Gut-related molecules as potential biomarkers in patients with decompensated cirrhosis.

INTRODUCTION AND OBJECTIVES: Microbial translocation contributes to cirrhosis progression and complications. This study aims to investigate whether molecules related to intestinal permeability or microbial translocation can serve as prognostic biomarkers in patients with decompensated cirrhosis. MATERIALS AND METHODS: We prospectively evaluated hospitalized patients with decompensated cirrhosis for liver function, complications during hospitalization, in-hospital mortality, composite outcomes of in-hospital mortality and complications, 12-month mortality, and survival rates. Blood samples were collected upon admission, and 1,3 beta-d-glucan, zonulin, calprotectin, and lipopolysaccharide-binding protein were measured using commercial kits. RESULTS: Ninety-one patients with decompensated cirrhosis were enrolled. The mean age was 58 ±â€¯12 years; 57% were male. The three main cirrhosis etiologies were hepatitis C (35%), alcohol (25%), and non-alcoholic steatohepatitis (17%). In terms of liver function, 52% were Child C, and 68% had model for end-stage liver disease ≥15. The in-hospital and one-year mortality rates were 31% and 57%, respectively. Child-Pugh, 1,3 beta-glucan, and model for end-stage liver disease were positively correlated; zonulin was associated with complications during hospitalization (acute kidney injury) and composite outcomes, and calprotectin was associated with all outcomes except 12-month mortality. CONCLUSIONS: Serum calprotectin and zonulin levels emerge as noninvasive prognostic biomarkers for potentially unfavorable outcomes in patients with decompensated cirrhosis.

Computed tomography and magnetic resonance enterography findings in Crohn's disease: what does the clinician need to know from the radiologist?

The purpose of this pictorial essay was to discuss and illustrate computed tomography and magnetic resonance enterography findings in patients with Crohn's disease. These noninvasive and easily performed methods for the evaluation of Crohn's disease are useful for differentiating between active and fibrotic bowel disease, and can help to guide treatment (medical vs surgical). Although inflammatory and fibrostenotic findings of Crohn's disease may overlap, computed tomography and magnetic resonance enterography can help to identify the presence, extent, and severity of active inflammation that may respond to medical therapy, and the existence of fistulas and fibrostenosis that may benefit from surgical management.

Prevalence of occult hepatitis B virus infection in kidney transplant recipients.

In this cross-sectional study, 207 hepatitis B surface antigen (HBsAg)-negative kidney transplant recipients were evaluated based on demographic and epidemiological data and on the levels of serological markers of hepatitis B virus (HBV) and hepatitis C virus infection and liver enzymes. Patients with HBV or human immunodeficiency virus infection were excluded. Sera were analysed for the presence of HBV-DNA. HBV-DNA was detected in two patients (1%), indicating occult hepatitis B (OHB) infection (the HBV-DNA loads were 3.1 and 3.5 IU/mL in these patients). The results of the liver function tests were normal and no serological markers indicative of HBV infection were detected. The prevalence of OHB infection was low among kidney transplant recipients, most likely due to the low HBsAg endemicity in the general population of the study area.

A single nucleotide polymorphism, rs129679860, in the IL28B locus is associated with the viral kinetics and a sustained virological response in a chronic, monoinfected hepatitis C virus genotype-1 Brazilian population treated with pegylated interferon-ribavirin.

Single nucleotide polymorphisms (SNPs) in the interleukin (IL)28B locus have been associated with a sustained virological response (SVR) in interferon-ribavirin (IFN-RBV)-treated chronic hepatitis C virus (HCV)-infected patients in European and African populations. In this study, the genotype frequency of two IL28B SNPs (rs129679860 and rs8099917) in a cohort of chronic HCV-monoinfected patients in Brazil was evaluated and the SNP sufficient to predict the treatment response outcome was determined. A total of 66 naïve genotype-1 chronic HCV-infected patients were genotyped and the associated viral kinetics and SVR were assessed. The overall SVR was 38%. Both the viral kinetics and SVR were associated with rs129679860 genotypes (CC = 62% vs. CT = 33% vs. TT = 18%, p = 0.016). However, rs8099917 genotypes were only associated with SVR (TT = 53% vs. TG = 33% vs. GG = 18%; p = 0.032). In this population, the analysis of a single SNP, rs12979860, successfully predicts SVR in the IFN-RBV treatment of HCV.

Time trends and geographic distribution of hepatocellular carcinoma in Brazil: An ecological study.

The incidence of hepatocellular carcinoma (HCC) is increasing globally, and HCC is the fourth leading cause of cancer-related death. This ecological study aimed to investigate the time trends and geographic distribution of HCC in Brazil. Data from the Brazilian Health Public System were retrospectively collected from January 2005 to December 2018. Hospitalization and intrahospital lethality rates for HCC were stratified by age and sex. Hospitalization rates and associated lethality per 100,000 inhabitants in each municipality were included in a worksheet to build maps displaying the estimates and the geographic distribution of HCC. From 2005 to 2018, a total of 75,466 admissions for HCC were registered and the mean hospitalizations increased from 2.1 to 5.8/100,000 inhabitants (176%). The greatest increase occurred among patients older than 50, particularly in males above 70 years old. Prevalence rates increased throughout the country, with the highest levels detected in the South and Southeast. However, the increase was proportionally higher in the Northeast (377%), especially in municipalities not integrated into metropolitan regions. The HCC lethality rate remained relatively stable in both sexes, ranging from 21% to 25% (19%), but it was higher among older patients. The length of hospital stay did not differ between survivors and nonsurvivors throughout the study period. HCC hospitalizations are rising, particularly above 50 years of age and in rural areas, not paralleled by lethality rates. This suggests ongoing changes in environmental and socioeconomic factors in Brazil.

Noninvasive predictors of esophageal varices in patients with hepatosplenic schistosomiasis mansoni.

BACKGROUND: No previous study have evaluated transient elastography for predicting esophageal varices in hepatosplenic schistosomiasis. AIM: To investigate noninvasive methods of predicting esophageal varices in patients with hepatosplenic schistosomiasis mansoni. METHODS: Cross-sectional multicentric study included 51 patients with hepatosplenic schistosomiasis. Patients underwent ultrasonography-dopplerfluxometry, upper endoscopy, complete blood cell count and transient elastography (Fibroscan®) for liver and spleen stiffness measurement (LSM and SSM). Noninvasive scores previously established for cirrhotic population were studied: platelet count to spleen diameter ratio (PSR), LSM-spleen diameter to platelet ratio score (LSPS) and varices risk score (VRS). We proposed a version of LSPS and VRS by replacing LSM with SSM and named them SSPS and modified-VRS, respectively. RESULTS: Esophageal varices were detected in 42 (82.4%) subjects. Individuals with varices presented higher SSM (73.5 vs 36.3 Kpa, p = 0.001), splenic vein diameter (10.8 vs 8.0 mm, p = 0.017), SSPS (18.7 vs 6.7, p = 0.003) and modified-VRS (4.0 vs 1.4, p = 0.013), besides lower PSR (332 vs 542, p = 0.038), than those without varices. SSPS was independently associated with varices presence (OR=1.19, 95%CI 1.03-1.37, p = 0.020) after multivariate analysis. In a model excluding noninvasive scores, SSM was independently associated with varices diagnosis (OR=1.09, 95%CI 1.03-1.16, p = 0.004). AUROC was 0.856 (95%CI 0.752-0.961, p = 0.001) for SSM and 0.816 (95%CI 0.699-0.932, p = 0.003) for SSPS (p = 0.551). CONCLUSIONS: Spleen-related variables were predictors of esophageal varices: SSM, splenic vein diameter, SSPS, modified-VRS and PSR. Multivariate models indicated that SSM and SSPS are useful tools for predicting varices in non-cirrhotic portal hypertension by hepatosplenic schistosomiasis and may be used in clinical practice.

Acute hepatitis C in Brazil: results of a national survey.

The incidence of acute hepatitis C has decreased in the world. However, new cases are still reported. The objective of this study was to obtain data of acute hepatitis C in Brazil and to identify risk factors of transmission, diagnostic criteria, clinical presentation, evolution, and treatment. A questionnaire was sent to all members of the Brazilian Society of Hepatology. Sixteen centers participated with a total of 170 cases between 2000 and 2008. Among them, 37 had chronic renal failure on hemodialysis and were evaluated separately. The main diagnostic criterion in non-uremic patients was ALT (alanine aminotransferase) elevation associated with risk factors. In patients with chronic renal failure, anti-hepatitis C virus (HCV) seroconversion was the most frequent criterion. Among the 133 non-uremic patients the main risk factors were hospital procedures, whereas in hemodialysis patients, dialysis was the single risk factor in 95% of the cases. Jaundice was more frequent in non-uremic patients (82% vs. 13%; P < 0.001) and ALT levels were higher in these individuals (P < 0.001). Spontaneous clearance was more frequent in non-uremic patients (51% vs. 3%; P < 0.001). Sixty-five patients were treated: 39 non-uremic patients and 26 on dialysis. Sustained virological response rates were 60% for non-uremic and 58% for uremic patients (P = 0.98). There was no association of these rates with the study variables. These findings show that cases of acute hepatitis C are still occurring and have been related predominantly to hospital procedures. Measures to prevent nosocomial transmission should be adopted rigorously and followed to minimize this important source of infection observed in this survey.

Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients.

Mutations located in the 109-amino acid fragment of NS5B are typically associated with resistance to interferon (IFN) and ribavirin (RIB) and to new antiviral drugs. The prevalence of these mutations was examined in 69 drug-naïve individuals with hepatitis C virus (HCV) infections in Rio de Janeiro, Brazil. Mutations related to non-response to IFN/RIB were observed in all subtypes studied (1a, 1b, 2b, 3a and 4). The most common mutation was Q309R, present in all subtypes, except subtype 2b with frequency above 20%. D244N was detected only in subtype 3a and A333E was detected only in subtype 2b. We did not detect the S282T, S326G or T329I mutations in any of the samples analysed. Of note, the C316N mutation, previously related to a new non-nucleoside compound (HCV796 and AG-021541), was observed in only eight of 33 (24%) samples from subtype 1b. Site 316 was under positive selection in this HCV variant. Our data highlight the presence of previously described resistance mutations in HCV genotypes from drug-naïve patients.

Limited cardiopulmonary capacity in patients with liver cirrhosis when compared to healthy subjects.

OBJECTIVES: The present study compared cardiorespiratory capacity between cirrhotic patients and healthy subjects. METHODS: Nineteen cirrhotic patients and 19 healthy subjects, paired by age and gender, participated in the study. Volunteers performed an incremental cardiopulmonary test with a ramp protocol, a ventilatory and metabolic variables were obtained and analyzed. The recovery was analyzed by calculating the time needed for 50% of oxygen consumption (VO2) recovery to occur as the median between the peak of the exercise and the end of recovery on the VO2 curve (T1/2). The VE/VCO2 slope were performed by the linear regression of ventilation (VE) and carbon dioxide production (VCO2) data. RESULTS: During resting condition, cirrhotic patients presented significantly higher levels of VO2 compared to healthy subjects. The VE/ VO2 and VE/ VCO2 values were significantly higher in the control group at the anaerobic threshold and at the peak of the test compared to cirrhotic patients. Time under effort was significantly higher for healthy subjects. CONCLUSIONS: Based on these findings, it is possible to conclude that liver cirrhosis can compromise the patients' quality of life, mainly by inducing metabolic alterations which can impair functional capacity and lead to a sedentary lifestyle.

Cardiovascular Acute Effects of Traditional vs. Paired Set Resistance Training in Patients With Liver Cirrhosis.

Purpose: This study compared the acute effects of two different resistance training methods on heart rate variability, blood pressure, and rating of perceived exertion in patients with liver cirrhosis. Methods: Ten patients with Child-Pugh A (seven women and three men) participated in two experimental sessions, in random order: The traditional set condition consisted of three sets of six exercises performed in a sequential manner, while the paired set condition consisted of alternating sets between two exercises (three pairs of exercises). Ten repetitions were performed for each set with 70% of a 10 repetition maximum load and with 2 min rest between sets. Blood pressure and heart rate variability were assessed pre-workout and for 60 min post-workout. The rating of perceived exertion was assessed at the end of the third set for each exercise. Results: Significant alterations in heart rate variability were observed when considering the lowest value obtained during recovery, in which the SDNN was reduced in both the traditional set and paired set conditions, as well as the root mean square of standard deviation for the traditional set condition (p < .05). Additionally, for the paired set condition, there was a significant reduction in the HFnu band and a significant increase in the LFnu band (p < .05). Effect size showed reductions in diastolic and mean blood pressure until 30 min in a small magnitude for traditional sets. Conclusion: Similar cardiovascular responses were observed between methods eliciting normal physiological responses within safe limits for patients with liver cirrhosis.

Association between serum and dietary antioxidant micronutrients and advanced liver fibrosis in non-alcoholic fatty liver disease: an observational study.

BACKGROUND: Despite clinical trials with antioxidant supplementation, few studies have been conducted to evaluate the nutritional status of antioxidant vitamins and minerals, and none have reported on the status of these serum antioxidants associated with the dietary intake of antioxidants by non-alcoholic fatty liver disease (NAFLD) patients. OBJECTIVE: To evaluate association between serum and dietetics antioxidants with liver fibrosis in patients with NAFLD. METHODS: Across-section analysis with out with 72 patients diagnosed with NAFLD. Hepatic fibrosis was measured by FibroScan®, and liver stiffness ≥7.9 kPa was considered to indicate advanced fibrosis. Retinol, alpha-tocopherol, ascorbic acid, beta-carotene, serum zinc, and selenium were evaluated, as was the dietary intake of these micronutrients in the previous 24 h (using 24-h dietary recall). The Mann-Whitney test was used to compare the fibrosis groups and, a linear regression analysis was performed to determine associated risk factors between age, sex, BMI, hepatic fibrosis, and serum antioxidants. RESULTS: A high proportion of inadequate serum retinol (20.8%), vitamin C (27%), and selenium (73.6%) was observed in the patients with NAFLD, in addition to a significant inadequacy of vitamin A (98.3%) and vitamin E (100%) intake. Patients with advanced liver fibrosis had reduced levels of serum retinol (P = 0.002), with liver fibrosis being the independent risk factor associated with serum retinol lower. CONCLUSION: Hepatic fibrosis was associated with a reduction in serum retinol and was reduced in advanced fibrosis. NAFLD patients showed an important serum deficiency and insufficient dietary intake of the evaluated micronutrients.

Higher cut-off values of non-invasive methods might be needed to detect moderate-to-severe steatosis in morbid obese patients: a pilot study.

To evaluate the diagnostic value of described thresholds of controlled attenuation parameter (CAP) and biomarker scores for liver steatosis and to evaluate new cut-offs to detect moderate-to-severe steatosis (S2-3) in patients with morbid obesity. In this prospective study, 32 patients with morbid obesity with indications for bariatric surgery (15 women and 17 men, mean age = 36 years, median BMI = 40.2 kg/m2) underwent CAP, magnetic resonance spectroscopy (MRS), three biomarker scores (Steato-ELSA, Fatty Liver Index (FLI), and Hepatic Steatosis Index (HSI)), and liver biopsy. Subjects were divided into an exploratory cohort (reliable CAP and liver biopsy) and a confirmatory cohort (reliable CAP and MRS) to evaluate new thresholds for CAP and biomarker scores to detect S2-3. Receiver operator characteristic (ROC) curves analyses were performed and the optimal cut-off points were identified using the maximal Youden index. A total of 22 patients had CAP measure and liver biopsy (exploratory cohort) and 24 patients had CAP measure with MRS (confirmatory cohort). New cut-offs were identified for detection of S2-3 by the non-invasive tests using liver biopsy as the reference standard (exploratory cohort). Considering the new proposed cut-offs for detection of S2-3 for CAP (≥ 314 dB/m), Steato-ELSA (≥ 0.832), FLI (≥ 96), and HSI (≥ 53), for the exploratory and confirmatory cohorts sensitivities were: 71-75%, 86-81%, 85-81%, and 71-69% and specificities were: 94-89%, 75-63%, 63-63%, and 75-88%, respectively. Higher cut-offs for CAP and biomarker scores may be better to diagnose moderate-to-severe steatosis in patients with morbid obesity.

Can gadoxetic acid-enhanced magnetic resonance imaging be used to avoid liver biopsy in patients with nonalcoholic fatty liver disease?

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. The diagnosis of nonalcoholic steatohepatitis (NASH), the most severe form of NAFLD, is crucial and has prognostic and therapeutic implications. However, currently this diagnosis is based on liver biopsy and has several limitations. AIM: To evaluate the performance of gadoxetic acid-enhanced magnetic resonance imaging (GA-MRI) in differentiating isolated steatosis from NASH in patients with NAFLD. METHODS: In this prospective study, 56 patients with NAFLD (18 with isolated steatosis and 38 with NASH) underwent GA-MRI. The contrast enhancement index (CEI) was calculated as the rate of increase of the liver-to-muscle signal intensity ratio from before and 20 min after intravenous GA administration. Between-group differences in mean CEI were examined using Student's t test. The area under the receiver operator characteristic curve and the diagnostic performance of gadoxetic acid-enhanced magnetic resonance imaging were evaluated. RESULTS: The mean CEI for all subjects was 1.82 ± 0.19. The mean CEI was significantly lower in patients with NASH than in those with isolated steatosis (P = 0.008). Two CEI cut-off points were used: < 1.66 (94% specificity) to characterize NASH and > 2.00 (89% sensitivity) to characterize isolated steatosis. CEI values between 1.66 and 2.00 indicated liver biopsy, and the procedure could be avoided in 40% of patients with NAFLD. CONCLUSION: GA-MRI is an effective noninvasive method that may be useful for the differentiation of NASH from isolated steatosis, and could help to avoid liver biopsy in patients with NAFLD.

Hepatitis C Virus-Infected Responders and Relapsers to Treatment Show Similar Genetic Profiles of IL28B and IL10 Single Nucleotide Polymorphisms.

Genotype 1 of hepatitis C virus (HCV) is the most prevalent worldwide. Pegylated-interferon and ribavirin therapy is still used in the developing world but has less efficiency in this genotype. Single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 (IL28B) and rs1800896, rs1800871, and rs1800872 (IL10) are related to treatment outcome, but previous studies clustered nonresponse and relapse patients. The aim of this study is to analyze the frequency of those SNPs in HCV genotype 1 for response, nonresponse, or relapse. Patients were classified according to treatment outcome. Genomic DNA was extracted by blood samples and SNPs were defined by PCR and sequencing. Data analysis was performed with R project. The frequency of rs12979860 CC was similar among responders (0.48) and relapsers (0.46) and lower among nonresponders (0.18). The same trend was observed for rs8099917 TT. rs12979860 CC showed a protective effect for relapsers compared to nonresponders (OR = 0.25) as it occurs with responders (OR = 0.17). Haplotypes 12979860/C rs8099917/T were associated with protection against the nonresponder phenotype compared to responders (OR = 0.27) or relapsers (OR = 0.37). Frequency of rs12979860 and rs8099917 is different between relapsers and nonresponders, but similar between relapsers and responders.

Limited cardiopulmonary capacity in patients with liver cirrhosis when compared to healthy subjects

SUMMARY OBJECTIVES: The present study compared cardiorespiratory capacity between cirrhotic patients and healthy subjects. METHODS: Nineteen cirrhotic patients and 19 healthy subjects, paired by age and gender, participated in the study. Volunteers performed an incremental cardiopulmonary test with a ramp protocol, a ventilatory and metabolic variables were obtained and analyzed. The recovery was analyzed by calculating the time needed for 50% of oxygen consumption (VO2) recovery to occur as the median between the peak of the exercise and the end of recovery on the VO2 curve (T1/2). The VE/VCO2 slope were performed by the linear regression of ventilation (VE) and carbon dioxide production (VCO2) data. RESULTS: During resting condition, cirrhotic patients presented significantly higher levels of VO2 compared to healthy subjects. The VE/ VO2 and VE/ VCO2 values were significantly higher in the control group at the anaerobic threshold and at the peak of the test compared to cirrhotic patients. Time under effort was significantly higher for healthy subjects. CONCLUSIONS: Based on these findings, it is possible to conclude that liver cirrhosis can compromise the patients' quality of life, mainly by inducing metabolic alterations which can impair functional capacity and lead to a sedentary lifestyle.

Intravoxel Incoherent Motion Diffusion Weighted MR Imaging at 3.0 T: Assessment of Steatohepatitis and Fibrosis Compared with Liver Biopsy in Type 2 Diabetic Patients.

OBJECTIVE: To evaluate the capability of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) to assess steatohepatitis and fibrosis determined by histopathology in type 2 diabetic patients. METHODS: Fifty-nine type 2 diabetic patients (49 women, 10 men; mean age, 54 ± 9 years) were submitted to liver biopsy for the evaluation of non-alcoholic fatty liver disease (NAFLD) and underwent DWI on a 3.0T MR system using 10 b values. Institutional approval and patient consent were obtained. Pure molecular-based (D), perfusion-related (D*), and vascular fraction (f) were calculated using a double exponential model and least squares curve fitting. D, D*, and f were compared between patients with and without steatohepatitis and between patients with and without fibrosis. The variables were compared by using the Ranksum test and Student t-test. RESULTS: Steatohepatitis was observed in 22 patients and fibrosis in 16 patients. A lower D median (0.70 s/mm2 vs. 0.83 s/mm2, p<0.05) and a lower D* median (34.39 s/mm2 vs. 45.23 s/mm2, p<0.05) were observed among those with steatohepatitis. A lower D median (0.70 s/mm2 vs. 0.82 s/mm2, p<0.05) and a lower D* median (35.01 s/mm2 vs. 44.76 s/mm2, p=0.05) were also observed among those with fibrosis. CONCLUSION: IVIM-DWI has the potential to aid in the characterization of steatohepatitis and fibrosis.

Low bone mineral density in noncholestatic liver cirrhosis: prevalence, severity and prediction.

BACKGROUND: Metabolic bone disease has long been associated with cholestatic disorders. However, data in noncholestatic cirrhosis are relatively scant. AIMS: To determine prevalence and severity of low bone mineral density in noncholestatic cirrhosis and to investigate whether age, gender, etiology, severity of underlying liver disease, and/or laboratory tests are predictive of the diagnosis. PATIENTS/METHODS: Between March and September/1998, 89 patients with noncholestatic cirrhosis and 20 healthy controls were enrolled in a cross-sectional study. All subjects underwent standard laboratory tests and bone densitometry at lumbar spine and femoral neck by dual X-ray absorptiometry. RESULTS: Bone mass was significantly reduced at both sites in patients compared to controls. The prevalence of low bone mineral density in noncholestatic cirrhosis, defined by the World Health Organization criteria, was 78% at lumbar spine and 71% at femoral neck. Bone density significantly decreased with age at both sites, especially in patients older than 50 years. Bone density was significantly lower in post-menopausal women patients compared to pre-menopausal and men at both sites. There was no significant difference in bone mineral density among noncholestatic etiologies. Lumbar spine bone density significantly decreased with the progression of liver dysfunction. No biochemical variable was significantly associated with low bone mineral density. CONCLUSIONS: Low bone mineral density is highly prevalent in patients with noncholestatic cirrhosis. Older patients, post-menopausal women and patients with severe hepatic dysfunction experienced more advanced bone disease. The laboratory tests routinely determined in patients with liver disease did not reliably predict low bone mineral density.

Prevalence of occult hepatitis B virus infection in kidney transplant recipients

In this cross-sectional study, 207 hepatitis B surface antigen (HBsAg)-negative kidney transplant recipients were evaluated based on demographic and epidemiological data and on the levels of serological markers of hepatitis B virus (HBV) and hepatitis C virus infection and liver enzymes. Patients with HBV or human immunodeficiency virus infection were excluded. Sera were analysed for the presence of HBV-DNA. HBV-DNA was detected in two patients (1%), indicating occult hepatitis B (OHB) infection (the HBV-DNA loads were 3.1 and 3.5 IU/mL in these patients). The results of the liver function tests were normal and no serological markers indicative of HBV infection were detected. The prevalence of OHB infection was low among kidney transplant recipients, most likely due to the low HBsAg endemicity in the general population of the study area.