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.
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.
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).
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.
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.
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•NAFLD-related significant fibrosis predicts the occurrence of type 2 diabetes mellitus and arterial hypertension.•The annual incidence of metabolic outcomes is four-times higher in the presence of significant fibrosis.•Neither steatosis nor NASH predict the appearance of metabolic outcomes.•Hepamet fibrosis score >0.12 is associated with the risk of developing type 2 diabetes mellitus.
A key strategic issue in pre‐disaster planning for humanitarian logistics is the pre‐establishment of adequate capacity and resources that enable efficient relief operations. This paper develops a ...two‐stage stochastic optimization model to guide the allocation of budget to acquire and position relief assets, decisions that typically need to be made well in advance before a disaster strikes. The optimization focuses on minimizing the expected number of casualties, so our model includes first‐stage decisions to represent the expansion of resources such as warehouses, medical facilities with personnel, ramp spaces, and shelters. Second‐stage decisions concern the logistics of the problem, where allocated resources and contracted transportation assets are deployed to rescue critical population (in need of emergency evacuation), deliver required commodities to stay‐back population, and transport the transfer population displaced by the disaster. Because of the uncertainty of the event's location and severity, these and other parameters are represented as scenarios. Computational results on notional test cases provide guidance on budget allocation and prove the potential benefit of using stochastic optimization.
Direct‐acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus infection, including those with compensated cirrhosis. However, fewer data are ...available in patients with more advanced liver disease. Our retrospective, noninterventional, national, multicenter study in patients from the Spanish Hepa‐C registry investigated the effectiveness and safety of interferon‐free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 patients with cirrhosis (Child‐Turcotte‐Pugh CTP class A, n = 564; CTP class B/C, n = 175), 90% achieved sustained virologic response 12 weeks after treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94% versus 78%, and 4% versus 14%, respectively; both P < 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P < 0.001). Incident decompensation was the most common serious adverse event (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among CTP class B/C versus CTP class A patients (6.4% versus 0.9%; P < 0.001). Baseline Model for End‐Stage Liver Disease (MELD) score alone (cut‐off 18) was the best predictor of survival. Conclusion: Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≥18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. (Hepatology 2017;65:1810‐1822).
Worldwide, measures are being implemented to eradicate hepatitis B (HBV) and C (HCV) viruses, which can be transmitted from the mother during childbirth. This study aims to determine the prevalence ...of HBV and HCV in pregnant women in Spain, focusing on country of origin, epidemiological factors and risk of vertical transmission (VT).
Multicentre open-cohort study performed during 2015. HBV prevalence was determined in 21870 pregnant women and HCV prevalence in 7659 pregnant women. Epidemiological and risk factors for VT were analysed in positive women and differences between HBV and HCV cases were studied.
HBV prevalence was 0.42% (91/21870) and HCV prevalence was 0.26% (20/7659). Of the women with HBV, 65.7% (44/67) were migrants. The HBV transmission route to the mother was unknown in 40.3% of cases (27/67) and VT in 31.3% (21/67). Among risk factors for VT, 67.7% (42/62) of the women had viraemia and 14.5% (9/62) tested HBeAg-positive. All of the neonates born to HBV-positive mothers received immunoprophylaxis, and none contracted infection by VT. In 80% (16/20) of the women with HCV, the transmission route was parenteral, and nine were intravenous drug users. Viraemia was present in 40% (8/20) of the women and 10% (2/20) were HIV-coinfected. No children were infected. Women with HCV were less likely than women with HBV to breastfeed their child (65% vs. 86%).
The prevalences obtained in our study of pregnant women are lower than those previously documented for the general population. Among the women with HBV, the majority were migrants and had a maternal family history of infection, while among those with HCV, the most common factor was intravenous drug use. Despite the risk factors observed for VT, none of the children were infected. Proper immunoprophylaxis is essential to prevent VT in children born to HBV-positive women.
Background/Aims To investigate the effect of sustained virological response (SVR) on impaired fasting glucose (IFG) and/or type 2 diabetes (T2DM); to assess the influence of glucose abnormalities on ...the SVR rate. Methods 1059 patients with chronic HCV; normal glucose (< 100 mg/dl) in 734, IFG (between 100 and 125 mg/dl) in 218, and T2DM (⩾126 mg/dl) in 107 cases, were treated with interferon plus ribavirin over 24 or 48 weeks, depending on viral genotype. Results The SVR rate was lower in patients with IFG and/or T2DM than in patients with normal glucose concentrations 143/325 (44%) vs. 432/734 (58.8%); P = 0.002. In the follow-up, abnormal glucose concentrations were observed in 74 of 304 (24.3%) non-responders and in 49 of 430 (11.4%) sustained responders (log-rank: 13.8; P = 0.00002). Reverse stepwise logistic regression analysis identified the independent variables predictive of IFG or T2DM development as: sustained response (OR: 0.44; 95%CI = 0.20–0.97; P = 0.004) and fibrosis stage (OR: 1.46; 95%CI = 1.06–2.01; P = 0.02). Family history of DM, steatosis, gender, HCV viral load, genotype, triglycerides, cholesterol and BMI did not enter the multivariate analysis equation. Conclusions SVR reduces the risk of IFG and/or T2DM development in patients with chronic hepatitis C while altered glucose metabolism impairs sustained response to viral treatment.
The vertical transmission of hepatitis C virus (HCV‐VT) is a major route of HCV infection in children, but the risk factors remain incompletely understood. This study analyzed the role of interleukin ...28B (IL28B) in HCV‐VT and in the spontaneous clearance of HCV among infected infants. Between 1991 and 2009, 145 mothers were recruited for this study: 100 were HCV‐RNA+ve / human immunodeficiency virus negative (HIV−ve), with 128 children, and 33 were HCV‐RNA−ve/HCV antibody+ve, with 43 children. The infants were tested for HCV‐RNA at birth and at regular intervals until the age of 6 years. IL28B (single nucleotide polymorphism rs12979860) was determined in the mothers and children. HCV‐VT was assumed when children presented HCV‐RNA+ve in two subsequent blood samples. HCV‐VT‐infected infants were categorized as: (1) transient viremia with posterior HCV‐RNA−ve and without serum‐conversion; (2) persistent infection with serum‐conversion. Of the 31 mothers with CC polymorphism, 19 (61%) were HCV‐RNA+ve, whereas among the 68 mothers with non‐CC polymorphism, 56 (82%) were HCV‐RNA+ve. In all, 26 of 128 (20%) infants born to the HCV‐RNA+ve mothers acquired HCV infection, but only 9 (7%) were chronically infected. The rate of HCV‐VT was higher among the mothers with higher HCV viremia. No HCV‐VT was detected in the HCV‐RNA−ve women. Neither the mothers' nor the childrens' IL‐28 status was associated with an increased risk of HCV‐VT. The factors influencing viral clearance among the infected children were genotype non‐1 and genotype CC of IL28B. In logistic regression, child CC polymorphism was the only predictor of HCV‐clearance in HCV genotype‐1. Conclusion: High maternal viral load is the only predictive factor of HCV‐VT. IL28B plays no role in HCV‐VT, but IL28B CC child polymorphism is associated independently with the spontaneous clearance of HCV genotype‐1 among infected children. (HEPATOLOGY 2011;)
Poly(ADP-ribose)polymerases (PARPs) are a family of NAD+ consuming enzymes that play a crucial role in many cellular processes, most clearly in maintaining genome integrity. Here, we present an ...extensive analysis of the alteration of mitochondrial morphology and the relationship to PARPs activity after oxidative stress using an in vitro model of human hepatic cells. The following outcomes were observed: reactive oxygen species (ROS) induced by oxidative treatment quickly stimulated PARPs activation, promoted changes in mitochondrial morphology associated with early mitochondrial fragmentation and energy dysfunction and finally triggered apoptotic cell death. Pharmacological treatment with specific PARP-1 (the major NAD+ consuming poly(ADP-ribose)polymerases) and PARP-1/PARP-2 inhibitors after the oxidant insult recovered normal mitochondrial morphology and, hence, increased the viability of human hepatic cells. As the PARP-1 and PARP-1/PARP-2 inhibitors achieved similar outcomes, we conclude that most of the PARPs effects were due to PARP-1 activation. NAD+ supplementation had similar effects to those of the PARPs inhibitors. Therefore, PARPs activation and the subsequent NAD+ depletion are crucial events in decreased cell survival (and increased apoptosis) in hepatic cells subjected to oxidative stress. These results suggest that the alterations in mitochondrial morphology and function seem to be related to NAD+ depletion, and show for the first time that PARPs inhibition abrogates mitochondrial fragmentation. In conclusion, the inhibition of PARPs may be a valuable therapeutic approach for treating liver diseases, by reducing the cell death associated with oxidative stress.
Background & Aims:
Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect ...bona fide cases.
Methods:
A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed.
Results:
Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (
P < .0001), and had the worst outcome (Cox regression,
P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (
P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1–151;
P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6–37;
P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09–1.22;
P < .0001).
Conclusions:
Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.
We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide ...representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain.
Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded.
Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin.
Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.
Background & Aims:
We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin.
...Methods:
Patients (n = 159; 94 men; age, 41.7 ± 11.1 years) with chronic hepatitis C (genotype 1, n = 113; non-1 genotype, n = 46) received treatment with interferon plus ribavirin. Serum levels of leptin and insulin were measured, and the insulin resistance index (HOMA-IR: homeostasis model of assessment) and body mass index were calculated.
Results:
A sustained virological response was associated with lower age, insulin resistance index, body mass index, and γ-glutamyltranspeptidase and serum leptin levels. There was no association with viral load, sex, type of interferon, or cholesterol levels. A sustained virological response was achieved in 43.4% (46/113) of genotype 1 and 89% (32/36) of genotype 2 and 3 (
P = .0001) patients. Necroinflammatory activity and steatosis were not associated with the sustained virological response rate. Multivariate regression analysis indicated that the independent variables related to sustained virological response were genotype (odds ratio, 3.57; 95% confidence interval, 1.49–8.3;
P = .001), insulin resistance index (odds ratio, 1.82; 95% confidence interval, 1.08–3.06;
P = .012), and fibrosis (odds ratio, 1.36; 95% confidence interval, 1.01–1.84;
P = .029). A sustained virological response in patients with genotype 1 and insulin resistance (HOMA-IR > 2) occurred in 23 of 70 (32.8%; 95% confidence interval, 21.9%–43.9%) patients, vs. 26 of 43 (60.5%; 95% confidence interval, 45.9%–75.1%) genotype 1 patients without insulin resistance (
P = .007; odds ratio, 3.12, 95% confidence interval, 1.42–6.89).
Conclusions:
Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin.
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