreasing values of albumin (HR 0.34, 95% CI 0.13–0.87, p = 0.024), platelets (HR 0.98, 95% CI 0.98–0.99, p = 0.001), and increasing values of liver stiffness (HR 1.03, 95% CI 1.00–1.06, p = 0.016). Conclusions: In a Spanish cohort of NAFLD patients, HCC was rare in non-cirrhotic patients. NITs might play a relevant role at predicting HCC.The study was conducted in accordance with the Declaration of Helsinki and approved by the Vall d’Hebron University Hospital Campus Institutional Review Board (study protocol code PR(AG)626/2021)

Risk of infections in patients with NAFLD and Type 2 Diabetes under treatment with SGLT2 inhibitors and relationship with liver outcomes: A retrospective case-control study

Hepatic outcomes; Infections; Sodium-glucose co-transporter-2 inhibitorsResultados hepáticos; Infecciones; Inhibidores del cotransportador de sodio-glucosa-2Resultats hepàtics; Infeccions; Inhibidors del cotransportador de sodi-glucosa-2Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in developed countries, with its incidence growing parallel to the epidemics of obesity and type 2 diabetes mellitus (T2DM). Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are becoming a cornerstone in the management of cardiovascular health and some studies suggest the potential role in NAFLD. However, patients under treatment with SGLT2i are at risk of developing genitourinary fungal infections (GFIs). Moreover, both NAFLD and SGLT2i have a strong influence on the immune system, and therefore the risk of infections other than GFIs could be increased in NAFLD patients treated with SGLT2i. We aimed to examine the possible association of SGLT2i with infections and hepatic outcomes in NAFLD patients. Methods: We conducted a case-control study including NAFLD patients with T2DM visited at the Liver Unit outpatient clinic from 2016 to 2021 with a minimum follow-up of 6 months by selecting 65 patients receiving SGLT2i and 130 matched patients with other types of antidiabetic treatment. Results: During follow-up, GFIs were significantly higher in the SGLT2i group (15.4% vs. 3.8%; p=0.008), whereas there were no differences in the occurrence of overall infections (41.5% vs. 30%; p=0.1) nor in other types of specific infections. In the multivariable analysis, treatment with SGLT2i was not independently associated with higher odds of overall infection. On the other hand, SGLT2i patients showed a significantly lower incidence of hepatic events (1.5% vs. 10.7%; p=0.02). There were no significant different in all-cause mortality between cases and controls. Conclusions: NAFLD patients with T2DM receiving SGLT2i more frequently presented GFIs, whereas the incidence of other types of infections was not found to be higher than in other patients with NAFLD and T2DM treated with other drugs. Moreover, SGLT2i-treated patients had a lower occurrence of hepatic events. Further studies are warranted to validate our data.Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898