Patient-specific genetic factors predict treatment failure in sofosbuvir-treated patients with chronic hepatitis C.

BACKGROUND & AIMS: According to pivotal clinical trials, cure rates for sofosbuvir-based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance-associated substitutions or clinical risk factors, yet the role of patient-specific genetic factors has not been well explored. We determined if patient-specific genetic factors help predict patients likely to fail sofosbuvir treatment in real-world treatment situations. METHODS: We recruited sofosbuvir-treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case-control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1-dependent production of sofosbuvir's active metabolite, interferon-λ signalling variants expected to impact a patient's immune response to the virus and an HLA variant associated with increased spontaneous and treatment-induced viral clearance. RESULTS: Three hundred and fifty-nine sofosbuvir-treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified CES1 variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR): 5.43; 95% confidence interval (CI): 1.64-18.01; P = .0057), replicated associations with IFNL4 variants predicted to increase interferon-λ signalling (eg rs12979860; OR: 2.25; 95% CI: 1.25-4.06; P = .0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in IL10RB; OR: 1.81; 95% CI: 1.01-3.24; P = .047). CONCLUSIONS: Ultimately, this work demonstrates that patient-specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner.

Sociodemographic risk factors for hepatitis C virus infection in a prospective cohort study of 257 persons in Canada who inject drugs.

Background: Approximately 60% of incident hepatitis C virus (HCV) infections are due to intravenous drug use; therefore, understanding the socio-demographics of people who inject drugs (PWID) is necessary to achieve HCV elimination. Methods: In this prospective cohort study of PWID, we determined patients' baseline HCV antibody, hepatitis B virus (HBV), and HIV serological status. HCV antibody- negative (anti-HCV-negative) cases were followed for seroconversion (median 17 mo with q3m testing) as part of a larger study to develop a vaccine for HCV. An interviewer-administered baseline questionnaire completed with all patients evaluated socio-demographic and clinical characteristics. Results: We tested 257 PWID (median age 40 [range 49-31]y, 81% men, 63% Caucasian, 28% Indigenous). Of these, 28% were positive for HCV antibodies (anti-HCV-positive) (median age 42 [range 49-36]y, 74% men, 69% Caucasian, 29% Indigenous). Compared with anti-HCV-negative PWID, anti-HCV-positive PWID reported injecting more morphine and hydromorphone, using more hydromorphone via non-injection routes, and were more likely to be enrolled in methadone programs. More than 60% reported previous HCV testing, but recent testing (<2 y) was more frequent in the anti-HCV-negative group (p = 0.03). All were HBV negative, but more than 50% of the anti-HCV-positive group had anti-HBs titres more than 10 IU/L compared with 35% of the anti-HCV-negative group (p = 0.01), and 3 of 257 were HIV positive (1 co-infected with HCV-HIV). Conclusions: In this prospective study, differences in age, timing of HCV testing and risk behaviours were found between anti-HCV-positive and anti-HCV-negative groups.

Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial.

PURPOSE: In obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH. METHODS: In a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota. RESULTS: Independent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P < 0.05). There were no adverse side effects that deterred individuals from consuming oligofructose for treatment of this disease. CONCLUSIONS: Independent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted. CLINICAL TRIAL: This trial was registered at Clinicaltrials.com as NCT03184376.

Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis.

BACKGROUND & AIMS: The prevalence of fatty liver underscores the need for non-invasive characterization of steatosis, such as the ultrasound based controlled attenuation parameter (CAP). Despite good diagnostic accuracy, clinical use of CAP is limited due to uncertainty regarding optimal cut-offs and the influence of covariates. We therefore conducted an individual patient data meta-analysis. METHODS: A review of the literature identified studies containing histology verified CAP data (M probe, vibration controlled transient elastography with FibroScan®) for grading of steatosis (S0-S3). Receiver operating characteristic analysis after correcting for center effects was used as well as mixed models to test the impact of covariates on CAP. The primary outcome was establishing CAP cut-offs for distinguishing steatosis grades. RESULTS: Data from 19/21 eligible papers were provided, comprising 3830/3968 (97%) of patients. Considering data overlap and exclusion criteria, 2735 patients were included in the final analysis (37% hepatitis B, 36% hepatitis C, 20% NAFLD/NASH, 7% other). Steatosis distribution was 51%/27%/16%/6% for S0/S1/S2/S3. CAP values in dB/m (95% CI) were influenced by several covariates with an estimated shift of 10 (4.5-17) for NAFLD/NASH patients, 10 (3.5-16) for diabetics and 4.4 (3.8-5.0) per BMI unit. Areas under the curves were 0.823 (0.809-0.837) and 0.865 (0.850-0.880) respectively. Optimal cut-offs were 248 (237-261) and 268 (257-284) for those above S0 and S1 respectively. CONCLUSIONS: CAP provides a standardized non-invasive measure of hepatic steatosis. Prevalence, etiology, diabetes, and BMI deserve consideration when interpreting CAP. Longitudinal data are needed to demonstrate how CAP relates to clinical outcomes. LAY SUMMARY: There is an increase in fatty liver for patients with chronic liver disease, linked to the epidemic of the obesity. Invasive liver biopsies are considered the best means of diagnosing fatty liver. The ultrasound based controlled attenuation parameter (CAP) can be used instead, but factors such as the underlying disease, BMI and diabetes must be taken into account. Registration: Prospero CRD42015027238.

A quantitative metabolomics profiling approach for the noninvasive assessment of liver histology in patients with chronic hepatitis C.

BACKGROUND: High-throughput technologies have the potential to identify non-invasive biomarkers of liver pathology and improve our understanding of basic mechanisms of liver injury and repair. A metabolite profiling approach was employed to determine associations between alterations in serum metabolites and liver histology in patients with chronic hepatitis C virus (HCV) infection. METHODS: Sera from 45 non-diabetic patients with chronic HCV were quantitatively analyzed using (1)H-NMR spectroscopy. A metabolite profile of advanced fibrosis (METAVIR F3-4) was established using orthogonal partial least squares discriminant analysis modeling and validated using seven-fold cross-validation and permutation testing. Bioprofiles of moderate to severe steatosis (≥33 %) and necroinflammation (METAVIR A2-3) were also derived. The classification accuracy of these profiles was determined using areas under the receiver operator curves (AUROCSs) measuring against liver biopsy as the gold standard. RESULTS: In total 63 spectral features were profiled, of which a highly significant subset of 21 metabolites were associated with advanced fibrosis (variable importance score >1 in multivariate modeling; R(2) = 0.673 and Q(2) = 0.285). For the identification of F3-4 fibrosis, the metabolite bioprofile had an AUROC of 0.86 (95 % CI 0.74-0.97). The AUROCs for the bioprofiles for moderate to severe steatosis were 0.87 (95 % CI 0.76-0.97) and for grade A2-3 inflammation were 0.73 (0.57-0.89). CONCLUSION: This proof-of-principle study demonstrates the utility of a metabolomics profiling approach to non-invasively identify biomarkers of liver fibrosis, steatosis and inflammation in patients with chronic HCV. Future cohorts are necessary to validate these findings.

Noninvasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis.

BACKGROUND: Liver disease is the third leading cause of mortality in patients with cystic fibrosis (CF). However, detection of CF-associated liver disease (CFLD) is challenging. OBJECTIVE: To evaluate the diagnostic performance of noninvasive methods for the detection of CFLD with a focus on transient elastography (TE). METHODS: Patients at the Adult CF Clinic of Calgary and Southern Alberta (n=127) underwent liver stiffness measurement (LSM) by TE using the FibroScan (FS, Ecosens, France) M probe; aspartate aminotransferase to platelet ratio index (APRI) and FibroTest (FT) scores were also calculated. The diagnostic performance of these tools for the detection of CFLD (defined as two or more the following criteria: abnormal liver biochemistry, hepatomegaly or sonographic abnormalities other than steatosis) were compared using the area under ROC curves. RESULTS: Forty-seven percent of the cohort was male. The median age was 27 years (interquartile range [IQR] 22 to 37 years) and body mass index 21 kg/m(2) (IQR 19 kg/m(2) to 23 kg/m(2)); 25% of patients were on ursodeoxycholic acid and 12% had undergone lung transplantation. The prevalence of CFLD was 14% (n=18). FS was successful in all patients; one (0.8%) patient had poorly reliable results (IQR/M >30% and LSM ≥7.1 kPa). Compared with patients without CFLD (n=109), individuals with CFLD had higher median LSM according to FS (3.9 kPa [IQR 3.4 to 4.9 kPa] versus 6.4 kPa [IQR 4.4 to 8.0 kPa]), APRI (0.24 [IQR 0.17 to 0.31] versus 0.50 [IQR 0.22 to 1.18]) and FT scores (0.08 [IQR 0.05 to 1.5] versus 0.18 [IQR 0.11 to 0.35]; all P<0.05). Area under ROC curve for FS, APRI and FT for the detection of CFLD were 0.78 (95% CI 0.65 to 0.92), 0.72 (95% CI 0.56 to 0.87) and 0.76 (95% CI 0.62 to 0.90) (P not significant). At a threshold of >5.2 kPa, the sensitivity, specificity, positive and negative predictive values of LSM according to FS for detecting CFLD were 67%, 83%, 40% and 94%, respectively. CONCLUSIONS: FS, APRI and FT were useful noninvasive methods for detecting CFLD in adults.

Acceptability and yield of birth-cohort screening for hepatitis C virus in a Canadian population being screened for colorectal cancer: a cross-sectional study.

BACKGROUND: Screening for hepatitis C virus (HCV) is recommended in patients born between 1945 and 1965 ("baby boomers") in the United States. Because these patients are often screened for colorectal cancer, dual screening for HCV may enhance case identification. Our objectives were to assess the acceptability and yield of screening for HCV among patients undergoing screening for colorectal cancer. METHODS: Patients referred for a colonoscopy to screen for colorectal cancer completed an anonymous survey regarding the acceptability of screening for HCV, risk factors and prior testing. The impacts of demographics and risk factors for HCV on willingness to be screened were determined using logistic regression, and the stored sera of 483 patients who had undergone screening for colorectal cancer between February 2011 and August 2012 were tested for HCV antibodies. RESULTS: Among 1012 survey respondents (median age 56 yr; 911 [90.0%] were baby boomers, 880 [87.0%] were white and 223 [22.0%] were born outside Canada), 123 patients (12.2%) reported prior testing for HCV. HCV was previously diagnosed in 9 of these patients (0.9%, representing 1.0% of the patients who were baby boomers): 5 (55.6% of those diagnosed) reported risk factors. Excluding patients diagnosed with HCV, 903 (90.0%) respondents indicated that they would consent to testing of blood or saliva for HCV. After adjusting for age, sex and status of immigration, patients who were white (odds ratio [OR] 3.38, 95% confidence interval [CI] 1.81-6.32) and patients with risk factors (> 1 v. 0: OR 3.67, 95% CI 1.12-12.02) had a greater acceptance of screening. Among 483 patients screened for colorectal cancer, 3 were anti-HCV positive (0.6%, 95% CI 0.1%-1.8%), representing 0.8% (95% CI 0.2%-2.4%) of the patients who were baby boomers. INTERPRETATION: Acceptance of screening for HCV is high among patients undergoing screening for colorectal cancer in the Calgary area. However, the low prevalence of HCV suggests that the cost-effectiveness of birth-cohort screening in this population warrants evaluation.

A novel method to identify fat malabsorption: the Serum Retinyl Palmitate Test.

BACKGROUND: Malabsorptive etiologies of chronic diarrhea are important to identify. The 72-h stool for fecal fat test (FFT), the gold standard for diagnosing fat malabsorption, is fraught with limitations that impact its reliability. Vitamin A, a fat-soluble vitamin, parallels the absorption of lipids. We assessed the feasibility and validate a novel clinical test, retinyl palmitate (RP), for the diagnosis of fat malabsorption, and to compare the results to the FFT. METHODS: Using a case-control study design, patients with chronic diarrhea secondary to suspected malabsorption, and healthy control subjects were identified. A Dietitian taught subjects to consume a 100g fat diet for the FFT with measurements of stool fat after 72-h. Serum levels of Vitamin A (retinol) and RP were measured by reversed-phase high pressure liquid chomatography. Two-way comparisons were made between the groups using 2 sample Wilcoxon rank-sum tests. RESULTS: Sixteen patients completed this study (8 cases and 8 control subjects). Fecal fat results were available for 15/16 patients. The sensitivity of the FFT was 100% (identified all cases), but the FFT specificity was 42%, as 4/7 control patients were identified as malabsorbers. Cases with short bowel syndrome had the lowest RP levels but this did not meet statistical significance. There was no significant difference for serum RP levels when comparing cases and control patients' AUC. CONCLUSIONS: Serum RP is useful to identify malabsorption, albeit in severe cases. Furthermore, we have shown that the 72-hour FFT has poor performance characteristics, highlighting the need for more useful diagnostics in identifying malabsorption.

Liver stiffness by transient elastography predicts liver-related complications and mortality in patients with chronic liver disease.

BACKGROUND: Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. METHODS: In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic. RESULTS: Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0-23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10-19.9, 20-39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03-1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75-0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%). CONCLUSIONS: Liver stiffness by TE accurately predicts the risk of death or hepatic complications in patients with chronic liver disease. TE may facilitate the estimation of prognosis and guide management of these patients.

The feasibility and reliability of transient elastography using Fibroscan®: a practice audit of 2335 examinations.

BACKGROUND: Liver stiffness measurement (LSM) using transient elastography is widely used in the management of patients with chronic liver disease. OBJECTIVES: To examine the feasibility and reliability of LSM, and to identify patient and operator characteristics predictive of poorly reliable results. METHODS: The present retrospective study investigated the frequency and determinants of poorly reliable LSM (interquartile range [IQR]/median LSM [IQR/M] >30% with median liver stiffness ≥7.1 kPa) using the FibroScan (Echosens, France) over a three-year period. Two experienced operators performed all LSMs. Multiple logistic regression analyses examined potential predictors of poorly reliable LSMs including age, sex, liver disease, the operator, operator experience (<500 versus ≥500 scans), FibroScan probe (M versus XL), comorbidities and liver stiffness. In a subset of patients, medical records were reviewed to identify obesity (body mass index ≥30 kg/m2). RESULTS: Between July 2008 and June 2011, 2335 patients with liver disease underwent LSM (86% using the M probe). LSM failure (no valid measurements) occurred in 1.6% (n=37) and was more common using the XL than the M probe (3.4% versus 1.3%; P=0.01). Excluding LSM failures, poorly reliable LSMs were observed in 4.9% (n=113) of patients. Independent predictors of poorly reliable LSM included older age (OR 1.03 [95% CI 1.01 to 1.05]), chronic pulmonary disease (OR 1.58 [95% CI 1.05 to 2.37), coagulopathy (OR 2.22 [95% CI 1.31 to 3.76) and higher liver stiffness (OR per kPa 1.03 [95% CI 1.02 to 1.05]), including presumed cirrhosis (stiffness ≥12.5 kPa; OR 5.24 [95% CI 3.49 to 7.89]). Sex, diabetes, the underlying liver disease and FibroScan probe were not significant. Although reliability varied according to operator (P<0.0005), operator experience was not significant. In a subanalysis including 434 patients with body mass index data, obesity influenced the rate of poorly reliable results (OR 2.93 [95% CI 0.95 to 9.05]; P=0.06). CONCLUSIONS: FibroScan failure and poorly reliable LSM are uncommon. The most important determinants of poorly reliable results are older age, obesity, higher liver stiffness and the operator, the latter emphasizing the need for adequate training.

Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: The histopathology of nonalcoholic fatty liver disease (NAFLD) is similar to that of alcoholic liver disease. Colonic bacteria are a source of many metabolic products, including ethanol and other volatile organic compounds (VOC) that may have toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. Recent data suggest that the composition of the gut microbiota in obese human beings is different from that of healthy-weight individuals. The aim of this study was to compare the colonic microbiome and VOC metabolome of obese NAFLD patients (n = 30) with healthy controls (n = 30). METHODS: Multitag pyrosequencing was used to characterize the fecal microbiota. Fecal VOC profiles were measured by gas chromatography-mass spectrometry. RESULTS: There were statistically significant differences in liver biochemistry and metabolic parameters in NAFLD. Deep sequencing of the fecal microbiome revealed over-representation of Lactobacillus species and selected members of phylum Firmicutes (Lachnospiraceae; genera, Dorea, Robinsoniella, and Roseburia) in NAFLD patients, which was statistically significant. One member of phylum Firmicutes was under-represented significantly in the fecal microbiome of NAFLD patients (Ruminococcaceae; genus, Oscillibacter). Fecal VOC profiles of the 2 patient groups were different, with a significant increase in fecal ester compounds observed in NAFLD patients. CONCLUSIONS: A significant increase in fecal ester VOC is associated with compositional shifts in the microbiome of obese NAFLD patients. These novel bacterial metabolomic and metagenomic factors are implicated in the etiology and complications of obesity.

Feasibility and reliability of the FibroScan S2 (pediatric) probe compared with the M probe for liver stiffness measurement in small adults with chronic liver disease.

BACKGROUND: The success of liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is influenced by anthropometric factors. In smaller adults, the M probe may fail due to narrow intercostals spaces and rib interference. We aimed to compare LSM using the FibroScan S2 (pediatric) probe with the M probe in small adults with chronic liver disease. MATERIAL AND METHODS: In this prospective study, 41 liver disease patients and 18 controls with a thoracic perimeter ≤ 75 cm underwent LSM using the FibroScan M and S2 probes. TE failure was defined as no valid LSMs and unreliable examinations as < 10 valid LSMs, an interquartile range (IQR)/LSM > 30%, or success rate < 60%. RESULTS: TE failure was not observed and reliability did not differ between the M and S2 probes (86% vs. 95%; P = 0.20). Liver stiffness measured using the M and S2 probes was highly correlated (ρ = 0.81; P < 0.0005) and median liver stiffness did not differ between probes (4.5 vs. 4.4 kPa; P = 0.10). However, in participants with a skin-capsular distance ≥ 15 mm, median liver stiffness was higher using the S2 probe (5.5 vs. 4.9 kPa; P = 0.008). When compared with validated liver stiffness cut-offs, the S2 probe would have overestimated the stage of fibrosis compared with the M probe in 10% of patients. CONCLUSIONS: The FibroScan S2 probe does not improve the feasibility of LSM in adults of smaller stature and may overestimate liver stiffness compared with the M probe. The FibroScan M probe should remain the preferred tool for LSM in small adults with chronic liver disease.

The Fatty Liver Index has limited utility for the detection and quantification of hepatic steatosis in obese patients.

PURPOSE: Noninvasive tools for the detection of hepatic steatosis are needed. The Fatty Liver Index (FLI), which includes body mass index (BMI), waist circumference, triglycerides, and γ-glutamyl-transferase, has been proposed as a screening tool for fatty liver. Our objective was to validate the FLI for the detection and quantification of hepatic steatosis in an obese population. METHODS: Patients with chronic liver disease and BMI ≥ 28 kg/m(2) underwent liver biopsy and FLI determination. FLI performance for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROCs), and a novel model for the prediction of significant steatosis (≥5 %) was derived. RESULTS: Among 250 included patients, 65 % were male, and the median BMI was 33 kg/m(2); 48 % had nonalcoholic fatty liver disease, and 77 % had significant (≥5 %) steatosis. The FLI was weakly correlated with the percentage (ρ = 0.25, p = 0.0001) and grade of steatosis (ρ = 0.28, p < 0.00005). The median FLI was higher among patients with significant steatosis (91 vs. 80 with <5 % steatosis; p = 0.0001) and the AUROC for this outcome was 0.67 (95 % CI 0.59-0.76). At an optimal FLI cut-off of 79, the FLI was 81 % sensitive and 49 % specific, and had positive and negative predictive values of 84 and 43 %, respectively. A novel index including triglycerides, glucose, alkaline phosphatase, and BMI outperformed the FLI for predicting significant steatosis [AUROCs 0.78 vs. 0.68; p = 0.009 (n = 247)]. CONCLUSIONS: In obese patients, the FLI is a poor predictor of significant steatosis and has limited utility for steatosis quantification compared with liver histology. A novel index including triglycerides, glucose, alkaline phosphatase, and BMI may be useful, but requires validation.

Controlled Attenuation Parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography.

BACKGROUND: Accurate tools for the noninvasive detection of hepatic steatosis are needed. The Controlled Attenuation Parameter (CAP) specifically targets liver steatosis using a process based on transient elastography. METHODS: Patients with chronic liver disease and body mass index (BMI) ≥28 kg/m(2) underwent biopsy and liver stiffness measurement (LSM) with simultaneous CAP determination using the FibroScan(®) M probe. The performance of the CAP for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROC). RESULTS: A total of 153 patients were included: 69% were male, median BMI was 32 kg/m(2); 47% had nonalcoholic fatty liver disease (NAFLD); and 65% had significant (≥10%) steatosis. The CAP was significantly correlated with the percentage of steatosis (ρ = 0.47) and steatosis grade (ρ = 0.51; both P < 0.00005). The median CAP was higher among patients with significant steatosis (317 [IQR 284-339] vs. 250 [227-279] dB/m with <10% steatosis; P < 0.0005) and the AUROC for this outcome was 0.81 (95% CI 0.74-0.88). At a cut-off of 283 dB/m, the CAP was 76% sensitive, 79% specific, and had positive and negative predictive values of 87% and 64%, respectively. CAP performance was not influenced by measurement variability, but was higher in patients with mild (F0-F1) fibrosis (AUROC 0.89 vs. 0.72 with F2-F4; P = 0.03). The AUROCs of the CAP for ≥5%, >33% and >66% steatosis were 0.79, 0.76 and 0.70, respectively. CONCLUSIONS: The CAP is a promising tool for the noninvasive detection of hepatic steatosis. Advantages of CAP include its ease of measurement, operator-independence and simultaneous availability with LSM for fibrosis assessment.

Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients.

UNLABELLED: Failure of liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) and unreliable results occur in ≈ 5% and 15% of patients, respectively, mainly due to obesity. In this multicenter study, we evaluated the feasibility and performance of the novel FibroScan XL probe in 276 patients with chronic liver disease (42% viral hepatitis, 46% nonalcoholic fatty liver disease [NAFLD]) and a body mass index (BMI) ≥ 28 kg/m(2) . Patients underwent liver biopsy and TE with the standard M and XL probes. TE failure was defined as no valid LSMs and unreliable examinations as <10 valid LSMs or an interquartile range (IQR)/LSM >30% or success rate <60%. Probe performance for diagnosing ≥ F2 fibrosis and cirrhosis (F4) versus biopsy were examined using areas under receiver operating characteristic curves (AUROC). FibroScan failure was less frequent with the XL probe than the M probe (1.1% versus 16%) and the XL probe was more often reliable (73% versus 50%; both P < 0.00005). Reliable results with the XL probe were obtained in 61% of patients in whom the M probe was unreliable. Among 178 patients with ≥ 10 valid LSMs using both probes, liver stiffness was highly correlated between probes (ρ = 0.86; P < 0.0005); however, median liver stiffness was lower using the XL probe (6.8 versus 7.8 kPa; P < 0.00005). The AUROC of the XL and M probes were similar for ≥ F2 fibrosis (0.83 versus 0.86; P = 0.19) and cirrhosis (0.94 versus 0.91; P = 0.28). CONCLUSION: Compared with the M probe, the FibroScan XL probe reduces TE failure and facilitates reliable LSM in obese patients. Although the probes have comparable accuracy, lower liver stiffness cutoffs will be necessary when the XL probe is used to noninvasively assess liver fibrosis.

Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe.

BACKGROUND & AIMS: The FibroScan XL probe facilitates liver stiffness measurement (LSM) by transient elastography (TE) in obese patients, yet factors affecting its accuracy have not been described. Our objectives were to examine the prevalence, risk factors, and causes of discordance between fibrosis estimated by the FibroScan XL probe and biopsy. METHODS: Two hundred and ten patients with chronic liver disease (45% viral hepatitis, 55% nonalcoholic fatty liver disease (NAFLD) and a body mass index (BMI) ≥ 28 kg/m(2)) underwent liver biopsy and TE with the FibroScan XL probe. Predictors of discordance ≥ 2 fibrosis stages between measures, which occurred in 11% of patients (n=24), were identified by comparing patient, TE, and biopsy characteristics of discordant and non-discordant cases. RESULTS: Fibrosis estimated by the FibroScan XL probe was greater than biopsy in 75% (18/24) of discordant cases. Although biopsy quality was not associated with discordance, discordant cases were less likely to have ≥ 10 valid shots (75% vs. 97%; p=0.001), a success rate ≥ 60% (67% vs. 95%; p <0.0005), and an interquartile range over median liver stiffness (IQR/M) <21% (37% vs. 57%; p=0.07) than non-discordant cases. However, only increased BMI (odds ratio [OR] 1.09 per kg/m(2); 95% confidence interval [CI] 1.01-1.18; p=0.04) was independently associated with discordance; liver stiffness was of borderline significance (OR 1.73 per log(10)-transformed value; 95% CI 0.95-3.18; p=0.08). Discordance was 4- to 5-fold more frequent among patients with severe obesity (BMI ≥ 40 kg/m(2): 32% vs. 8%) and liver stiffness above the median of 7.0 kPa (20% vs. 4%; both p <0.0005). CONCLUSIONS: Discordance between liver fibrosis estimated by biopsy and TE using the FibroScan XL probe was infrequent in this obese population. Patients with severe obesity and elevated liver stiffness have the greatest risk of discordance.

Hyperglycemia in hospitalized patients receiving parental nutrition is associated with increased morbidity and mortality: a review.

Parenteral Nutrition (PN) is a valuable life saving intervention which can improve the nutritional status of hospitalized malnourished patients. PN is associated with complications including the development of hyperglycemia. This paper aims to provide a descriptive systematic review regarding the effects of PN-induced hyperglycemia in hospitalized patients, either in the intensive care unit or ward, while formulating and complementing existing guidelines on the administration of PN and glucose monitoring in hospitalized patients. Medline and Pubmed were searched for relevant articles describing complications arising from the development of hyperglycemia in patients receiving PN; four relevant studies were identified in the search. These articles had different glycemic targets and patient populations, and their protocols varied with regards to glycemic control. However, there was consistency regarding the association between hyperglycemia and mortality in patients receiving PN. These studies highlight the need for guidelines regarding monitoring and initiation of therapy in hyperglycemic patients. Unfortunately, all the currently available studies are retrospective in design; a large, prospective, randomized controlled trial regarding glycemic control in patients receiving PN is required for the development of standardized protocols.

Transient elastography for the noninvasive assessment of liver fibrosis: a multicentre Canadian study.

BACKGROUND: Liver stiffness measurement (LSM) using transient elastography (TE) is a promising tool for the noninvasive assessment of hepatic fibrosis. OBJECTIVES: To determine the feasibility and performance of TE in a North American cohort of patients with chronic liver disease. METHODS: LSMs were obtained using TE in 260 patients with chronic hepatitis B or C, or nonalcoholic fatty liver disease from four Canadian hepatology centres. The accuracy of TE compared with liver biopsy for the prediction of significant fibrosis (Metavir fibrosis score of F2 or greater), bridging fibrosis (Metavir fibrosis score of F3 or greater) and cirrhosis (Metavir fibrosis score of F4 ) was assessed using area under ROC curves (AUROCs), and compared with the aspartate aminotransferase-to-platelet ratio index. The influence of alanine aminotransferase (ALT) levels and other factors on liver stiffness was determined using linear regression analyses. RESULTS: failure of TE occurred in 2.7% of patients, while liver biopsies were inadequate for staging in 0.8%. Among the remaining 251 patients, the AUROCs of TE for Metavir fibrosis scores of F2 and F3 or greater, and F4 were 0.74 (95% CI 0.68 to 0.80), 0.89 (95% CI 0.84 to 0.94), and 0.94 (95% CI 0.90 to 0.97), respectively. LSM was more accurate than the aminotransferase-to-platelet ratio index for bridging fibrosis (AUROC 0.78) and cirrhosis (AUROC 0.88), but not significant fibrosis (AUROC 0.76). At a cut-off of 11.1 kPa, the sensitivity, specificity, and positive and negative predictive values for cirrhosis (prevalence 11%) were 96%, 81%, 39% and 99%, respectively. For significant fibrosis (prevalence 53%), a cut-off of 7.7 kPa was 68% sensitive and 69% specific, and had a positive predictive value of 70% and a negative predictive value of 65%. Liver stiffness was independently associated with ALT, body mass index and steatosis. The optimal LSM cut-offs for cirrhosis were 11.1 kPa and 11.5 kPa in patients with ALT levels lower than 100 U/L and 100 U/L or greater, respectively. For fibrosis scores of F2 or greater, these figures were 7.0 kPa and 8.6 kPa, respectively. CONCLUSIONS: the major role of TE is the exclusion of bridging fibrosis and cirrhosis. However, TE cannot replace biopsy for the diagnosis of significant fibrosis. Because liver stiffness may be influenced by significant ALT elevation, body mass index and/or steatosis, tailored liver stiffness cut-offs may be necessary to account for these factors.

Prevalence, risk factors and causes of discordance in fibrosis staging by transient elastography and liver biopsy.

BACKGROUND AND AIMS: Liver stiffness measurement (LSM) by transient elastography (TE) is widely used for the noninvasive assessment of fibrosis. Our objectives were to examine the prevalence, risk factors and causes of discordance between fibrosis estimated by TE and liver biopsy. METHODS: Two hundred and fifty-one patients with hepatitis B, C and nonalcoholic fatty liver disease underwent LSM by TE and liver biopsy. Predictors of discordance (≥2 fibrosis stages) between measures, which occurred in 14% of patients (n=35), were identified by comparing patient, TE and biopsy characteristics of discordant and nondiscordant cases. RESULTS: According to predefined criteria, 40% of discordances were attributed to TE error and 23% to biopsy error; 37% were indeterminate. In multivariate analysis, mild fibrosis (F0-2 vs. F3-4), and higher body mass index (BMI), ALT and LSM variability [assessed by the ratio of the interquartile range to median LSM (IQR/M)] were independently associated with discordance. Discordance was three-fold more common in patients with obesity (28 vs. 9%), ALT ≥60 U/L (20 vs. 7%) and IQR/M ≥0.17 (22 vs. 7%; all P<0.005). Based on these variables, a discordance risk score assigning 1 point to each factor was developed. The prevalence of discordance in patients with 0, 1, 2 and 3 factors were 2, 7, 20, and 55% respectively (P<0.0005). CONCLUSIONS: Discordance between liver fibrosis estimated by TE and biopsy occurs in one in seven patients. In assessing the validity of TE results, clinicians must recognize risk factors for discordance and in at-risk patients, consider alternative measures including biomarkers and possibly biopsy.