Pam Crotty

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

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/m2. 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. (HEPATOLOGY 2012)

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.

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

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.

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.

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.

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.

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.

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.

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.

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.