Point Shear Wave Elastography by Acoustic Radiation Force Impulse Quantification in Comparison to Transient Elastography for the Noninvasive Assessment of Liver Fibrosis in Chronic Hepatitis C: A Prospective International Multicenter Study.

PURPOSE: The aim of the present prospective European multicenter study was to demonstrate the non-inferiority of point shear wave elastography (pSWE) compared to transient elastography (TE) for the assessment of liver fibrosis in patients with chronic hepatitis C. MATERIALS AND METHODS: 241 patients with chronic hepatitis C were prospectively enrolled at 7 European study sites and received pSWE, TE and blood tests. Liver biopsy was performed with histological staging by a central pathologist. In addition, for inclusion of cirrhotic patients, a maximum of 10 % of patients with overt liver cirrhosis confirmed by imaging methods were allowed by protocol (n = 24). RESULTS: Owing to slower than expected recruitment due to a reduction of liver biopsies, the study was closed after 4 years before the target enrollment of 433 patients with 235 patients in the 'intention to diagnose' analysis and 182 patients in the 'per protocol' analysis. Therefore, the non-inferiority margin was enhanced to 0.075 but non-inferiority of pSWE could not be proven. However, Paired comparison of the diagnostic accuracy of pSWE and TE revealed no significant difference between the two methods in the 'intention to diagnose' and 'per protocol' analysis (0.81 vs. 0.85 for F ≥ 2, p = 0.15; 0.88 vs. 0.92 for F ≥ 3, p = 0.11; 0.89 vs. 0.94 for F = 4, p = 0.19). Measurement failure was significantly higher for TE than for pSWE (p = 0.030). CONCLUSION: Non-inferiority of pSWE compared to TE could not be shown. However, the diagnostic accuracy of pSWE and TE was comparable for the noninvasive staging of liver fibrosis in patients with chronic hepatitis C.

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels.

[Characterization and economic impact of medical patients presenting at the emergency department of an university hospital]. / Internistische Patienten in einer universitären Notaufnahme: Charakterisierung und ökonomische Bedeutung für das Gesamtklinikum.

BACKGROUND: The number of patients in German emergency departments has been rising for years. This means additional need of staff and infrastructure for hospitals. METHODS: In this monocentric retrospective analysis the patient population of the central emergency department (ZNA) at the university hospital Frankfurt was investigated. Major symptoms, diagnoses with respect to diagnose-related groups and modes of admission to the emergency department have been analyzed. RESULTS: During 3 months, a total of 7376 patients presented to the ZNA. Analysis focused on 2186 patients referred to the department of internal medicine: most patients presented spontaneously (50.6%), 38.2% were admitted by ambulance services, only 9.7% were admitted by a primary physician. 44.9% of these patients were hospitalized, mainly with cardiological, pneumological and gastroenterological disorders. The predominant major symptoms were acute chest pain (15.4%), abdominal pain (7.1%) and syncope or collapse (6.1%). Patients hospitalized via ZNA contributed 31.9% of the total revenues of internal medicine departments. 31.7% of all hospitalized patients were admitted to the hospital by the ZNA. CONCLUSION: Emergency departments become more and more a regular part of ambulatory patients health care and contribute efficiently to the economic revenue of hospitals.

[Integrated management of patients with chronic inflammatory bowel disease in the Rhine-Main Region: results of the first integrated health-care project IBD in Germany]. / Integrierte Versorgung von Patienten mit chronisch-entzündlichen Darmerkrankungen im Rhein-Main-Gebiet: Ergebnisse der ersten integrierten Versorgung CED in Deutschland.

INTRODUCTION: In our previous studies investigating the drug therapy in patients suffering from inflammatory bowel disease (IBD) in the Rhein-Main region, Germany, we detected serious discrepancies between treatment reality and treatment guidelines. Consecutively, patient outcome in this cohort was compromised. Following this pilot project a network between primary deliverers of care for IBD patients and one large health-care insurance company [BKK Taunus (Gesundheit), the second largest insurance company in Hessen, Germany] was established. PATIENTS AND METHODS: An analysis of treatment and socioeconomic data from 220 IBD patients (Crohn's disease - CD = 96, ulcerative colitis - UC = 124) entering the integrative health-care programme between 1.1.-30.9.2009 was performed. RESULTS: Remission rates for CD and UC in the integrated health-care programme could be improved from 60 - 73 % (CD) and from 61 - 79 % (UC). Guideline-conform treatment was observed in 81 % of patients with CD and 85 % with UC, respectively. Although medication costs increased, total costs could be cut by 162 304.- €, as secondary costs for hospitalisation and days off work could be reduced. CONCLUSION: The study shows that networking of deliverers of care for IBD patients with health insurances provides an excellent possibility to optimise medical treatment and can cut down costs significantly.

Acoustic radiation force impulse imaging for non-invasive assessment of liver fibrosis in chronic hepatitis B.

Acoustic radiation force impulse (ARFI) imaging is a novel ultrasound-based elastography method that is integrated in a conventional ultrasound machine. It might provide an alternative method to transient elastography for the noninvasive assessment of liver fibrosis. While previous studies have shown comparable diagnostic accuracy of ARFI to transient elastography in chronic hepatitis C, the aim of the present prospective multicenter study was to evaluate ARFI for the assessment of liver fibrosis in chronic hepatitis B. ARFI imaging involves the mechanical excitation of tissue using short-duration acoustic pulses to generate localized displacements in tissue. The displacements result in shear-wave propagation which is tracked using ultrasonic, correlation-based methods and recorded in m/s. In the present international prospective study, patients infected with chronic hepatitis B received ARFI imaging, blood tests and if available transient elastography. The results were compared to liver biopsy as reference method analysed by a central pathologist. In 92 of 114 patients, a comparison of ARFI with transient elastography was possible. ARFI imaging and transient elastography correlated significantly with histological fibrosis stage. The diagnostic accuracy expressed as areas under ROC curves for ARFI imaging and transient elastography was 0.75 and 0.83 for the diagnosis of significant fibrosis (F ≥ 2), 0.93 and 0.94 for the diagnosis of severe fibrosis (F ≥ 3), and 0.97 and 0.93 for the diagnosis of liver cirrhosis, respectively. No significant difference was found between ARFI and transient elastography. ARFI imaging is a reliable ultrasound-based method for the assessment of advanced stages of liver fibrosis in chronic hepatitis B.

Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C.

We systematically reviewed the evidence for long-term effectiveness and cost-effectiveness of antiviral treatment in patients with chronic hepatitis C. We performed a systematic literature search on the long-term effectiveness and cost-effectiveness of AVT in hepatitis C (1990-March 2007), and included health technology assessment (HTA) reports, systematic reviews, long-term clinical trials, economic studies conducted alongside clinical trials and decision-analytic modelling studies. All costs were converted to 2005euro. Antiviral therapy with peginterferon plus ribavirin in treatment-naïve patients with chronic hepatitis C was the most effective (3.6-4.7 life years gained [LYG]) treatment and was reasonably cost-effective (cost-saving to 84 700euro/quality adjusted life years [QALY]) when compared to interferon plus ribavirin. Some results also suggest cost-effectiveness (below 8400euro/(QALY) of re-treatment in nonresponders/relapsers. Results for patients with persistently normal alanine aminotransferase (ALT) levels or with special co-morbidities (e.g. HIV) or risk profiles were rare. We conclude that antiviral therapy may prolong life, improve long-term health-related quality-of-life and be reasonably cost-effective in treatment-naïve patients with chronic hepatitis C as well as in former relapsers/nonresponders. Further research is needed in patients with specific co-morbidities or risk profiles.

Real-time elastography and contrast-enhanced ultrasound for the assessment of thyroid nodules.

OBJECTIVE: Work-up of thyroid nodules remains challenging. Recent technologies enable determination of tissue elasticity and perfusion using ultrasound devices. The aim of the present study was to evaluate real-time elastography (RTE) and contrast-enhanced ultrasound with Sonovue (CEUS) for the differentiation of benign and malignant thyroid nodules. MATERIALS AND METHODS: Inclusion criteria were: nodules ≥1 cm, non-functioning or hypo-functioning on radionuclide scanning, and cytological/histological assessment. All patients received conventional ultrasound, RTE and CEUS. RTE was classified as: Elasticity-Score (ES)1 = soft, ES2 = predominantly soft, ES3 = predominantly hard, ES4 = hard nodule. CEUS-video clips were digitally recorded and analyzed using time-intensity-curves within selected regions-of-interest. RESULTS: Fifty-three nodules in 50 patients were available for analysis. Forty-six nodules were benign on cytology/histology, 6 nodules were papillary carcinoma and one nodule was a follicular carcinoma. Nodule margin irregularity was the ultrasound pattern most predictive of malignancy with sensitivity 57% (95% confidence interval: 18-90%) and specificity 85% (71-94% p<0.05). When using ES3&4 for the diagnosis of malignant nodules sensitivity and specificity were 86% (42-99.7%) and 87% (75-95%), respectively (p = 0.0003). The only malignant nodule missed with RTE was a follicular carcinoma. Sensitivity for the diagnosis of papillary carcinoma therefore was 100%. No specific CEUS pattern could be identified to differentiate between benign and malignant nodules. CONCLUSIONS: RTE seems to be a useful tool in the work-up of thyroid nodules to exclude papillary thyroid cancer. However, follicular carcinoma remains a challenging problem. CEUS did not improve the characterization of thyroid nodules in this preliminary study.

Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease.

PURPOSE: Transient elastography (FibroScan, [TE]) and serum fibrosis markers such as the FibroTest (FT) are established methods for the noninvasive staging of liver fibrosis. A study using real-time elastography (HI-RTE), which is integrated in a conventional ultrasound system, was recently published with comparable results to transient elastography. The aim of the present study was to validate real-time elastography using the formulas calculated in previous studies and to compare the results to transient elastography and FibroTest for the noninvasive assessment of liver fibrosis. MATERIALS AND METHODS: One hundred and thirty-four patients with chronic liver disease and either histological assessment of liver fibrosis (n = 112) or proven liver cirrhosis (n = 22) were included in the study. All patients received TE, HI-RTE, and biochemical evaluation on the same day as presentation. The calculation of the elasticity score of real-time elastography was performed in accordance with the two previously published studies. RESULTS: The Spearman correlation coefficient between transient elastography, real-time elastography and FibroTest with the histological Chevallier score was statistically significant with 0.78, 0.34, and 0.67, respectively (p < 0.01). The diagnostic accuracy expressed as areas under ROC curves was 0.84, 0.69 and 0.85 for the diagnosis of significant fibrosis (F > or = 2), and 0.97, 0.65, and 0.83 for the diagnosis of cirrhosis, respectively. CONCLUSION: Real-time elastography in its present form cannot replace transient elastography for noninvasive assessment of liver fibrosis.

[Transient elastography (FibroScan) for the non-invasive assessment of liver fibrosis: current status and perspectives]. / Nicht invasive Beurteilung des Leberfibrosestadiums mit der transienten Elastografie (FibroScan): Aktueller Stand und Perspektiven.

A precise staging of the degree of liver fibrosis is important for the estimation of prognosis, surveillance and treatment decision in patients with chronic liver diseases. At present, liver biopsy is still the reference standard for the assessment of liver fibrosis. However, it is an invasive method associated with patient discomfort and in rare cases with serious complications. In addition, the accuracy of liver biopsy is limited due to intra- and interobserver variability and sampling errors. Non-invasive markers and methods for the assessment of liver fibrosis have been intensively evaluated in many studies. The FibroScan (Echosens, France) uses the transient elastography principle for the measurement of liver stiffness. At present (January 2007), studies evaluating the FibroScan in a wide range of liver diseases have been published in 20 full papers and 76 abstracts. The present review gives an overview of the current literature. The best results are reported for the differentiation between cirrhosis and no cirrhosis. With the combination of FibroScan and non-invasive serum fibrosis markers, the accuracy for the diagnosis of significant fibrosis (Metavir F > or = 2) can be further improved. According to recent data the FibroScan can also be useful for the evaluation of treatment response in patients receiving antiviral treatment for chronic hepatitis C. In addition, several studies have shown, that the FibroScan can be applied to estimate the risk of complications associated with liver cirrhosis.

Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity.

BACKGROUND: Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. AIM: To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. METHODS: This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). RESULTS: Current limits defining normal serum alanine aminotransferase activity are not representative of a "healthy" status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (> or =F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (> or =20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. CONCLUSIONS: A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity.

The economics of treating chronic hepatitis C patients with peginterferon alpha-2a (40 kDa) plus ribavirin presenting with persistently normal aminotransferase.

Peginterferon alpha-2a (40 kDa) plus ribavirin is effective at achieving sustained viral response compared with no treatment in patients with chronic hepatitis C (CHC) and persistently normal aminotransferase levels (PNALT). The cost-effectiveness of treating CHC in the setting of PNALT has not been assessed. Disease progression in patients with PNALT was simulated in a Markov model. The rate of fibrosis progression, quality of life and costs for each health state were based on literature estimates. The perspective of the Italian National Health Service was adopted and costs (euro 2003) and benefits were discounted at 3%. Sensitivity analyses were performed on important parameters. The primary analysis compared combination therapy with peginterferon alpha-2a (40 kDa) plus ribavirin to no treatment in a cohort of patients with mean age 45 years, and was based on findings from a multinational, randomized trial in patients with PNALT. In genotype 1 patients, the risk of cirrhosis at 30 years is forecast to fall from 32% with no treatment to 19% with combination therapy, increasing quality-adjusted life years (QALYs) by 0.74 years at an incremental cost per QALY gained of euro 16,831. The 30-year risk of cirrhosis in genotype 2 or 3 is projected to fall to 9% with combination therapy, an increase in QALYs of 1.34 years, at an incremental cost per QALY gained of euro 3,000. Thus treatment of PNALT with peginterferon alpha-2a (40 kDa) plus ribavirin is projected to reduce the incidence of cirrhosis, increase life expectancy and have an acceptable cost-effectiveness ratio from a societal perspective.

Assessment, by transcription-mediated amplification, of virologic response in patients with chronic hepatitis C virus treated with peginterferon alpha-2a.

Transcription-mediated amplification (TMA) is an isothermal, autocatalytic target amplification method which has the potential to detect less than 50 hepatitis C virus (HCV) RNA copies/ml (10 IU/ml). The TMA assay was used to assess the presence of residual HCV RNA in plasma from patients treated with polyethylene glycol-modified interferon alpha-2a (peginterferon alpha-2a) who showed a virologic relapse after the end of therapy. Stored end-of-treatment and end-of-follow-up plasma samples from 177 of 267 patients treated with peginterferon alpha-2a (S. Zeuzem et al., N. Engl. J. Med. 343:1666--1672, 2000) were available for retesting by TMA. Plasma samples from patients in the same study who exhibited virologic relapse after treatment with standard interferon alpha-2a served as controls. Virologic response during the trial was defined as HCV RNA that was undetectable using a PCR-based test system with a sensitivity of 50 IU/mL (Cobas Amplicor HCV version 2.0) and was compared with TMA-based retesting results (VERSANT HCV RNA Qualitative Assay). Residual HCV RNA was detected in 4 of 60 cases (7%) by the TMA technology in end-of-treatment plasma samples from patients who relapsed after receiving peginterferon alpha-2a and in 6 of 18 patients (33%) following therapy with standard interferon alpha-2a. For peginterferon alpha-2a-treated patients with sustained virologic response, HCV RNA was detectable by TMA in end-of-treatment samples in 3 of 78 cases but in none of the end-of-follow-up samples. For all end-of-treatment and end-of-follow-up plasma samples of virologic nonresponders, a complete concordance between the PCR-based assay and TMA was observed. In conclusion, in patients with virologic relapse after the end of therapy, according to PCR, who were treated with peginterferon alpha-2a or standard interferon alpha-2a, residual HCV RNA was detectable in end-of-treatment samples by the TMA-based assay in 7 or 33% of cases, respectively. The lower rate of residual HCV RNA detection by TMA for patients treated with peginterferon alpha-2a than that for patients treated with standard interferon alpha-2a may be due to the maintained antiviral pressure of the long-acting peginterferon alpha-2a at the end-of-treatment visit.

What is (cost) effective in patients with chronic hepatitis C virus infection?

Hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and possibly hepatocellular carcinoma. Chronic hepatitis C infection is a leading cause of chronic liver disease and the most common indication for liver transplantation. Combination therapy of interferon alpha and ribavirin is currently the standard regimen for chronic hepatitis C. This combination can achieve viral clearance in approximately 40% of patients, and improve histology and prognosis. The most cost-effective approach to guide duration of combination therapy is HCV genotyping. Cost effectiveness cannot be improved further by taking other well-defined predictive factors for sustained virological response into account. Recent insights into HCV kinetics and the correlation between initial viral decline and sustained virological response will allow us to optimize and individually tailor antiviral treatment Individualized treatment according to the initial viral decline, together with further improvements in drugs (e.g. by long-acting pegylated interferons), will have new impact on antiviral efficacy and cost effectiveness.

Assessment of initial hexose uptake in adipocytes using the physiological substrate D-glucose. Particular relevance to human adipocytes.

The characteristics of U-[14C]D-glucose uptake into human and rat adipocytes have been examined. The initial rates of U-[14C]D-glucose uptake were found to be linear during the first 30 s, both basally and with maximum insulin stimulation. Phloretin was shown to be effective in stopping glucose flux for human adipocytes, although rapid separation of cells from medium was found to be necessary for accurate measurement of initial rate of glucose uptake into rat adipocytes. The pH and temperature dependency of U-[14C]D-glucose uptake were found to be similar to those reported for 3-0-methylglucose. The use of U-[14C]D-glucose for assessment of initial rate of glucose uptake into human adipocytes provides results directly relevant to D-glucose metabolism, in addition to being technically less demanding and much less expensive than methods using the non-physiological sugar analogue 3-0-[14C]methylglucose.