Thomas Karlas

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.

Acoustic radiation force impulse imaging (ARFI) for non-invasive detection of liver fibrosis: examination standards and evaluation of interlobe differences in healthy subjects and chronic liver disease.

Abstract Objective. Acoustic radiation force impulse imaging (ARFI) is a non-invasive method for the quantification of liver stiffness. We aimed to develop standards for the measuring procedure and studied the impact of different measuring sites. Materials and Methods. ARFI was tested in a tissue phantom and in 50 healthy volunteers. In addition, 116 patients with chronic liver disease underwent ARFI. The results were compared with histological staging (non-viral liver disease) and transient elastography (hepatitis C). ARFI diagnostic performance was evaluated with receiver operating characteristic curves. Results. ARFI results were not normally distributed in >20% of cases. Deep inspiration significantly increased ARFI values by 13% (p < 0.05). The mean shear-wave velocity in healthy individuals was 1.28 ± 0.19 m/s in the left liver lobe and 1.15 ± 0.17 m/s in the right liver lobe (p < 0.001). Similarly, in 79/116 patients with chronic liver disease a significant difference of shear-wave velocity between both liver lobes was detected. The histological staging correlated with ARFI results of the biopsy site (r = 0.661, p < 0.001) in non-viral liver disease (n = 47). The mean shear-wave velocity in cases with F1 and F2 fibrosis was increased in the left compared with the right liver lobe (2.1 ± 0.73 m/s vs. 1.75 ± 0.89 m/s, p = 0.041). Similar results were obtained in patients with hepatitis C (n = 69). Conclusion. Our study strengthens the necessity for definition of examination standards and demonstrates the usefulness of ARFI in non-viral liver disease. Interlobe variations of liver stiffness demand further investigation.

Non-Invasive Assessment of Hepatic Steatosis in Patients with NAFLD Using Controlled Attenuation Parameter and 1H-MR Spectroscopy

Introduction Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP) correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a head-to-head comparison between both methods. Methods Fifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2 34–66%, S3 ≥67%. Results Steatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiver-operating characteristics curves were 0.93 vs. 0.88 for steatosis ≥S1 and 0.94 vs. 0.88 for ≥S2, respectively. Boot-strapping analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2–4 fibrosis TE had sensitivity and specificity of 100% and 98.1% at a cut-off value of 8.85 kPa. Conclusion Our data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification. Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects, anthropometry, and presence of advanced liver fibrosis.

EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, Update 2017 (Long Version)

We present here the first update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography with a focus on the assessment of diffuse liver disease. The short version provides clinical information about the practical use of elastography equipment and interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing the evidence from meta-analyses. The role of elastography in different etiologies of liver disease and in several clinical scenarios is also discussed. All of the recommendations are judged with regard to their evidence-based strength according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. This updated document is intended to act as a reference and to provide a practical guide for both beginners and advanced clinical users.

Gastrointestinal complications of obesity: non-alcoholic fatty liver disease (NAFLD) and its sequelae.

Obesity is a major risk factor for malign and non-malign diseases of the gastrointestinal tract. Non-alcoholic fatty liver disease (NAFLD) is an outstanding example for the complex pathophysiology of the metabolic system and represents both source and consequence of the metabolic syndrome. NAFLD has a growing prevalence and will become the leading cause of advanced liver disease and cirrhosis. Obesity has a negative impact on NAFLD at all aspects and stages of the disease. The growing epidemic will strain health care resources and demands new concepts for prevention, screening and therapeutic approaches. A better understanding of the interplay of liver, gut and hormonal system is necessary for new insights in the underlying mechanisms of NAFLD and the metabolic syndrome including obesity. Identification of patients at risk for progressive liver disease will allow a better adaption of treatment strategies.

Acoustic radiation force impulse (ARFI) elastography in acute liver failure: necrosis mimics cirrhosis

Acoustic radiation force Impulse (ARFI) technology correlates shear-wave velocity with fibrosis. It can differentiate between advanced fibrosis and normal tissue in chronic liver disease. However, specificity is impaired by cholestasis, inflammation or oedema in acute hepatitis. In patients with acute liver failure (ALF) necessitating liver transplantation ARFI has not been evaluated yet. We investigated 3 patients with ALF and compared their ARFI results to those of healthy controls (n = 33) and cases with liver cirrhosis (n = 21). In the 3 ALF patients shear-wave velocities were 3.0, 2.5, and 2.7 m/s, respectively. These results were significantly increased compared to those of healthy controls (median: 1.13 m/s; p < 0.001) and similar to those of cirrhotic individuals (median: 2.93 m/s). Two individuals underwent liver transplantation. Explants showed massive necrosis, but no signs of chronic liver disease. Patient 3 recovered spontaneously and showed decreasing ARFI results during follow-up. In conclusion, hepatic necrosis can mimic liver cirrhosis at ARFI evaluation in ALF patients and this impairs the specificity of ARFI.

Predictive accuracy of single‐ and multi‐slice MRI for the estimation of total visceral adipose tissue in overweight to severely obese patients

The quantification of visceral adipose tissue (VAT) is increasingly being considered for risk assessment and treatment monitoring in obese patients, but is generally time‐consuming. The goals of this work were to semi‐automatically segment and quantify VAT areas of MRI slices at previously proposed anatomical landmarks and to evaluate their predictive power for whole‐abdominal VAT volumes on a relatively large number of patients. One‐hundred and ninety‐seven overweight to severely obese patients (65 males; body mass index, 33.3 ± 3.5 kg/m2; 132 females; body mass index, 34.3 ± 3.2 kg/m2) underwent MRI examination. Total VAT volumes (VVAT‐T) of the abdominopelvic cavity were quantified by retrospective analysis of two‐point Dixon MRI data (active‐contour segmentation, visual correction and histogram analysis). VVAT‐T was then compared with VAT areas determined on one or five slices defined at seven anatomical landmarks (lumbar intervertebral spaces, umbilicus and femoral heads) and corresponding conversion factors were determined. Statistical measures were the coefficients of variation and standard deviations σ1 and σ5 of the difference between predicted and measured VAT volumes (Bland–Altman analysis). VVAT‐T was 6.0 ± 2.0 L (2.5–11.2 L) for males and 3.2 ± 1.4 L (0.9–7.7 L) for females. The analysis of five slices yielded a better agreement than the analysis of single slices, required only a little extra time (4 min versus 2 min) and was substantially faster than whole‐abdominal assessment (24 min). Best agreements were found at intervertebral spaces L3–L4 for females (σ5/1 = 523/608 mL) and L2–L3 for males (σ5/1 = 613/706 mL). Five‐slice VAT volume estimates at the level of lumbar disc L3–L4 for females and L2–L3 for males can be obtained within 4 min and were a reliable predictor for abdominopelvic VAT volume in overweight to severely adipose patients. One‐slice estimates took only 2 min and were slightly less accurate. These findings may contribute to the implementation of analytical methods for fast and reliable (routine) estimation of VAT volumes in obese patients. Copyright

Therapy of Liver Abscesses

Background: Liver abscess (LA) is an uncommon but potentially life-threatening disease with significant morbidity and mortality. Methods: This review comprehensively describes epidemiology, pathogenesis, diagnosis, and treatment of LA, with a strong focus on antimicrobial treatment choices and the impact of multidrug-resistant pathogens. Results: In industrialized areas, pyogenic liver abscess (PLA) accounts for over 80% of the cases, whereas Entamoeba histolytica is responsible for up to 10% of the cases, with a higher incidence in tropical areas. Highly virulent strains of Klebsiella pneumoniae have emerged as a predominant cause of PLA in Asian countries and tend to spread to the USA, Australia, and European countries, therefore requiring special alertness. Most common symptoms of LA are fever, chills, and right upper quadrant abdominal pain, although a broad spectrum of non-specific symptoms may also occur. Conclusion: Imaging studies (ultrasound, computed tomography scan) and microbiological findings play a crucial role in the diagnosis of LA. The treatment of choice for PLA is a multimodal approach combining broad-spectrum antibiotics and aspiration or drainage of larger abscess cavities. Amebic LA can be cured by metronidazole therapy without drainage.

Assessment of Spleen Stiffness Using Acoustic Radiation Force Impulse Imaging (ARFI): Definition of Examination Standards and Impact of Breathing Maneuvers

PURPOSE Spleen elastography is a promising method for the characterization of portal hypertension in cirrhotic individuals. However, standardized examination procedures for spleen stiffness measurement have not been defined yet. We analyzed the distribution characteristics of spleen shear-wave velocity (ARFI) and assessed the influence of the respiratory position on spleen stiffness measured by ARFI. MATERIALS AND METHODS 25 healthy probands and 25 patients with Child A liver cirrhosis were prospectively characterized with conventional ultrasound, transient elastography, liver ARFI, and underwent spleen ARFI in two respiratory positions: breath hold after expiration (exp) and deep inspiration (insp). For each position 20 single measurements were performed. The distribution of spleen ARFI values was analyzed for normality and the appropriate number of measurements for spleen stiffness estimation was investigated. RESULTS Spleen ARFI results were normally distributed in > 95 % of cases. Performing 20 instead of 10 single measurements resulted in < 5 % deviation from the mean value after 20 measurements in the majority of cases. Cirrhotic patients had a higher spleen stiffness compared to healthy probands (exp: 3.25 ± 0.58 vs. 2.46 ± 0.35 m/s; p < 0.001). Deep inspiration caused an overall increase in spleen stiffness in both groups: probands 2.46 ± 0.35 m/s (exp) vs. 2.66 ± 0.36 m/s (insp), p = 0.01; cirrhotics 3.25 ± 0.58 m/s (exp) vs. 3.46 ± 0.38 m/s (insp), p = 0.03. However, cases with high spleen stiffness values (exp) show decreasing ARFI values in deep inspiration. CONCLUSION ARFI values of the spleen are normally distributed and the mean of 10 valid measurements can be used as a representative value. Deep inspiration significantly modulates spleen stiffness. Therefore, the respiratory position needs careful standardization.

Estimating steatosis and fibrosis: Comparison of acoustic structure quantification with established techniques.

AIM To compare ultrasound-based acoustic structure quantification (ASQ) with established non-invasive techniques for grading and staging fatty liver disease. METHODS Type 2 diabetic patients at risk of non-alcoholic fatty liver disease (n = 50) and healthy volunteers (n = 20) were evaluated using laboratory analysis and anthropometric measurements, transient elastography (TE), controlled attenuation parameter (CAP), proton magnetic resonance spectroscopy ((1)H-MRS; only available for the diabetic cohort), and ASQ. ASQ parameters mode, average and focal disturbance (FD) ratio were compared with: (1) the extent of liver fibrosis estimated from TE and non-alcoholic fatty liver disease (NAFLD) fibrosis scores; and (2) the amount of steatosis, which was classified according to CAP values. RESULTS Forty-seven diabetic patients (age 67.0 ± 8.6 years; body mass index 29.4 ± 4.5 kg/m²) with reliable CAP measurements and all controls (age 26.5 ± 3.2 years; body mass index 22.0 ± 2.7 kg/m²) were included in the analysis. All ASQ parameters showed differences between healthy controls and diabetic patients (P < 0.001, respectively). The ASQ FD ratio (logarithmic) correlated with the CAP (r = -0.81, P < 0.001) and (1)H-MRS (r = -0.43, P = 0.004) results. The FD ratio [CAP < 250 dB/m: 107 (102-109), CAP between 250 and 300 dB/m: 106 (102-114); CAP between 300 and 350 dB/m: 105 (100-112), CAP ≥ 350 dB/m: 102 (99-108)] as well as mode and average parameters, were reduced in cases with advanced steatosis (ANOVA P < 0.05). However, none of the ASQ parameters showed a significant difference in patients with advanced fibrosis, as determined by TE and the NAFLD fibrosis score (P > 0.08, respectively). CONCLUSION ASQ parameters correlate with steatosis, but not with fibrosis in fatty liver disease. Steatosis estimation with ASQ should be further evaluated in biopsy-controlled studies.