Article

FibroScan (Vibration Controlled Transient Elastography): Where Does It Stand in the US Practice.

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Abstract

With widespread screening and increasingly effective treatments for patients with viral hepatitis as well as the increasing prevalence of nonalcoholic fatty liver disease, the population presenting to the care of gastroenterologists and hepatologists is certain to rise. Assessment of advanced liver disease is traditionally invasive and expensive. Vibration controlled transient elastography (VCTE) commonly delivered by the FibroScan device (Echosens; Paris, France) is a recently FDA approved option for the noninvasive assessment of liver disease at the point of care. Herein we review the promise and pitfalls of VCTE with the aim of providing clinicians with a framework to interpret its results and apply this technology to the changing needs of our patients.

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... 9 VCTE has gained significant popularity in Europe since its introduction almost two decades ago, establishing itself as the noninvasive standard for liver fibrosis assessment. 16 Clinical practice guidelines issued by the European Association for the Study of the Liver recommend cirrhosis screening via VCTE for all patients with chronic hepatitis C. 8 VCTE is also approved in parts of Asia, and the China Foundation for Hepatitis Prevention and Control provided recommendations for its use in 2012. 17 In comparison, adoption of VCTE has been slower in the USA, with a later regulatory approval in 2013. ...
... 17 In comparison, adoption of VCTE has been slower in the USA, with a later regulatory approval in 2013. 16 Since then, several USA-based studies have been published, with most focusing on validating the diagnostic performance of VCTE in prospective longitudinal cohorts where patients with one or two CLD etiologies were selected based on a series of inclusion and exclusion criteria. 13,[18][19][20] However, there has been limited published data describing the use of VCTE by clinicians during regular, everyday clinical operations in real-life patient populations in the USA. ...
... Future single-etiology cohort studies are necessary to confirm the influence of CAP on LSM in other CLD diagnoses. Since hepatic steatosis influences VCTE CAP, 16 CAP's association with LSM suggests that patients with high liver fat content may have greater LSMs without advanced liver fibrosis. This may serve as a potential explanation for the phenomenon where fibrosis stage derived from VCTE LSM overstates histological fibrosis. ...
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Background and Aims Vibration-controlled transient elastography (VCTE) is a noninvasive tool that uses liver stiffness measurement (LSM) to assess fibrosis. Since real-life data during everyday clinical practice in the USA are lacking, we describe the patterns of use and diagnostic performance of VCTE in patients at an academic medical center in New York City. Methods Patients who received VCTE scans were included if liver biopsy was performed within 1 year. Diagnostic performance of VCTE in differentiating dichotomized fibrosis stages was assessed via area under the receiver operating characteristics (AUROC). Fibrosis stage determined from VCTE LSM was compared to liver biopsy. Results Of 109 patients, 49 had nonalcoholic fatty liver disease, 16 chronic hepatitis C, 15 congestive hepatopathy, and 22 at least two etiologies. AUROC was 0.90 for differentiating cirrhosis (stage 4) with a positive predictive value (PPV) range of 0.28 to 0.45 and negative predictive value range of 0.96 to 0.98. For 31 (32%) patients, VCTE fibrosis stage was at least two stages higher than liver biopsy fibrosis stage. Thirteen of thirty-five patients considered to have cirrhosis by VCTE had stage 0 to 2 and 12 stage 3 fibrosis on liver biopsy. Conclusions VCTE has reasonable diagnostic accuracy and is reliable at ruling out cirrhosis. However, because of its low PPV, caution must be exercised when used to diagnose cirrhosis, as misdiagnosis can lead to unnecessary health care interventions. In routine practice, VTCE is also sometimes performed for disease etiologies for which it has not been robustly validated.
... [25][26][27] Advantages of VCTE include low cost, point-of-care use in the clinic and a wealth of validated data as compared with ARFI; although it is confounded by obesity and ascites due to lack of direct visualization of the ROI. 28 Advantages of pSWE include higher rates of reliable measurements and less interference by obesity and ascites, as the ROI can be visualized beforehand; although it is hindered by the need for the Virtual Touch software to be downloaded onto the ultrasound machine and review by a radiologist. 28 A meta-analysis comparing VCTE and ARFI in liver disease found a similar predictive value for fibrosis and cirrhosis, but ARFI may have higher rates of reliable measurements. ...
... 28 Advantages of pSWE include higher rates of reliable measurements and less interference by obesity and ascites, as the ROI can be visualized beforehand; although it is hindered by the need for the Virtual Touch software to be downloaded onto the ultrasound machine and review by a radiologist. 28 A meta-analysis comparing VCTE and ARFI in liver disease found a similar predictive value for fibrosis and cirrhosis, but ARFI may have higher rates of reliable measurements. 29 However, no head-to-head comparisons have been done in the HF population. ...
Article
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Heart failure (HF) is a complex disease associated with multisystem organ failure, recurrent hospital admissions, and increased mortality. Acute decompensated heart failure (ADHF) increases central venous pressure (CVP) with resultant hepatic congestion, and this relationship has prognostic significance. The gold standard method of measuring CVP, right heart catheterization, is invasive and costly, prompting further investigation into more accurate non‐invasive assessments in HF patients, including liver elastography. Liver elastography relies on imaging techniques to assess liver stiffness measurements (LSM), with high values equating to increased stiffness. While this was developed to assess fibrosis in liver disease, LSM also reflect increased CVP and hepatic congestion. Multiple studies involving ADHF patients, find that increased LSM are independently predictive of increased cardiac events, all‐cause mortality, and worse post‐operative outcome after both acute HF exacerbation and left ventricular assist device (LVAD) placement. In this review, we discuss the role of LSM as a surrogate for CVP and their applications in determining prognosis in both the ADHF and LVAD populations.
... Patients must be reliable and willing to adhere to instruction to ensure safety. Levels of evidence of methotrexate therapy in psoriasis are outlined in Table IV, z and supporting statements for methotrexate associated hepatotoxicity are available in Table V. 58,[70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] APREMILAST Apremilast was approved by the FDA in 2014 and is the first oral medication for psoriasis in decades. It inhibits phosphodiesterase 4, resulting in an increased level of intracellular cyclic adenosine monophosphate, with subsequent downregulation of inflammatory responses involving T helper 1, T helper 17, and type 1 interferon pathways. ...
... Vibration-controlled transient elastography has been used to monitor fibrosis in psoriasis patients treated with methotrexate and is useful in lowering the need for liver biopsy. 56,[81][82][83] 7 Elastography can also be performed using magnetic resonance imaging techniques. Compared with vibration-controlled transient elastography, magnetic resonance elastography (MRE) is less studied, with unclear generalizability between centers/radiologists. ...
Article
In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released a set of guidelines for the management of psoriasis in adults with systemic nonbiologic therapies, including acitretin, apremilast, cyclosporine, fumaric acid esters, methotrexate, and tofacitinib. This review addresses dosing, efficacy, toxicity, drug-related interactions, and contraindications alongside evidence-based treatment recommendations for each systemic therapy. Important considerations for treatment such as drug selection, initiation of therapy, drug monitoring, and patient management also are discussed. Physicians are encouraged to use these recommendations to guide treatments based on individual patient needs and disease characteristics.
... Currently, there are two distinct approaches for noninvasive assessment of liver fibrosis, a "physical" approach based on the assessment of liver stiffness using elastography techniques and a "biological" approach based on the quantification of biomarkers in serum samples (14). For imagingbased approaches, vibration-controlled transient elastography (VCTE) and magnetic resonance elastography are the most widely used clinical tools (15)(16)(17). As for quantitative biological approaches, blood-based tests such as fibrosis 4 (FIB-4) index, which accounts for aspartate aminotransferase and alanine aminotransferase levels, the platelet count, and age to give a fibrosis index, is used commonly in the clinics (7,18). ...
... Although most current clinical trials utilize a liver biopsy to identify a suitable patient population, the invasive nature of biopsy limits its utility as a broader patient-screening tool for clinical trials (50), patient monitoring during trials, or for monitoring intervention efficacy. The fibrosis-4 index (FIB4), NAFLD fibrosis score (NFS), NIS4, and vibration-controlled transient elastography (VCTE) are currently available noninvasive tests to predict the presence and severity of hepatic fibrosis in NAFLD (16,17,19,50,59). However, these tests are based on simple variables such as age, liver enzymes, platelets, and liver physical stiffness, which unlike our cf-mRNA classifier are unlikely to reflect the real-time dynamics of NAFLD pathophysiology or hepatic transcriptome changes in response to therapeutic interventions for NAFLD. ...
Article
Hepatic fibrosis stage is the most important determinant of outcomes in patients with non-alcoholic fatty liver disease (NAFLD). There is an urgent need for non-invasive tests that can accurately stage fibrosis and determine efficacy of interventions. Here we describe a novel cf-mRNA-Sequencing approach that can accurately and reproducibly profile low levels of circulating mRNAs and evaluate the feasibility of developing a cf-mRNA-based NAFLD fibrosis classifier. Using separate discovery and validation cohorts with biopsy-confirmed NAFLD (n=176 and 59, respectively) and healthy subjects (n=23), we performed serum cf-mRNA RNA-Seq profiling. Differential expression analysis identified 2498 dysregulated genes between NAFLD and healthy subjects and 134 fibrosis-associated genes in NAFLD patients. Comparison between cf-mRNA and liver tissues transcripts revealed significant overlap of fibrosis associated genes and pathways indicating that the circulating cf-mRNA transcriptome reflects molecular changes in the livers of NAFLD patients. In particular, metabolic and immune pathways reflective of known underlying steatosis and inflammation were highly dysregulated in the cf-mRNA profile of patients with advanced fibrosis. Finally, we used an elastic net ordinal logistic model to develop a classifier that predicts clinically significant fibrosis (F2-4). In an independent cohort, the cf-mRNA classifier was able to identify 50% of patients with at least 90% probability of clinically significant fibrosis. We demonstrate a novel and robust cf-mRNA-based RNA-Seq platform for non-invasive identification of diverse hepatic molecular disruptions and for fibrosis staging with promising potential for clinical trials and clinical practice.
... All FibroScan tests were performed after overnight fasting. To compare the oxidative/antioxidant parameters in accordance with the level of hepatofibrosis, we divided subjects into two groups by LSM score, i.e., from 8.5 kPa to 16.0 kPa versus from 5.5 kPa to 8.5 kPa, on the basis of a previous study [22]. ...
... To explore the features of oxidative/antioxidant parameters by the level of hepatofibrosis, we divided subjects into two groups, i.e., 5.5 kPa ≤ LSM ≤ 8.5 kPa versus 8.5 kPa < LSM ≤ 16.0 kPa. A previous clinical study had reported that 8.5 kPa LSM was a cutoff score for bridging fibrosis in 900 chronic viral hepatitis subjects [22]. Then, we compared oxidative stress-related parameters in serum, such as ROS, MDA, TAC, SOD, catalase, GSH, GPx, and GRd. ...
Article
Full-text available
Oxidative stress plays a pivotal role in the progression of chronic hepatitis B; however, it is unclear whether the status of blood oxidative stress and antioxidant components differs depending on the degree of hepatic fibrosis. To explore the relationship between oxidative stress/antioxidant capacity and the extent of hepatic fibrosis, fifty-four subjects with liver fibrosis (5.5 ≤ liver stiffness measurement (LSM) score ≤ 16.0 kPa) by chronic hepatitis B virus (HBV) were analyzed. From the analysis of eight kinds of serum oxidative stress/antioxidant profiles and liver fibrosis degrees, the level of total antioxidant capacity (TAC) reflected a negative correlation with the severity of hepatic fibrosis (Pearson correlation, r = −0.35, p = 0.01). Moreover, TAC showed higher sensitivity (73.91%) than the aspartate transaminase (AST) to platelet ratio index (APRI, 56.52%) in the receiver operating characteristic (ROC) curves. Interestingly, the TAC level finely reflected the fibrosis degree in inactive carriers (HBV DNA < 2000 IU/mL), while the APRI did in active carriers (HBV DNA > 2000 IU/mL). In conclusion, TAC is a promising biomarker for evaluating the progression of liver fibrosis in patients with HBV, and this finding may indicate the involvement of TAC-composing factors in the pathogenesis of hepatic fibrosis in chronic HBV carriers.
... Transient elastography is a useful point-of-care tool to help measure and monitor liver stiffness and liver steatosis [38][39][40][41][42][43]. Transient elastography measurements are generally well tolerated in children above the age of 5 years [44]. ...
Article
Full-text available
Analysis of the liver using imaging for persons with cystic fibrosis (CF) continues to evolve as new medical therapies are developed improving and extending life. In the 2010s, therapies targeted at modulating protein folding became available to those with CF. Therapeutic options have continued to expand, now providing both correction of protein folding and stabilization for most gene mutations that code for the CF transmembrane receptor protein (CFTR). Today, approximately 80% of persons with CF are eligible for highly effective modulator therapy. With these advancements, the impact of CF on the liver has become more complex, adding metabolism of CFTR modulators to intrinsic CF hepatobiliary involvement (CFHBI) and adding not previously appreciated vascular changes within the liver due to increased longevity in persons with CF. A combination of serum biomarkers and imaging is needed to add clarity to the diagnosis and monitoring of the severity of liver disease. A substantial portion of persons with CF will develop at least CFHBI and a subset will develop advanced cystic fibrosis-associated liver disease (aCFLD); therefore, diagnosis and monitoring need to begin in childhood. In this review, we cover the use of and need for imaging, including elastography, ultrasound, and magnetic resonance imaging (MRI), in diagnosing and monitoring CFHBI and its associated complications.
... -Ngày này siêu âm Fibroscan là một phương pháp mới và đang được phát triển rộng rãi để chẩn đoán tổn thương gan. Đây là một phương pháp có nhiều ưu việt: không đau, không xâm lấn, không có tác dụng phụ, có độ chính xác cao tương đương sinh thiết gan, mang tính khách quan và có thể thực hiện thăm khám nhiều lần [1]. Fibroscan có khả năng đánh giá đồng thời độ đàn hồi dựa trên công nghệ siêu âm đàn hồi định lượng và độ nhiễm mỡ, xơ hóa gan bằng cách tính toán từ tín hiệu siêu âm trong phép đo độ đàn hồi gan. ...
Article
Mục tiêu: Mô tả đặc điểm hình ảnh siêu âm fibroscan gan ở bệnh nhân (BN) đái tháo đường (ĐTĐ) típ 2. Đối tượng và phương pháp: Mô tả cắt ngang, tiến cứu trên 142 BN ĐTĐ típ 2 được siêu âm Fibroscan tại bệnh viện Quân y 103 từ 4/2023 đến 2/2024. Kết quả: Chỉ số gan nhiễm mỡ trên Fibroscan trung bình là 250,2 ± 63,8 dB/m. Đa số bệnh nhân có gan nhiễm mỡ độ S3 trên Fibroscan (28,9%). Không có sự khác biệt giữa mức độ gan nhiễm mỡ trên Fibroscan và thời gian mắc bệnh đái tháo đường típ 2. Chỉ số xơ hóa gan trên Fibroscan trung bình là 6,16 ± 3,1 kPa. Phần lớn BN có xơ hóa độ F1 trên Fibroscan (14,1%). Không có sự khác biệt chỉ số xơ hóa gan trung bình theo thời gian. Kết luận: Chỉ số gan nhiễm mỡ trên Fibroscan trung bình là 250,2 ± 63,8 dB/m. Đa số bệnh nhân có gan nhiễm mỡ độ S3 trên Fibroscan (28,9%). Chỉ số xơ hóa gan trên Fibroscan trung bình là 6,16 ± 3,1 kPa. Phần lớn BN có xơ hóa độ F1 trên Fibroscan (14,1%). Thời gian mắc bệnh đái tháo đường típ 2 không ảnh hưởng tới mức độ gan nhiễm mỡ và xơ hóa trên Fibroscan..
... The patients who were undergone TE must be fasted for 6 hours before operation. (11) Using TE as the reference standard of liver fibrotic measurement, the diagnostic performance of APRI and FIB-4 scores were evaluated. The TE cut-off levels of 7.0 kPa and 12.5 kPa were defined for significant fibrosis (F  2) and cirrhosis, respectively. ...
... However, these non-invasive tests (NITs) have their limitations, and high BMI negatively impacts the diagnostic reliability of TE in NAFLD patients, especially if the M probe is used [14]. The accuracy of liver stiffness measurements (LSMs) is operator-dependent and affected by the degree of necroinflammation in the liver, cholestasis, and hepatic congestion [19]. One study showed that even with the TE-XL probe, a reliable liver stiffness measurement could only be obtained in up to 85% of the study population [12]. ...
Article
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Background and Objectives: The prevalence of NAFLD (non-alcoholic fatty liver disease) is increasing, and up to 64% of Asian patients with NAFLD are obese. Non-invasive tests (NITs) for the assessment of liver fibrosis are increasingly being used, but data on their performance in obese Asian patients are lacking. In this pilot cross-sectional study, we aim to compare the distribution of serum and radiological markers of fibrosis between obese Asian biopsy-proven NAFLD patients with and without fibrosis and estimate the diagnostic accuracies of these indices. Materials and Methods: Obese Asian patients with NAFLD and who had undergone a liver biopsy showing histological evidence of NAFLD were invited to participate. Liver fibrosis was assessed using laboratory (APRI, AAR, BARD, FIB4, NFS, and Asia–Pacific NAFLD advanced fibrosis score) and imaging modalities (TE: transient elastography, MRE: magnetic resonance elastography, and SWU: shear wave ultrasonography). Results: A total of 16 patients were included in the final analysis. On liver biopsy, nine patients (56.3%) had significant fibrosis (F2 or higher), and six of these patients had advanced fibrosis (F3 or higher). F4 fibrosis was present in one patient (6.3%). For the laboratory markers, we found that the BARD score correctly identified five out of six patients with advanced fibrosis (83.4%, p value 0.045). Among all the NITs studied, liver stiffness measured by TE had the highest accuracy of 87.5% in its established threshold of 8.5 kPa for the detection of advanced fibrosis. MRE also performed well (81.2% in 3.64 kPa). Conclusions: In conclusion, TE has performed well in the detection of advanced fibrosis in obese Asian patients with biopsy-proven NAFLD in our pilot study. Further large-scale definitive studies are needed to validate the results of our findings.
... The increased prevalence of the underlying liver disease in the general population has led to an increase of 9% in the annual rates of incidence of NAFLD-associated HCC [16]. Currently, liver biopsy is the most reliable approach for identifying the presence of steatohepatitis and fibrosis in patients with NAFLD, but it is generally acknowledged that biopsy is limited by cost, sampling error, and procedure-related morbidity and mortality [17]. Liver fibroscan is a non-invasive diagnostic tool used to measure the level of liver fibrosis, or scarring, in patients with liver disease. ...
Article
Full-text available
Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is a multifaceted molecular complex condition shaped by genetic and environmental factors., there is a critical need for an early diagnostic and monitoring tool for NAFLD, as it represents a hepatic manifestation of the widely prevalent metabolic syndrome. An enzyme known as Lipoprotein-Associated Phospholipase A2 (Lp-PLA2), which is involved in both inflammation and lipid production, emerges as a potential contributor to the pathogenesis of metabolic syndrome and, by extension, NAFLD. Aim of the study: To investigate the potential diagnostic and prognostic value of the serum level of Lp-PLA2 as a reliable non-invasive marker in NAFLD. Patients and Methods: In this case-control study, a total of 80 participants were enrolled and divided into two groups: a normal control group (40) and a case group with NAFLD (40). All participants underwent comprehensive assessments, including medical history taking, clinical examinations, laboratory investigations, and measurement of serum Lp-PLA2 concentration. Additionally, calculations were performed to determine the Fatty Liver Index (FLI) and the NAFLD Fibrosis Score (NFS). Results: The analysis of data has shown direct correlation between Lp-PLA2 with the blood level of liver enzymes, LDL-cholesterol, and NFS. Cutoff value for Lp-PLA2 greater than 5.8 ng/mL yielded sensitivity and specificity values of 77.5 and 87.5%, with positive and negative predictive values of 86.1% and 79.5%, respectively. Conclusion: Lp-PLA2 holds promise as a diagnostic and potentially prognostic marker for NAFLD. Lowering LDL-cholesterol levels, through cholesterol-lowering treatments, may also reduce Lp-PLA2 activity, potentially offering therapeutic avenues for NAFLD.
... The CAP Technique is an ultrasound-based method for the quantification of steatosis (>10% steatosis). Although the test does not seem to be very dependable [52], the Asia-Pacific guidelines still recommend CAP as a useful tool in NAFLD patients. ...
Article
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Metabolic dysfunction associated fatty liver disease (MAFLD) has been recently recognized as a new global chronic liver disease entity with non-alcoholic fatty liver disease (NAFLD) associated with overweight/obesity or type 2 diabetes mellitus (T2DM) and evidence of metabolic dysregulation. Due to the rising rates of obesity and diabetes, MAFLD is considered a rapidly emerging chronic liver disease globally. Nearly 25–30% of the global population poses health issues due to MAFLD with a substantial economic burden to societies. Disease progression depends on the persistence of risk factors and etiological agents, from simple steatosis, hepatitis, fibrosis, to cirrhosis, and if untreated, leads to hepatocellular carcinoma. In this review article we summarize various risk and etiological factors, diagnostic techniques, and therapeutic evaluation of pharmacological agents developed for MAFLD. Effective pharmaceutical agents for the treatment of MAFLD (and NAFLD) are lacking, and research is ongoing to search for effective medications in this direction. Currently, pioglitazone is advised for MAFLD patients, whereas Vitamin E is advised for non-diabetic MAFLD patients with ≥F2 non-cirrhosis. Current approaches to disease management emphasize diet control, lifestyle changes, and weight loss. In this review, we summarized the pharmacological agents currently being developed and their current status to treat patients with MAFLD.
... To address this issue, non-invasive tests to assess liver fibrosis have been developed and can be divided into two groups including serum indices and imaging methods [6]. Regarding imaging techniques, transient elastography is the most validated imaging method that can be used as a reference method for liver stiffness assessment in chronic liver diseases [7,8]. However, significant drawbacks have prevented it from being widely used and include its availability and expense as well as its limited utility in those with severe obesity or ascites [8]. ...
Article
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Background The accurate evaluation of liver fibrosis is crucial for the treatment and follow up of chronic hepatitis B (CHB) patients. Aim We examined the efficiency of serum Mac-2 Binding Protein Glycosylation isomer (M2BPGi) in diagnosing liver fibrosis stages in CHB patients. Methods A cross-sectional study was conducted on 177 adult CHB patients visiting the University Medical Center Ho Chi Minh City, Vietnam between October 2019 and December 2021. M2BPGi, ARFI, APRI, and FIB-4 were tested against FibroScan® for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The optimal M2BPGi cut-off values were identified based on the area under the receiver operating characteristic (AUROC) curve. Results There was a strong agreement between M2BPGi and FibroScan® (r = 0.77, P < 0.001). The optimal M2BPGi cut-off index (C.O.I) for detecting significant fibrosis (F ≥ 2) was 0.79 with an AUROC of 0.77, 67.3% sensitivity, 70% specificity, 60.6% NPV, and 75.3% PPV. Compared with APRI (61%) and FIB-4 (47%), M2BPGi had the greatest sensitivity for diagnosing F ≥ 2. M2BPGi combined with APRI yielded highest diagnosis performance for F ≥ 2 with an AUROC of 0.87. The optimal cut-off index of M2BPGi for diagnosing cirrhosis (F4) was 1.3 with an AUROC of 0.91, 88% sensitivity, 87.4% specificity, 97% NPV, and 61% PPV. The AUROC of M2BPGi for diagnosing F4 was comparable to that of ARFI (0.93). Conclusions With cut-off values of 0.79 C.O.I and 1.3 C.O.I, M2BPGi could be an effective method for diagnosing significant fibrosis and cirrhosis in CHB patients, respectively. Graphical Abstract
... Patient preparation involved a 6 h fast preceding the examination (drinks were allowed, but only non-carbonated beverages were permitted). As per good practice, liver stiffness was calculated over at least 10 valid measurements, with a ratio of the interquartile range (IQR) to the median of the liver stiffness (IQR/Median) of ≤25% [25][26][27]. Notably, CAP, through the SmartExam program, was continuously computed during the entire examination until the CAP gauge reached 100%. The hepatic steatosis grade was defined by CAP cut-off values previously established. ...
Article
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Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of the study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients fulfilling the 2013 ACR/EULAR classification criteria were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), activity index, videocapillaroscopy, echocardiography, and lung function data were analyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis. In addition, hepatic steatosis was evaluated by means of controlled attenuation parameter (CAP) findings. Specifically, CAP values ≥ 238 ≤ 259 dB/m were considered consistent with mild steatosis (S1), values ≥ 260 ≤ 290 dB/m were compatible with moderate steatosis (S2), and values ≥ 291 dB/m were indicative of severe steatosis (S3). Results The median age of patients was 51 years, with a median disease duration of 6 years. The median LS was 4.5 (2.9–8.3) kPa; 69.5% of patients had no evidence of fibrosis (F0); 27.1% displayed LS values between 5.2 and 7 kPa; and only 3.4% of patients had LS values > 7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164–343). Overall, 66.1% of patients did not show evidence of steatosis (CAP values < 238 dB/m); 15.2% showed values consistent with mild (S1) steatosis (CAP value ≥ 238 ≤ 259 dB/m); 13.5% had moderate (S2) steatosis (CAP value ≥ 260 ≤ 290 dB/m); and 5.1% were deemed to have severe steatosis (S3) due to CAP values ≥ 291 dB/m. Conclusions Although systemic sclerosis is associated with fibrosis of the skin and several organs, only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Therefore, fibrosis of the liver did not appear to be a significant concern in SSc patients, albeit moderate fibrosis could still be detected in a significant proportion of subjects. A prolonged follow-up may clarify whether liver fibrosis in SSc patients may still progress. Likewise, the prevalence of significant steatosis was low (5.1%) and depended on the same variables associated with fatty liver disease in the general population. TE was shown to be an easy and valuable method for detection and screening of hepatic fibrosis in SSc patients with no additional risk factors for liver disease and may be useful to assess the potential progression of liver fibrosis over time.
... Patient preparation involved a 6-hour fasting preceding the examination (drink was allowed, but only non-carbonated beverages were permitted). As per good practice, liver stiffness was calculated over at least 10 valid measurements, with a ratio of the interquartile range (IQR) to the median of the liver stiffness (IQR/Median) of ≤25% [24][25][26]. Notably, CAP, through the SmartExam program, was continuously computed during the entire examination until the CAP gauge reached 100%. The hepatic steatosis grade was defined by CAP cut-off values previously established. ...
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Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue, characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients, satisfying the 2013 ACR/EULAR classification criteria, were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), ac-tivity index, video-capillaroscopy, echocardiography, and lung function data were ana-lyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis and steatosis. Specifically, values ≥ 238 CAP ≤ 259 dB/m were considered consistent with mild steatosis (S1), 260 ≥ CAP ≤ 290 dB/m with moderate steatosis (S2) and ≥291 dB/m with severe steatosis (S3) Results The median age of patients was 51 years, with a median disease duration of 6 years. Median LS was 4.5 (2.9–8.3) kPa; 41 patients (69.5%) had no evidence of fibrosis (F=0), 16 (27.1%) displayed LS values between 5.2 and 7 kPa; only 2 patients (3.4%) had LS values >7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164–343). Overall, 39 patients (66.1%) did not show evidence of steatosis (CAP values <238 dB/m); 9 patients (15.2%) showed values consistent with mild (S1) steatosis (CAP value ≥238 ≤259 dB/m); 8 patients (13.5%) had moderate (S2) steatosis (CAP value ≥260 ≤290 dB/m); 3 patients (5.1%) were deemed to have severe steatosis (S3) due to CAP values ≥291 dB/m. Conclusions Only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Likewise, the prevalence of significant steatosis was low (5.1%) and depending on the same variables associated with fatty liver in the general population. TE was shown to be an easy and valuable method for detection and screening of liver fibrosis in SSc patients with no additional risk factors for liver disease.
... The examination of obese patients can be overcome using XL probes with higher penetrance. The results may also be influenced by the patient's habitus, the operator's experience, a high grade of inflammation, cholestasis, and venous congestion after a meal, or, when the patient suffers from portal vein thrombosis [8]. ...
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Background and objectives: Recently, rapid progress has been made in the development of noninvasive methods for liver fibrosis assessment. The study aimed to assess the correlation between LSM and serum fibrosis markers to identify patients with advanced liver fibrosis in daily clinical practice. Methods: Between 2017 and 2019, 89 patients with chronic liver disease of various etiology, 58 males and 31 females, were enrolled in the study and underwent ultrasound examination, vibration-controlled transient elastography (VCTE), AST to Platelet Ratio Index (APRI score), Fibrosis-4 (FIB-4) score, and enhanced liver fibrosis (ELF) test. Results: The diagnoses were as follows: NAFLD (30.3%), HCV (24.3%), HBV (13.1%), ALD (10.1%), other (7.8%). Their median age was 49 (21–79), and their median BMI was 27.5 (18.4–39.5). The median liver stiffness measurement (LSM) was 6.7 kPa (2.9–54.2 kPa), the median of the ELF test was 9.0 (7.3–12.6), and the median APRI was 0.40 (0.13–3.13). Advanced fibrosis assessed by LSM was present in 18/89 (20.2%) patients. The LSM values correlated with the ELF test results (r2 = 0.31, p < 0.0001), with the APRI score (r2 = 0.23, p < 0.0001), the age of the patients (r2 = 0.14, p < 0.001), and with the FIB-4 values (r2 = 0.58, p < 0.0001). The ELF test values correlated with the APRI score (r2 = 0.14, p = 0.001), the age (r2 = 0.38, p < 0.0001), and the FIB-4 (r2 = 0.34, p < 0.0001). By determining the confidence intervals of the linear model, we proved that patients younger than 38.1 years have a 95% probability of absence of advanced liver fibrosis when assessed by VCTE. Conclusions: We identified APRI and FIB-4 as simple tools for screening liver disease in primary care in an unselected population of patients. The results also showed that individuals younger than 38.1 years had a negligible risk of advanced liver fibrosis.
... Therefore, early detection may promote early intervention to prevent disease progression. TE is increasingly used in adults to detect hepatic steatosis and fibrosis [24,25]. Limited data in non-obese children show an age-dependent increase in LSM but not CAP [26]. ...
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The pilot study evaluated contingency management (CM) for family-based obesity therapy (FBT). The secondary outcome assessed the association of the hepatic transient electrography (TE) parameters, including the controlled attenuation parameter (CAP) and liver stiffness (LSM), and changes in liver function blood tests and BMI changes in youth involved in intensive FBT. It included youth-parent dyads from an urban pediatric center randomized to weekly behavioral therapy (BT, n= 4) who received fixed financial compensation for attendance, or BT+CM (n= 5) who received an escalating monetary reward for weight loss. At week 30, all youth and parents had weight-loss trends without significant differences between groups. While the TE measures and blood tests were normal in the youth at baseline and week 30, the CAP changes correlated with BMI changes (R2= 0.86, P< 0.001) and LSM changes with alanine aminotransferase changes (R2= 0.79, P=0.005). In conclusion, BT+CM did not significantly add to the BMI improvement seen with BT alone in youth and their parents. However, in youth with obesity and normal liver blood tests, TE may be useful for monitoring changes in fatty liver disease.
... Thus, three main techniques were emerged for non-invasive detection and quantification of liver fat and iron content. First, a clinically used technique is to measure the stiffness of liver by the vibrationcontrolled transient elastography (VCTE) using FibroScan ® (FS) device [5][6] (Echosens, Paris, France). Ultrasound (US) attenuation measurement using controlled attenuation parameter (CAP) [7] is an additional parameter introduced in 2010 to non-invasively assess liver steatosis [8] and recently improved [9]. ...
... LSM is sensitive to advanced fibrosis and cirrhosis, while the specificity of ruling out F1 and F2 fibrosis is still to be improved. In addition, LSM would be affected by various factors including obesity, subcutaneous fat thickness, high ALT level and cholestasis 88 . Agile 3+ and Agile 4 combining LSM with routine clinical parameters were two recently developed models to identify advanced fibrosis and cirrhosis respectively. ...
Article
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Nonalcoholic steatohepatitis (NASH) is the aggressive form of nonalcoholic fatty liver disease (NAFLD), characterized as steatosis-associated inflammation and liver injury. Without effective treatment or management, NASH would develop life-threatening outcomes. In this situation, evaluation and identification of those at-risk for adverse outcomes are important. The key issues in screening NASH patients are the assessment of advanced fibrosis, differentiation of NASH from simple steatosis, and their dynamic changes during follow-up. Currently, the staging for NASH and evaluation of effectiveness for drugs still rely on pathological diagnosis, while liver biopsy brings sample error issues and subjectivity. To address this problem, optimizing the pathological assessment and developing noninvasive surrogate methods for accessible, accurate, and safe evaluation is of significance. Although noninvasive methods including elastography, serum soluble biomarkers and combined models have been widely studied in the last decade, the application of noninvasive diagnostic measurements in clinical practice is still insufficient. Much work remains to be done in establishing cost-effective strategies both for screening for at-risk NASH and identify the changes of disease severity. In this review, we summarized the current state of the noninvasive methods for detecting steatosis, steatohepatitis and fibrosis of NASH, introduced the noninvasive assessment for screening at-risk patients, and focused on the characteristics should be monitored in the follow-up.
... Obesity can make performing TE difficult. 27 Experience of the operator can also affect the validity of a result. Other confounding factors include extra-hepatic cholestasis, raised serum aminotransferases (>5-fold the ULN), right heart failure, and excessive alcohol intake. ...
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The purpose of the meeting was to work towards unified best practice in the treatment of primary biliary cholangitis (PBC). This centred on a theme of collaboration, with the intention of pooling and sharing the collective experience of healthcare professionals globally. A talk from a patient representative introduced the concept of a patient-centric treatment approach and offered an alternative perspective on PBC care. This was followed by a review of the European Association for the Study of the Liver (EASL) PBC guidelines, which highlighted the importance of risk stratification for individualised and optimal treatment. This led into a session related to biochemical response and the identification of patients suitable for second-line therapy. Another key topic was ‘challenges in PBC management’, in which symptom management techniques focussing on pruritus and fatigue were highlighted. Following this, non-invasive imaging techniques and their evolving use in disease staging and risk assessment were discussed. The advancing therapeutic landscape of PBC was presented, including discussion of emerging therapeutic targets such as farnesoid X receptors (FXR), fibroblast growth factor 19 (FGF-19), and peroxisome proliferator-activated receptors (PPAR). Obeticholic acid (OCALIVA®▼, Intercept Pharmaceuticals, Inc., London, UK) is the first-in-class FXR agonist licensed for the second-line treatment of PBC, and its optimal therapeutic use was discussed through the presentation of clinical data and case studies.
... TE was measured using the FibroScan ® device (Echosens ® , Paris, France). After an induction pulse, the shear wave velocity through a hepatic tissue cylinder (approximately 1 × 4 cm) is converted to a stiffness measure (kPa), and returned as the median value of the successful measures [21,22]. Four unblinded experienced operators performed the measures, and patients fasted for four hours prior to examination. ...
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Background: Elastography can be measured with different imaging techniques and is increasingly used for noninvasive assessment of hepatic fibrosis. Little is known about the performance, and interrelation of different elastographic techniques, in prediction of hepatic fibrosis in pediatric liver disease. Objectives: We aimed to determine the discriminatory value for advanced fibrosis (Metavir F3-4) and evaluate the applicability of 2D shear wave ultrasound elastography (USe), Transient Elastography (TE) and Magnetic Resonance elastography (MRe) in pediatric liver disease. Methods: In patients with pediatric liver disease aged 0–19 years, USe, TE and MRe were compared with histopathological fibrosis stage. Multivariate logistic regression models for advanced fibrosis were considered. Discriminative performance was assessed by the area under the receiver operating characteristic curve and the Brier Score. Primary analyses included complete cases. Multiple imputation was used as sensitivity analysis. Results: In 93 histologically evaluated patients USe, TE and MRe were performed 89, 93 and 61 times respectively. With increased liver stiffness values, significantly increased odds for presenting F3-4 were seen in individual models for ALT < 470 U/L, whereas the effect for ALT > 470 U/L was non-significant. Area under the curve and Brier Score for discrimination of advanced fibrosis were 0.798 (0.661–0.935) and 0.115 (0.064–0.166); 0.862 (0.758–0.966) and 0.118 (0.065–0.171); 0.896 (0.798–0.994) and 0.098 (0.049–0.148) for USe, TE and MRe respectively. No significant increase in discriminatory ability was found when combining elastographic modalities. Conclusions: In pediatric liver disease, USe, TE and MRe had a good discriminatory ability for assessment of advanced liver fibrosis, although TE and MRe performed best. In most children with pediatric liver disease, TE is a reliable and easily applicable measure.
... There are multiple confounding factors that can increase the liver stiffness value on ultrasound elastography (inflammation, fatty infiltration, cholestasis, congestive hepatopathy, or a postprandial increase in blood flow) [18][19][20][21][22]. Furthermore, when performing liver ultrasound elastography, the technician must choose between a standard M probe and an XL probe for overweight and obese patients, who have a significant amount of intercostal fat. When an M probe is used in obese patients, 19% will produce an uninterpretable result [18,[23][24][25][26]. Because of these, several studies in the past have excluded obese patients (BMI >/= 30 kg/m 2 ). ...
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Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of advanced liver disease in the USA. Liver biopsy, the gold standard diagnostic test for evaluating liver fibrosis, is associated with significant risk and expense. The accuracy of ultrasound elastography and Fibrosis-4 index (FIB-4) in the obese NAFLD population is unknown. We aimed to compare the accuracy of ultrasound elastography and FIB-4 to liver biopsy in ruling out cirrhosis in NAFLD patients at a tertiary, transplant referral center in the US. Methods: We retrospectively evaluated 93 patients with a mean age of 53 years (SD: 13 years) who underwent liver ultrasound elastography and liver biopsy, and additionally calculated their FIB-4 at the time of biopsy. We compared the liver stiffness measurement (LSM) obtained from ultrasound elastography and FIB-4 with the pathology results for ruling out cirrhosis. Results: 85% of the patients were white, 53% were female, average BMI was 34.7 (SD: 6.7), 52% had diabetes, and 53% had hypertension. For biopsy-proven cirrhosis (prevalence 15%), a cut-off value of 12.5 kilopascals (kPa) for F4 had a sensitivity of 92% and a specificity of 54%. Values below this threshold excluded cirrhosis with 98% certainty. Compared to FIB-4, ultrasound elastography showed higher accuracy in ruling out cirrhosis (92% vs. 80% sensitivity, 98% vs. 95% negative predictive value (NPV), respectively). Conclusion: To our knowledge, this is the first study in a tertiary transplant referral center in the USA to show that ultrasound elastography was superior to FIB-4 and can be used as a reliable screening test to rule out cirrhosis in obese NAFLD patients at a 12.5 kPa cut-off. Therefore, helping to avoid the risk and expense associated with liver biopsy.
... 2 Of these imaging techniques, transient elastography (FibroScan; Echosens, France), which is a rapid and reproducible ultrasound-based technique, has been approved by the United States Food and Drug Administration as a reference method for liver stiffness assessment in chronic liver diseases. 4 In the updated guidelines of the European Association for the Study of Liver in 2021, FibroScan (FS) remains the most validated non-invasive method in evaluating liver fibrosis. 3 It is noted that FS is not the only ultrasound-based technique used for liver stiffness measurement but also has several disadvantages. ...
Article
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Background Acoustic radiation force impulse point shear wave elastography (ARFI-pSWE), measuring shear-wave velocity (SWV), has been utilized to examine the liver stiffness caused by different etiologies. However, information on its reliability in staging liver fibrosis in chronic hepatitis B (CHB) patients is scarce. Purpose The aim of the study is to examine the diagnostic performance of ARFI-pSWE and determine the optimal SWV cut-off values to predict significant fibrosis ( F ≥2) and cirrhosis (F4) in CHB patients. Material and Methods All 114 adult CHB patients visiting the University Medical Center, Ho Chi Minh City, Vietnam between February 2019 and March 2021 underwent liver stiffness measurement using ARFI-pSWE and FibroScan. SWV results were tested against FibroScan for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The area under the receiver operating characteristic (AUROC) curve was used to identify the optimal SWV cut-off values. Results There was a strong agreement between ARFI-pSWE and FibroScan ( r = 0.92, p <0.001). The optimal SWV cut-off value for detecting significant fibrosis was 1.37 m/s with an AUROC of 0.975, sensitivity of 83.3%, specificity of 100%, PPV of 100%, and NPV of 81%. The optimal cut-off value for predicting cirrhosis was 1.70 m/s with an AUROC of 0.986, sensitivity of 97%, specificity of 93%, PPV of 95%, and NPV of 96%. Conclusion ARFI-pSWE could be an effective technique for evaluating liver fibrosis in CHB patients. SWV cut-off values of 1.37 and 1.70 m/s could be used to diagnose significant fibrosis and cirrhosis, respectively.
... TE is a technology that indirectly measures the liver stiffness value by measuring the propagation velocity of the shear wave excited by the vibration of the patient's skin by a low-frequency mechanical source, thereby reflecting the degree of liver fibrosis. Vibration-controlled transient elastography (VCTE) produced by FibroScan company in the United States is currently the most commonly used assessment method for liver fibrosis [15]. In addition, VCTE has been validated in large-scale clinical trials of various liver diseases, and it is recommended to use VCTE in hepatitis B patients rather than serological indicators for liver fibrosis assessment [16]. ...
Article
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Liver fibrosis is a common liver disease that seriously endangers human health. Liver biopsy is the gold standard for diagnosing liver fibrosis, but its clinical use is limited due to its invasive nature. Ultrasound image examination is a widely used liver fibrosis examination method. Clinicians can diagnose the severity of liver fibrosis according to their own experience by observing the roughness of the texture of the ultrasound image, and this method is highly subjective. Under the premise that artificial intelligence technology is widely used in medical image analysis, this paper uses convolutional neural network analysis to extract the characteristics of ultrasound images of liver fibrosis and then classify the degree of liver fibrosis. Using neural network for image classification can avoid the subjectivity of manual classification and improve the accuracy of judging the degree of liver fibrosis, so as to complete the prevention and treatment of liver fibrosis. Therefore, the following work is done in this paper: (1) the research background, research significance, research status at home and abroad, and the impact of the development of medical imaging on the diagnosis of liver fibrosis are introduced; (2) the related technologies of deep learning and deep convolutional network are introduced, and the indicators of liver fibrosis degree assessment are constructed by using ultrasonic image extraction features; (3) using the collected liver fibrosis dataset to conduct model evaluation experiments, four classic CNN models are selected to compare and analyze the recognition rate. The experiments show that the GoogLeNet model has the best classification and recognition effect.
... Previous research proposed LSM values as indicators for liver fibrosis [24], with cut-off values for FibroScan of >9.5 kPa for determining advanced fibrosis [51]. However, there is a discrepancy of opinion whether LSM values truly reflect fibrosis, as the published threshold values vary between different research groups [52][53][54]. In addition to TE, other noninvasive tests for liver fibrosis have been introduced, of which APRI and FIB4 are the most commonly employed [55]. ...
Article
Objectives: To determine the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) treatment in Chinese patients with GT1b chronic hepatitis virus C (HCV) infections. Methods: In this retrospective study, 49 treatment-naive patients with chronic GT1b HCV infection were treated with GZR (100 mg) plus EBR (50 mg) for 12 weeks. The viral response was the primary endpoint and fibrosis stage changes during and after treatment, as well as the incidence of treatment-emergent adverse events (TEAE) were secondary endpoints. Results: After 2-week EBR/GZR treatment, the virologic response rate was 85.1% (80/94) and reached 100% (94/94) after 8 and 12 weeks of therapy. Sustained virologic response (SVR) rates were 100% at the 12, 24 and 48-week follow-ups. Multivariate analysis revealed that the baseline viral load of HCV RNA may affect the rapid 2-week virologic response (OR: 0.36, 95% CI: 0.14-0.92, P=0.034), but did not influence efficacy during further treatment or follow-ups. Fifteen patients with ≥1 TEAE (16.0%) were observed and 7 (7.4%) and 8 (8.5%) patients had mild ALT or AST elevations (1.1-2.5× BL), but no serious drug-related AEs occurred. Liver stiffness measurement (LSM), the AST to platelet ratio index (APRI) and the fibrosis index based on 4 factor (FIB4) scores were consistently reduced, especially in patients with high baseline assessments after 12 weeks' treatment and during follow-ups. Conclusions: A 12-week EBR/GZR regimen shows high efficacy and safety in Chinese patients with GT1b HCV infections.
... Stepwise or even concomitant use of two unrelated non-invasive tests might be the most favorable strategy to increase the reliability of the obtained result, i.e., predicted stage of liver fibrosis, as supported by guidelines [16,[124][125][126][127][128]. However, even transient elastography (TE) as the non-invasive method considered among the most reliable in stratifying the patients according to their risk of having advanced fibrosis, as supported by the largest body of scientific evidence, is not without limitations [129]. Indeed, according to the published data, this method tends to overestimate the presence of advanced fibrosis amongst patients with NAFLD, as the stage suggested by TE was confirmed by liver biopsy in only 50% of patients in a cohort of patients with type 2 diabetes [130]. ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of liver morbidity worldwide and, as such, represents the pathogenic background for the increasing incidence of hepatocellular carcinoma (HCC). The annual incidence of NAFLD-related HCC is expected to increase by 45–130% by 2030. Diabetes mellitus is the most important risk factor for HCC development in NAFLD, with the risk further increased when associated with other metabolic traits, such as obesity, arterial hypertension and dyslipidemia. The highest risk of HCC exists in patients with advanced fibrosis or cirrhosis, although 20–50% of HCC cases arise in NAFLD patients with an absence of cirrhosis. This calls for further investigation of the pathogenic mechanisms that are involved in hepatocarcinogenesis, including genetics, metabolomics, the influence of the gut microbiota and immunological responses. Early identification of patients with or at risk of NAFLD is of utmost importance to improve outcomes. As NAFLD is highly prevalent in the community, the identification of cases should rely upon simple demographic and clinical characteristics. Once identified, these patients should then be evaluated for the presence of advanced fibrosis or cirrhosis and subsequently enter HCC surveillance programs if appropriate. A significant problem is the early recognition of non-cirrhotic NAFLD patients who will develop HCC, where new biomarkers and scores are potential solutions to tackle this issue.
... Disease activity was defined as CRP ≥10 mg/l and/or FCP ≥150 μg/g. The degree of liver steatosis and fibrosis was assessed by transient elastography (FibroScan) [14]. Liver steatosis was defined as a Controlled Attenuation Parameter (CAP) ≥248. ...
Article
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Purpose Liver steatosis is a frequently reported condition in patients with inflammatory bowel disease (IBD). Different factors, both metabolic and IBD-associated, are believed to contribute to the pathogenesis. The aim of our study was to calculate the prevalence of liver steatosis and fibrosis in IBD patients and to evaluate which factors influence changes in steatosis and fibrosis during follow-up. Methods From June 2017 to February 2018, demographic and biochemical data was collected at baseline and after 6–12 months. Measured by transient elastography (FibroScan), liver steatosis was defined as Controlled Attenuation Parameter (CAP) ≥248 and fibrosis as liver stiffness value (Emed) ≥7.3 kPa. IBD disease activity was defined as C-reactive protein (CRP) ≥10 mg/l and/or fecal calprotectin (FCP) ≥150 μg/g. Univariate and multivariate regression analysis was performed; a p-value of ≤0.05 was considered significant. Results Eighty-two out of 112 patients were seen for follow-up; 56% were male. The mean age was 43 ± 16.0 years, and mean BMI was 25.1 ± 4.7 kg/m². The prevalence of liver steatosis was 40% and of fibrosis was 20%. At baseline, 26 patients (32%) had an active episode of IBD. Using a multivariate analysis, disease activity at baseline was associated with an increase in liver steatosis (B = 37, 95% CI 4.31–69.35, p = 0.027) and liver fibrosis (B = 1.2, 95% CI 0.27–2.14, p = 0.016) during follow-up. Conclusions This study confirms the relatively high prevalence of liver steatosis and fibrosis in IBD patients. We demonstrate that active IBD at baseline is associated with both an increase in liver steatosis and fibrosis during follow-up.
... It is agreed that fluid and parietal adipose tissues attenuate shear wave propagation, which can result in invalid examinations in patients with anatomic distortions, ascites, and elevated central venous pressures or in those who are obese [11,12]. In particular, the risk of overestimating LS values may emanate from a non-fasting state, excess of alcohol intake, physical exercise, acute hepatitis, inflammatory flares, congestive heart failure, hepatic parenchymal infiltration, cholestasis, and portal vein thrombosis [11][12][13][14][15][16]. Thus, TE should be performed in fasting patients (for at least 2 h), and results interpreted in light of potential confounders [9]. ...
Chapter
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Studies on normal (or healthy) individuals are an essential step in the process of diagnostic research. However, deciding what is normal in medicine can be difficult. In this chapter, we discuss how to adapt the concept of normality to clinical decisions, particularly in the field of liver disease. In addition, we summarize the main evidence on the measurement of liver stiffness in healthy individuals and propose thresholds to be used in clinical practice.
... CAP measures the attenuation of the US beam that travels through the liver tissue, usually at a frequency of 3.5 MHz. CAP is available on the FibroScan (FS) device, which concomitantly assesses CAP and liver stiffness using vibrationcontrolled transient elastography (VCTE) (Sandrin et al. 2003;Tapper et al. 2015). The operation of FS does not require special skills in US. ...
Article
Controlled attenuation parameter (CAP) is a measurement of ultrasound attenuation used to assess liver steatosis non-invasively. However, the standard method has some limitations. This study assessed the performance of a new CAP method by ex vivo and in vivo assessments. The major difference with the new method is that it uses ultrasound data continuously acquired during the imaging phase of the FibroScan examination. Seven reference tissue-mimicking phantoms were used to test the performance. In vivo performance was assessed in two cohorts (in total 195 patients) of patients using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as a reference. The precision of CAP was improved by more than 50% on tissue-mimicking phantoms and 22%-41% in the in vivo cohort studies. The agreement between both methods was excellent, and the correlation between CAP and MRI-PDFF improved in both studies (0.71 to 0.74; 0.70 to 0.76). Using MRI-PDFF as a reference, the diagnostic performance of the new method was at least equal or superior (area under the receiver operating curve 0.889-0.900, 0.835-0.873). This study suggests that the new continuous CAP method can significantly improve the precision of CAP measurements ex vivo and in vivo.
... The ideal VCTE examination takes place with a patient who has fasted for 3 hours prior to the measurement [17,18]. Depending on the thickness of the abdominal wall, one of the handheld probes is chosen and, together with the applied conduction gel, the probe is placed intercostally overlying the right hepatic lobe [19][20][21]. ...
Article
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Chronic infection with hepatitis C virus (HCV) is one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC). Surveillance of these patients is an essential strategy in the prevention chain, including in the pre/post-antiviral treatment states. Ultrasound elastography techniques are emerging as key methods in the assessment of liver diseases, with a number of advantages such as their rapid, noninvasive, and cost-effective characters. The present paper critically reviews the performance of vibration-controlled transient elastography (VCTE) in the assessment of HCV patients. VCTE measures liver stiffness (LS) and the ultrasonic attenuation through the embedded controlled attenuation parameter (CAP), providing the clinician with a tool for assessing fibrosis, cirrhosis, and steatosis in a noninvasive manner. Moreover, standardized LS values enable proper staging of the underlying fibrosis, leading to an accurate identification of a subset of HCV patients that present a high risk for complications. In addition, VCTE is a valuable technique in evaluating liver fibrosis prior to HCV therapy. However, its applicability in monitoring fibrosis regression after HCV eradication is currently limited and further studies should focus on extending the boundaries of VCTE in this context. From a different perspective, VCTE may be effective in identifying clinically significant portal hypertension (CSPH). An emerging prospect of clinical significance that warrants further study is the identification of esophageal varices. Our opinion is that the advantages of VCTE currently outweigh those of other surveillance methods.
... 11 In our study, the data revealed that age was associated with more advanced stages of the disease, which is consistent with previous NAFLD studies. 12 Moreover, in our study were older on average (50.38±7.44 years old) than those from cohorts analysed by other authors in similar setting the frequencies of cardiovascular disease and chronic inflammatory diseases are higher in older populations. 13 The specificity and sensitivity of fibro scan were highest at ≥F4. ...
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Background: Alcohol-associated liver disease includes a variety of clinical disorders which include steatosis, Alcoholic steato hepatitis, alcoholic hepatitis of varying degrees of severity, alcoholic cirrhosis, and alcohol associated cirrhosis complicated by hepatocellular carcinoma (HCC). In patients with alcoholic liver disease the presence of hepatic (liver) fibrosis and progression into cirrhosis is a prognostic variable and having impact on survival. To assess hepatic (liver) fibrosis using serum fibro scores fibrosis-4 (FIB-4) scores, AST platelet ratio index (APRI scores) and to compare these results with fibro scan to rule out severe fibrosis in patients with alcohol related disease.Methods: A cross sectional clinical study conducted on 50 patients with alcohol associated chronic liver disease between December 2019 to December 2020 who were in follow up in outpatient department (OPD) and admitted in the Department of Medical Gastroenterology. APRI and FIB-4 scores were calculated and compared with fibro scan values.Results: The results of 50 patients were analysed, including, males with a mean age. Among the study population, 6 (12%) participants had no significant FIB-4, 16 (32%) participants had intermediate FIB-4 and 28 (56%) participants had likely cirrhosis. 33 (66%) participants had no significant APRI, 6 (12%) participants had significant APRI and 11 (22%) participants had cirrhosis liver. Among the people with fibro scan KPA F0-F1 (<7), all of them 100% were no significant FIB-4. Among the people with fibro scan KPA F2 (7 To 9.50), 2 (50%) were no significant FIB-4 and intermediate FIB-4 for each respectively.Conclusions: FIB-4 score correlated better than APRI score in assessing patients with and without severe fibrosis and cirrhosis in the setting of alcohol associated liver disease patients.
... 81 Other potential confounders of LSM include inflammation, cholestasis, congestion, food intake, and portal vein thrombosis. 82,83 In addition, optimal VCTE LSM thresholds with the 2 different probes (M and XL) have not been defined. MR elastography is a noninvasive, MR imagingebased method for LSM and has also been shown to distinguish between advanced and nonadvanced fibrosis. ...
Article
Purpose Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and has the potential risk for progressing to nonalcoholic steatohepatitis (NASH), which is associated with a greater risk for complications of chronic liver disease. Noninvasive testing has been evaluated for diagnosis, risk stratification, disease progression, and assessing response to therapy. The purpose of this narrative review was to outline the current noninvasive testing modalities for the diagnostic evaluation of NAFLD and NASH, while discussing possible markers that could be used for monitoring response to therapies. Methods The PubMed and Cochrane databases were searched for relevant articles that evaluated the diagnosis of NAFLD/NASH with serum biomarkers and/or imaging. Findings Serum biomarkers, imaging modalities, and combinations/serial algorithms involved in the diagnosis of NAFLD and NASH are outlined. In addition, noninvasive modalities that have been used for assessing response to therapies in clinical trials are discussed. Implications Liver biopsy currently remains the gold standard for diagnosis and is often used in clinical trials to assess treatment response. However, developing safe and accessible noninvasive modalities for diagnosis and monitoring will have greater impact and relevance, as biopsy may not always be feasible in all clinical settings.
Article
It is critical to assess the extent and progression of liver fibrosis for patients to receive suitable treatments, but its diagnostic methods remain unmet. Extracellular matrix protein 1 (ECM1) has previously been reported to be a key factor in the induction and progression of liver fibrosis. However, little is known about the use of ECM1 as a biomarker to evaluate fibrosis. In a CCl4-induced mouse model of liver fibrosis, the present study demonstrated that ECM1 decreased with gradually increasing fibrosis. Using biopsy as a reference, the serum ECM1 levels decreased with increasing fibrosis stage in 247 patients with liver fibrosis, but there were no significant changes between fibrosis stage 2 and stage 0–1. To improve the performance of ECM1, age, platelet count, and ECM1 concentration were combined to calculate an EPA (ECM1-platelet-age) score (ranging from 0 to 10). The areas under the receiver operating characteristic curve of the EPA scores for the detection of F⩾2, F⩾3, and F4 were 0.6801, 0.7377, and 0.8083, respectively, which showed a comparable or significantly greater diagnostic performance for assessing fibrosis than that of the AST/ALT ratio, APRI score, or FIB-4 score. In HBV patients following antiviral treatment, the dynamics of the EPA score depended on the status of liver fibrosis development. The accuracy of the EPA score in predicting fibrosis regression and progression was 66.00% and 71.43%, respectively, while that of the LSM, another useful method for monitoring hepatic fibrosis changes during treatment, was only 52.00% and 7.14%, respectively. Compared with healthy controls, there were lower levels of serum ECM1 in HBV patients and individuals with HCV infection, MAFLD, ALD, PBC, and DILI. These findings suggested that individuals with reduced ECM1 levels may have a risk of developing liver injury, and further examinations or medical care are needed. In conclusion, the ECM1-containing EPA score is a valuable noninvasive test for staging fibrosis and predicting the progression of liver fibrosis. Additionally, ECM1 alone is an indicator for distinguishing patients with liver injury from healthy controls.
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Both experimental and clinical liver fibrosis leave a metabolic footprint that can be uncovered and defined using metabolomic approaches. Metabolomics combines pattern recognition algorithms with analytical chemistry, in particular, 1H and 13C nuclear magnetic resonance spectroscopy (NMR), gas chromatography–mass spectrometry (GC–MS) and various liquid chromatography–mass spectrometry (LC–MS) platforms. The analysis of liver fibrosis by each of these methodologies is reviewed separately. Surprisingly, there was little general agreement between studies within each of these three groups and also between groups. The metabolomic footprint determined by NMR (two or more hits between studies) comprised elevated lactate, acetate, choline, 3-hydroxybutyrate, glucose, histidine, methionine, glutamine, phenylalanine, tyrosine and citrate. For GC–MS, succinate, fumarate, malate, ascorbate, glutamate, glycine, serine and, in agreement with NMR, glutamine, phenylalanine, tyrosine and citrate were delineated. For LC–MS, only β-muricholic acid, tryptophan, acylcarnitine, p-cresol, valine and, in agreement with NMR, phosphocholine were identified. The metabolomic footprint of liver fibrosis was upregulated as regards glutamine, phenylalanine, tyrosine, citrate and phosphocholine. Several investigators employed traditional Chinese medicine (TCM) treatments to reverse experimental liver fibrosis, and a commentary is given on the chemical constituents that may possess fibrolytic activity. It is proposed that molecular docking procedures using these TCM constituents may lead to novel therapies for liver fibrosis affecting at least one-in-twenty persons globally, for which there is currently no pharmaceutical cure. This in-depth review summarizes the relevant literature on metabolomics and its implications in addressing the clinical problem of liver fibrosis, cirrhosis and its sequelae.
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Background: Vibration Controlled Transient Elastography (VCTE) using FibroScan serves as a non-invasive and dependable diagnostic approach for Non-alcoholic Fatty Liver Disease (NAFLD), which is globally recognized as the most prevalent chronic liver condition. It allows for the early detection and management of NAFLD and Non-alcoholic Steatohepatitis (NASH), effectively preventing the progression to severe liver diseases. The ease of use and portability of VCTE make it highly suitable for widespread adoption in primary care and community settings, thereby facilitating large-scale screening for liver health. The integration of VCTE into point-of-care settings could streamline referrals, promote lifestyle interventions, reduce healthcare costs, and notably benefit underserved communities. Point-of-care VCTE demonstrates comparable diagnostic accuracy for detecting steatosis. The rationale for opting for point-of-care testing over standard laboratory testing is influenced by the presence of trained personnel at labs, which could potentially impact quality, coupled with constraints on conducting bulk VCTE tests within the existing framework. Given that most labs are situated in urban areas with limited accessibility, necessitating patients to take time off, conducting point-of-care testing in GI clinics or PCP offices emerges as a more practical option. Our study aimed to assess the diagnostic accuracy of VCTE for detecting fibrosis and steatosis in point-of-care settings. Methods: A comprehensive literature search identified studies reporting on point-of-care VCTE. Meta-analysis was conducted using a random-effects model, and results were presented in terms of pooled proportions alongside relevant 95% confidence intervals. Heterogeneity was assessed using I2%. Results: The analysis encompassed data from 11,665 patients across 31 studies. For diagnosing fibrosis stage ≥F1, the respective summary Area Under the Receiver Operating Characteristic Curve (sAUROC), pooled sensitivity, and specificity were 0.76, 67.7%, and 77.2%. For stage ≥F2 (significant fibrosis), they were 0.78, 78.2%, and 71.44%, respectively. For stage ≥F3 (advanced fibrosis), they were 0.87, 86%, and 72.9%. For stage =F4 (cirrhosis), they were 0.87, 89.3%, and 73.4%. Point-of-care VCTE demonstrated similar diagnostic accuracy for steatosis. VCTE's compliance rate was found to be 93.4%, surpassing rates observed for MRI-Proton Density Fat Fraction (MRI-PDFF). Patient preference studies favored VCTE over liver biopsy, especially in regions where the latter is publicly funded, with patients often willing to cover VCTE costs themselves. However, there is a noted decline in follow-up engagement over time, highlighting the need for strategies to maintain long-term adherence to VCTE monitoring, which can potentially be improved through the integration of point-of-care VCTE with doctor's appointments. Conclusion: VCTE exhibits high diagnostic accuracy for detecting fibrosis and steatosis in patients with NAFLD in point-of-care settings. Future studies should focus on evaluating the implementation of point-of-care fibroscans
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The recurring upsurge in mortality and morbidity intimidates the detection of bacterial pathogens crucial in the disciplines of food safety, health care, and medicine. There is an essential requirement to improve existing antimicrobial therapeutic strategies due to exponential growth in antimicrobial resistance and the frozen pool for antibiotic medication, and therefore accurate and rapid bacterial identification is critical. Several approaches like polymerase chain reactions, immunoassays, and culture procedures—the three current gold standards for detecting bacteria—have the conspicuous drawbacks of prolonged turnaround times and poor accuracy. Hence, their potential usage as point-of-care devices is substantially constrained. Current-edge detection methods have been recommended and constructed over the period to address these shortcomings. Biosensors are one of those pioneering detection tools that are capable of identifying a variety of biomolecules, which are extensively utilized for the effective detection of pathogens. This chapter provides a comprehensive overview of several biosensing systems with a greater emphasis on technological advancements in improving detection sensitivity and specificity. The mechanism of detection along with the advantages and disadvantages of each kind of biosensor is carefully discussed, with the variables impacting their perspective as potential point-of-care devices.
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Background: Non-invasive tests, such as Fibrosis-4 index and transient elastography (commonly FibroScan), are utilized in clinical pathways to risk stratify and diagnose non-alcoholic fatty liver disease (NAFLD). In 2018, a clinical decision support tool (CDST) was implemented to guide primary care providers (PCPs) on use of FibroScan for NAFLD. Aim: To analyze how this CDST impacted health care utilization and patient outcomes. Methods: We performed a retrospective review of adults who had FibroScan for NAFLD indication from January 2015 to December 2017 (pre-CDST) or January 2018 to December 2020 (post-CDST). Outcomes included FibroScan result, laboratory tests, imaging studies, specialty referral, patient morbidity and mortality. Results: We identified 958 patients who had FibroScan, 115 before and 843 after the CDST was implemented. The percentage of FibroScans ordered by PCPs increased from 33% to 67.1%. The percentage of patients diagnosed with early F1 fibrosis, on a scale from F0 to F4, increased from 7.8% to 14.2%. Those diagnosed with advanced F4 fibrosis decreased from 28.7% to 16.5%. There were fewer laboratory tests, imaging studies and biopsy after the CDST was implemented. Though there were more specialty referrals placed after the CDST was implemented, multivariate analysis revealed that healthcare utilization aligned with fibrosis score, whereby patients with more advanced disease had more referrals. Very few patients were hospitalized or died. Conclusion: This CDST empowered PCPs to diagnose and manage patients with NAFLD with appropriate allocation of care towards patients with more advanced disease.
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There is a paucity of data regarding the impact of liver fibrosis on patients with stage D heart failure (HF). We conducted a retrospective study (January 1, 2017 to December 12, 2020) in patients with stage D HF who underwent liver biopsy as part of their advanced HF therapy evaluation. Baseline characteristics and 1-year outcomes were compared between no- or mild-to-moderate-fibrosis (grade 0 to 2) and advanced-fibrosis (grade 3 to 4) groups. Of 519 patients with stage D HF, 136 who underwent liver biopsy (113 [83%] no or mild-to-moderate fibrosis and 23 [17%] advanced fibrosis) were included. A total of 71 patients (52%) received advanced HF therapies (23 heart transplantation, 48 left ventricular assist devices). One-year mortality was higher among patients with advanced fibrosis (52% vs 18%, p <0.001). Further subgroup analysis suggested a trend toward increased 1-year mortality among patients with advanced fibrosis who underwent advanced therapies (37% vs 13%, p = 0.09). There was a trend of lower likelihood of receiving advanced HF therapies in the advanced-fibrosis group, only 1 heart transplantation and 7 left ventricular assist devices, but it did not reach statistical significance (35% vs 56%, p = 0.06). After adjustment for confounders, degree of liver fibrosis was an independent predictor of mortality (odds ratio 6.2; 95% 1.27 to 30.29, p = 0.02). We conclude that advanced liver fibrosis is common among patients with stage D HF who undergo evaluation for advanced HF surgical therapies and significantly increases 1-year mortality. Further larger studies are needed to support our findings.
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The gold standard for assessing liver fibrosis is a liver biopsy. However, the procedure is invasive and is associated with pain and sometimes fatal consequences. The accuracy of liver biopsy results is further harmed by intra- and inter-observer variability. Small samples only. This muddles the two types of observer variability discussed above. Due to these limitations, non-invasive approaches for fibrosis testing have been developed. Various biochemical serum indicators or imaging techniques that provide a physical measure of hepatic stiffness are non-invasive approaches for assessing liver fibrosis.
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Chronic liver disease incidence is increasing among children worldwide due to a multitude of epidemiological changes. Most of these chronic insults to the pediatric liver progress to fibrosis and cirrhosis to different degrees. Liver and immune physiology differs significantly in children from adults. Because most of pediatric liver diseases have no definitive therapy, a better understanding of population and disease-specific fibrogenesis is mandatory. Furthermore, fibrosis development has prognostic significance and often guide treatment. Evaluation of liver fibrosis continues to rely on the gold-standard liver biopsy. However, many high-quality studies put forward the high diagnostic accuracy of numerous diagnostic modalities in this setting. Herein, we summarize and discuss the recent literature on fibrogenesis with an emphasis on pediatric physiology along with a detailed outline of disease-specific signatures, noninvasive diagnostic modalities, and the potential for antifibrotic therapies.
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Liver fibrosis is a disease that affects patients with hepatitis B virus or hepatitis C virus, harmful alcohol consumption levels, and nonalcoholic fatty liver disease. It is important to assess the cause, disease severity, and prognosis at the time of presentation to determine suitable treatment. The aim of this review article is to outline the recent advances in the diagnosis, management, and treatment of liver fibrosis. A PubMed review was performed encompassing the years 1982–2019 using the following search terms: ‘liver fibrosis’, ‘hepatitis C virus’, ‘hepatitis B virus’, ‘non-alcoholic fatty liver disease’, and ‘alcoholic liver disease’. Results showed that the cornerstone therapy for liver fibrosis is to remove the offending agent and treat the underlying disease. The gold standard method of diagnosis is liver biopsy; however, this procedure is invasive and thus multiple laboratory and radiologic tests are used to help determine the degree of fibrosis. There are few pharmacological agents known to treat fibrosis and they are disease specific. For example, the only proven therapy for fibrosis improvement in alcoholic liver disease is abstinence. The authors concluded that liver fibrosis carries a high morbidity and mortality risk with few therapeutic options depending on the cause and degree of fibrosis. Larger multicentre prospective studies are needed to examine effective agents to prevent, stop, or reduce fibrosis.
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Background The prevalence of non-alcoholic fatty liver disease (NAFLD) in China as assessed using vibration-controlled transient elastography (VCTE) and its consistency with ultrasound are still unknown. We aimed to conduct a head-to-head comparison of consecutive measurements of NAFLD with ultrasound or VCTE to evaluate the discrepancy in the prevalence and distribution of NAFLD screened by two non-invasive techniques. Methods We collected VCTE and ultrasound examination data from 4,388 participants who underwent health check-ups at the Health Promotion Center of Jiangsu Province Hospital between January 2017 and December 2019. The major outcome was the presence of hepatic steatosis, which was defined as a median controlled attenuation parameter (CAP) ≥ 248 dB/m by VCTE or the definition of steatosis by ultrasound. Results Among the 4,388 participants, 2,214 were diagnosed with NAFLD by VCTE (CAP ≥ 248 dB/m, 50.46%). Participants with severe steatosis (CAP ≥ 280 dB/m) were commonly male (77.94% vs. 50.38%, P < 0.001), were obese (45.09% vs. 1.79%, P < 0.001), had a worse metabolic profile, had elevated liver enzyme levels, and had advanced fibrosis. The prevalence of ultrasound-diagnosed NAFLD was 56.42%. After consistency analysis, VCTE and ultrasound showed moderate agreement regarding the diagnosis of NAFLD (κ = 0.475). We then compared the characteristics and clinical features of the four groups classified by the diagnosis results of the two techniques. NAFLD participants diagnosed by VCTE only were older, more obese, and had worse metabolic and biochemical profiles than NAFLD participants diagnosed by ultrasound only; in particular, the former had a higher proportion of abnormal alanine aminotransferase and aspartate aminotransferase levels and a higher proportion of advanced fibrosis than the latter. Conclusions More than half of Chinese adults were affected by NAFLD according to VCTE. Screening based on VCTE is more likely to identify NAFLD patients with severe clinical features than ultrasound. Therefore, VCTE is a more practical non-invasive tool for the screening and follow-up of NAFLD.
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Background: Transient elastography (TE) is an FDA approved, non-invasive tool to estimate liver stiffness measurement (LSM) in patients with non-alcoholic fatty liver disease (NAFLD). Our aim was to analyze if body mass index (BMI) would predict the severity of liver stiffness using TE scores. Methods: We performed a cross-sectional study of patients with NAFLD who presented to the hepatology clinic between January 2019 through January 2021. Fibrosis severity was divided into the following categories: F0 to F1 (2-7 kPa), F2 (>7 to 10 kPa), F3 (>10 to 14 kPa) and F4 (>14 kPa). We used ordered logistic regression models to determine the odds ratio (OR) and 95% confidence interval (CI) of having a higher LSM severity compared to lower associated with BMI. Models were adjusted for patient demographics and comorbidities. Results: Among 284 patients, 56.7% were females, and the median (interquartile range, IQR) age was 62 [51-68] years and BMI 31.9 (28.1, 36.2) kg/m2; 47% of patients were in the F0 to F1 stage, 24% F2, 16% F3, and 13% F4. The correlation between BMI and TE score was 0.31 (P<0.001). With 1 kg/m2 increase in BMI there was 1.10 times higher odds of having a higher LSM severity (adjusted OR, 1.10; 95% CI: 1.05-1.14). Compared to patients with BMI <25 kg/m2, the adjusted OR (95% CI) of having a higher fibrosis stage was 1.82 (0.61-5.44), 5.93 (2.05-17.13), and 8.56 (2.51-29.17) for patients with BMI of 25 to <30, 30 to <40, and ≥40 respectively. Conclusions: BMI correlates with the severity of LSM using TE scores in NAFLD patients even after adjusting for potential confounding variables. This suggests TE as an appreciable study for liver stiffness even in obese individuals.
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Background/aim We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
Article
Transient elastography is an imaging technique utilizing shear wave technology to measure liver stiffness. Recent studies have shown success in utilizing this technique in children. Transient elastography is useful in estimating degree of fibrosis in various pediatric liver diseases, including biliary atresia, alpha-1-antitrypsin deficiency, Alagille syndrome, cystic fibrosis related liver disease, and NASH among others. However, confounding factors may affect elastography measurements such as obesity, severe inflammation, non-fasting state and hepatic congestion and should be considered when interpreting these measurements. Future studies will correlate liver stiffness on transient elastography and severity of disease.
Article
Objective To assess changes in non-invasive liver fibrosis measurements after chronic hepatitis C (HCV) eradication by direct-acting antivirals (DAA) in Egyptian adolescents. Study design Liver stiffness measurement (LSM), by vibration-controlled transient elastography and non-invasive fibrosis scores (FIB-4, APRI), was obtained before and 12 months after eradication with ledipasvir-sofosbuvir. The primary outcome was > 30% decrease in LSM with resulting fibrosis stage regression for initial fibrosis ≥ F2 and non-progression of F0-1, using Ishak score (F0-F6). The secondary outcome was change in non-invasive fibrosis scores post-treatment. Results Analyzing 85 patients, the median baseline LSM was 5.8 (IQR 4.2-6.5) and at follow-up 5.1 (IQR 4-6) kPa, P=0.045; 62 (73%) met the primary outcome; 16 (19%) regression and 46 (54%) non-progression of LSM. Of 18 with initial fibrosis ≥ F2; 13 regressed to F0-1 and 2 from F6 to F5, 1 unchanged F3, 1 increased to F3 and 1 to F4. Among 67 with baseline fibrosis F0-F1, 62 were unchanged and 5 increased; 4 to F2 and 1 to F3. Although 23 (27%) had > 30% LSM increase, only 7 (8%), with associated comorbidities (4 β-thalassemia, 3 hepatic steatosis), had increased fibrosis stage. The median baseline FIB-4 and APRI scores were 0.34 (IQR 0.22-0.47) and 0.35 (0.24-0.57), while at follow-up 0.3 (IQR 0.22-0.34) and 0.2 (0.18-2.8) (P <.001, <.001), respectively. Conclusions HCV eradication by DAA in Egyptian adolescents was associated with non-progression or regression of liver fibrosis, by non-invasive fibrosis measurements, twelve-months post-treatment in the majority of cases.
Article
Background Intestinal fibrosis and subsequent strictures represent an important burden in inflammatory bowel disease (IBD). The detection and evaluation of the degree of fibrosis in stricturing Crohn’s disease (CD) is important to address the best therapeutic strategy (medical anti-inflammatory therapy, endoscopic dilation, surgery). Ultrasound elastography (USE) is a non-invasive technique that has been proposed in the field of IBD for evaluating intestinal stiffness as a biomarker of intestinal fibrosis. Objective The aim of this review is to discuss the ability and current role of ultrasound elastography in the assessment of intestinal fibrosis. Results and Conclusion Data on USE in IBD are provided by pilot and proof-of-concept studies with small sample size. The first type of USE investigated was strain elastography, while shear wave elastography has been introduced lately. Despite the heterogeneity of the methods of the studies, USE has been proven to be able to assess intestinal fibrosis in patients with stricturing CD. However, before introducing this technique in current practice, further studies with larger sample size and homogeneous parameters, testing reproducibility, and identification of validated cut-off values are needed.
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AIM: To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan ® (FS). METHODS: We first performed sequential LS analysis before and after normalization of serum transaminases in a learning cohort of 50 patients with ALD admitted for alcohol detoxification. LS decreased in almost all patients within a mean observation interval of 5.3 d. Six patients (12%) would have been misdiagnosed with F3 and F4 fibrosis but LS decreased below critical cutoff values of 8 and 12.5 kPa after normalization of trans-aminases. RESULTS: Of the serum transaminases, the decrease in LS correlated best with the decrease in glutamic oxaloacetic transaminase (GOT). No significant changes in LS were observed below GOT levels of 100 U/L. After establishing the association between LS and GOT levels, we applied the rule of GOT < 100 U/L for reliable LS assessment in a second validation cohort of 101 patients with histologically confirmed ALD. By excluding those patients with GOT > 100 U/L at the time of LS assessment from this cohort, the area under the receiver operating characteristic (AUROC) for cirrhosis detection by FS improved from 0.921 to 0.945 while specificity increased from 80% to 90% at a sensitivity of 96%. A similar AUROC could be obtained for lower F3 fibrosis stage if LS measurements were restricted to patients with GOT < 50 U/L. Histological grading of inflammation did not further improve the diagnostic accuracy of LS. CONCLUSION: Coexisting steatohepatitis markedly increases LS in patients with ALD independent of fibrosis stage. Postponing cirrhosis assessment by FS during alcohol withdrawal until GOT decreases to < 100 U/mL significantly improves the diagnostic accuracy.
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Objectives: Screening for esophageal varices (EV) is recommended in patients with cirrhosis. Noninvasive tests had shown varying sensitivity (Se) and specificity (Sp) for predicting EV. Splenomegaly is a common finding in liver cirrhosis because of portal and splenic congestion. These changes can be quantified by transient elastography; hence, the aim of this study was to investigate the utility of spleen stiffness (SS) in evaluating EV in comparison with other noninvasive tests. Methods: We measured SS and liver stiffness (LS) by using FibroScan in 200 consecutive cirrhotic patients who met the inclusion criteria. Patients were also assessed by hepatic venous pressure gradient (HVPG), upper gastrointestinal endoscopy, LS-spleen diameter to platelet ratio score (LSPS), and platelet count to spleen diameter ratio (PSR). Results: Of 200 patients enrolled, 174 patients had valid LS and SS measurement, and 124 (71%) patients had EV (small, n=46 and large n=78). There was a significant difference in median LS (51.4 vs. 23.9 kPa, P=0.001), SS (54 vs. 32 kPa, P=0.001), LSPS (6.1 vs. 2.5, P=0.001), and PSR (812 vs. 1,165, P=0.001) between patients with EV and those without EV. LS ≥27.3 kPa had an Se of 91%, Sp of 72%, positive predictive value (PPV) of 89%, negative predictive value (NPV) of 76%, and a diagnostic accuracy of 86% in predicting EV. LSPS ≥3.09 had Se and Sp of 89% and 76%, respectively, and a PSR cutoff value of 909 or less had Se of 64%, Sp of 76%, and diagnostic accuracy of 68% in predicting EV. SS ≥40.8 kPa had Se (94%), Sp (76%), PPV (91%), NPV (84%), and diagnostic accuracy of 86% for predicting EV. SS was significantly higher in patients who had large varices (56 vs. 49 kPa, P=0.001) and variceal bleed (58 vs. 50.2 kPa, P=0.001). Combining LS+SS (27.3+40.8 kPa) had Se of 90%, Sp 90%, PPV 96%, NPV 79%, and a diagnostic accuracy of 90%. HVPG (n=52) showed significant correlation with SS (r=0.433, P=0.001), LSPS (r=0.335, P=0.01), and PSR (r=-0.270, P=0.05), but not with LS (r=0.178, P=0.20). Conclusions: Measurement of SS can be used for noninvasive assessment of EV and can differentiate large vs. small varices and nonbleeder vs. bleeder.
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Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population. In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured. Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes. Liver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.
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To determine the evolution of transient elastography (TE) in patients with alcoholic liver disease according to alcohol cessation or continuation. We retrospectively selected in our local database all patients who had two TE between June 2005 and November 2010 with chronic alcohol excessive consumption and excluded those with associated cause of liver disease. TE was performed at least one week apart by senior operator. TE examinations with less than ten successful measures or with an interquartile range above 30% were excluded. We retrospectively reviewed file of all patients to include only patient followed up by trained addictologist and for which definite information on alcohol consumption was available. Concomitant biological parameters [aspartate amino transferase (AST), alanine amino transferase and gamma-glutamyl transpeptidase (GGT)] within 4 wk of initial and final TE were recorded. Putative fibrosis score according to initial and final TE were determined with available cut-off for alcoholic liver disease and hepatitis C. Initial and final putative fibrosis score were compared according to alcohol consumption during follow-up. During the study period 572 patients had TE examination for alcoholic liver disease and 79 of them had at least two examinations. Thirty-seven patients met our criteria with a median follow-up of 32.5 wk. At the end of the study, 13 (35%) were abstinent, and 24 (65%) relapsers. Eight patients had liver biopsy during follow-up. TE decreased significantly during follow-up in 85% of abstinent patients [median (range): -4.9 (-6.1,-1.9)], leading to a modification of the putative fibrosis stage in 28%-71% of patient according to different cut-off value. In relapsers TE increased in 45% and decreased in 54% of patient. There was no statistical difference between initial and final TE in relapsers. In the overall population, using 22.6 kPa as cut-off for cirrhosis, 4 patients had cirrhosis at initial TE and 3 patients had cirrhosis at final TE. Using 19.5 kPa as cut-off for cirrhosis, 7 patients had cirrhosis at initial TE and 5 patients had cirrhosis at final TE. Using 12.5 kPa as cut-off for cirrhosis, 16 patients had cirrhosis at initial TE and 15 patients had cirrhosis at final TE. Evolution of biological data was in accordance with the relapse or abstinent status: abstinence ratio (duration of abstinence/duration follow-up) was correlated with AST ratio (r = -0.465, P = 0.007) and GGT ratio (r = -0.662, P < 0.0001). GGT was correlated with initial (r = 0.488, P = 0.002) and final TE (r = 0.49, P < 0.005). Final TE was correlated with AST (r = 0.362, P < 0.05). Correlation between TE ratio and AST ratio (r = 0.44, P = 0.01) revealed that TE varied proportionally to AST for all patients irrespective of their alcohol status. The same relationship was observed between TE ratio and GGT ratio (r = 0.65, P < 0.0001). Evolution of TE was significantly correlated with the ratio of time of abstinence to observation time (r = -0.387, P = 0.016) and the evolution of liver enzymes. TE significantly decreased with abstinence. Results of TE in alcoholic liver disease cannot be interpreted without taking into account alcohol consumption and liver enzymes.
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Transient elastography (TE), a non-invasive tool that measures liver stiffness, has been evaluated in meta-analyses for effectiveness in assessing liver fibrosis in European populations with chronic hepatitis C (CHC). However, these data cannot be extrapolated to populations in Asian countries, where chronic hepatitis B (CHB) is more prevalent. In this study, we performed a meta-analysis to assess the overall performance of TE for assessing liver fibrosis in patients with CHB. Studies from the literature and international conference abstracts which enrolled only patients with CHB or performed a subgroup analysis of such patients were enrolled. Combined effects were calculated using area under the receiver operating characteristic curves (AUROC) and diagnostic accuracy values of each study. A total of 18 studies comprising 2,772 patients were analyzed. The mean AUROCs for the diagnosis of significant fibrosis (F2), severe fibrosis (F3), and cirrhosis (F4) were 0.859 (95% confidence interval [CI], 0.857-0.860), 0.887 (95% CI, 0.886-0.887), and 0.929 (95% CI, 0.928-0.929), respectively. The estimated cutoff for F2 was 7.9 (range, 6.1-11.8) kPa, with a sensitivity of 74.3% and specificity of 78.3%. For F3, the cutoff value was determined to be 8.8 (range, 8.1-9.7) kPa, with a sensitivity of 74.0% and specificity of 63.8%. The cutoff value for F4 was 11.7 (range, 7.3-17.5) kPa, with a sensitivity of 84.6% and specificity of 81.5%. TE can be performed with good diagnostic accuracy for quantifying liver fibrosis in patients with CHB.
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Objectives: Liver stiffness measurement (LSM) by transient elastography is a noninvasive test of liver fibrosis, but cannot be performed in a significant proportion of obese patients. The aim of this study was to evaluate the performance of the new XL probe in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Liver biopsy and paired LSM by both the original M probe and XL probe were performed on 193 consecutive NAFLD patients in France and Hong Kong. Results: Compared with M probe, XL probe was more likely to achieve 10 valid measurements (95% vs. 81%; P<0.001) and a success rate of over 60% (90% vs. 74%; P<0.001). The areas under receiver operating characteristics curves of XL probe for F2, F3, and F4 disease were 0.80, 0.85, and 0.91, respectively. XL probe tended to generate lower LSM than M probe in the same patient. At a cutoff of 7.2 kPa, the sensitivity, specificity, positive, and negative predictive values for F3 or greater disease were 78%, 78%, 60%, and 89%, respectively. Discordance of at least two stages between XL probe and histology was observed in 16 (9%) patients. Body mass index (BMI) over 35 kg/m(2) was independently associated with discordance (adjusted odds ratio 9.09; 95% confidence interval 1.10-75.43). Reliable measurements by XL probe were obtained in 75% of the overall population and 65% of patients with BMI over 30 kg/m(2). Conclusions: LSM by XL probe can be performed successfully in most NAFLD patients, but obesity is associated with less accurate and reliable measurements.
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Liver stiffness measurement (LSM) using transient elastography (FibroScan®) can assess liver fibrosis noninvasively. This study investigated whether LSM can predict the development of liver-related events (LREs) in chronic hepatitis B (CHB) patients showing histologically advanced liver fibrosis. Between March 2006 and April 2010, 128 CHB patients with who underwent LSM and liver biopsy (LB) before starting nucleot(s)ide analogues and showed histologically advanced fibrosis (≥F3) with a high viral loads [HBV DNA ≥2,000 IU/mL] were enrolled. All patients were followed regularly to detect LRE development, including hepatic decompensation (variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome) and hepatocellular carcinoma (HCC). The mean age of the patient (72 men, 56 women) was 52.2 years. During the median follow-up period [median 27.8 (12.6-61.6) months], LREs developed in 19 (14.8%) patients (five with hepatic decompensation, 13 with HCC, one with both). Together with age, multivariate analysis identified LSM as an independent predictor of LRE development [P<0.044; hazard ratio (HR), 1.038; 95% confidence interval (CI), 1.002-1.081]. When the study population was stratified into two groups using the optimal cutoff value (19 kPa), which maximized the sum of sensitivity (61.1%) and specificity (86.2%) from a time-dependent receiver operating characteristic curve, patients with LSM>19 kPa were at significantly greater risk than those with LSM≤19 kPa for LRE development (HR, 7.176; 95% CI, 2.257-22.812; P = 0.001). LSM can be a useful predictor of LRE development in CHB patients showing histologically advanced liver fibrosis.
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The development of portal hypertension is a common consequence of chronic liver diseases leading to the formation of esophageal and gastric varices responsible for variceal bleeding, associated with a high mortality rate, as well as other severe complications such as portosystemic encephalopathy and sepsis. Measurement of hepatic venous pressure gradient (HVPG) and upper GI endoscopy are considered the gold standards for portal hypertension assessment in patients with cirrhosis. However, both types of investigation are invasive and HVPG measurement is routinely available and/or performed with adequate standards only in expert centres. There is thus a need for non invasive methods able to predict, with acceptable diagnostic accuracy, the progression of portal hypertension toward the levels of clinically significant (i.e. HVPG ≥ 10 mmHg) and severe (HVPG ≥ 12 mmHg) as well as the presence and the size of oesophageal varices. Transient elastography (TE) is a novel non invasive technology that allows measuring liver stiffness and that has gained popularity over the past few years. Although TE has been initially proposed to assess liver fibrosis, a good correlation has been reported between liver stiffness values and HVPG as well as the presence of oesophageal varices, suggesting that it could be an interesting tool for the non invasive evaluation of portal hypertension. This review is aimed at discussing the advantages and limits of TE and the perspectives for its rationale use in clinical practice for the management of patients with portal hypertension.
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To determine if liver stiffness (LS) measurements by means of transient elastography (TE) correlate with the presence of significant esophageal varices (EV) and if they can predict the occurrence of variceal bleeding. We studied 1000 cases of liver cirrhosis divided into 2 groups: patients without EV or with grade 1 varices (647 cases) and patients with significant varices (grade 2 and 3 EV) (353 cases). We divided the group of 540 cases with EV into another 2 subgroups: without variceal hemorrhage (375 patients) and patients with a history of variceal bleeding (165 cases). We compared the LS values between the groups using the unpaired t-test and we established cut-off LS values for the presence of significant EV and for the risk of bleeding by using the ROC curve. The mean LS values in the 647 patients without or with grade 1 EV was statistically significantly lower than in the 353 patients with significant EV (26.29 ± 0.60 kPa vs 45.21 ± 1.07 kPa, P < 0.0001). Using the ROC curve we established a cut-off value of 31 kPa for the presence of EV, with 83% sensitivity (95% CI: 79.73%-85.93%) and 62% specificity (95% CI: 57.15%-66.81%), with 76.2% positive predictive value (PPV) (95% CI: 72.72%-79.43%) and 71.3% negative predictive value (NPV) (95% CI: 66.37%-76.05%) (AUROC 0.7807, P < 0.0001). The mean LS values in the group with a history of variceal bleeding (165 patients) was statistically significantly higher than in the group with no bleeding history (375 patients): 51.92 ± 1.56 kPa vs 35.20 ± 0.91 kPa, P < 0.0001). For a cut-off value of 50.7 kPa, LS had 53.33% sensitivity (95% CI: 45.42%-61.13%) and 82.67% specificity (95% CI: 78.45%-86.36%), with 82.71% PPV (95% CI: 78.5%-86.4%) and 53.66% NPV (95% CI: 45.72%-61.47%) (AUROC 0.7300, P < 0.0001) for the prediction of esophageal bleeding. LS measurement by means of TE is a reliable noninvasive method for the detection of EV and for the prediction of variceal bleeding.
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The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR ≥ F2) in patients with chronic viral hepatitis. A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan® examinations). The overall accuracy of FibroScan® was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77-0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72-0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0-60% of patients (cirrhosis) and 9-30% of patients (significant fibrosis). The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.
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Liver biopsy is used as the 'gold standard' for the assessment of the stage and degree of activity in chronic hepatitis C and is of major importance in evaluating the effects of treatment. Because numerous therapeutic trials are undertaken with histological control, the reproducibility of liver biopsy interpretation appears essential. Therefore the aim of this study was to estimate intraobserver and interobserver variations in the assessment of features, classification, and numerical scoring of chronic viral hepatitis C among 10 pathologists specializing in liver diseases. These pathologists independently reviewed 30 liver biopsy specimens of viral hepatitis C and completed a histological form for each of the specimens. Five pairs of pathologists then were randomly designated. They independently reviewed the biopsy specimens and filled out a new coding form. The interobserver variation was calculated for each item among the 10 individuals and then among the five pairs with the intraclass correlation coefficient or κ statistics. Five features showed an almost perfect or a substantial degree of concordance among the 10 observers (i.e., cirrhosis, fibrosis, fibrosis grading of Knodell index, steatosis, portal lymphoid aggregates). The 17 other indicators showed a weaker concordance with, for instance, a moderate degree of concordance for piecemeal necrosis, disease activity, Knodell index, a fair degree of concordance for lobular necrosis, and only a slight degree of concordance for six items. Five items had a higher concordance when viewed by a pair of pathologists than when studied by only one pathologist (i.e., steatosis, periportal necrosis grading of Knodell index, lobular necrosis grading of Knodell index, centrilobular fibrosis, and ductular proliferation). Two showed a significant decrease, and the others were unchanged. This study reveals that certain features of major importance in assessing disease activity show significant observer variation. The acceptable degree of concordance of the Knodell index was related mainly to the substantial degree of concordance of the fibrosis score, whereas other numerical items displayed substantial observer variations. Simultaneous observation by two pathologists increased the reproducibility of numerical scoring and of certain viral hepatitis C lesions. A classification of chronic hepatitis C based on dissociated semiquantitative assessment of necroinflammatory lesions and fibrosis offered more reproducibility than the use of a global numerical index.
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Fibrosis is a common endpoint of clinical trials in chronic hepatitis C, and liver biopsy remains the gold standard for fibrosis evaluation. However, variability in the distribution of fibrosis within the liver is a potential limitation. Our aim was to assess the heterogeneity of liver fibrosis and its influence on the accuracy of assessment of fibrosis with liver biopsy. Surgical samples of livers from patients with chronic hepatitis C were studied. Measurement of fibrosis was performed on the whole section by using both image analysis and METAVIR score (reference value). From the digitized image of the whole section, virtual biopsy specimens of increasing length were produced. Fibrosis was assessed independently on each individual virtual biopsy specimen. Results were compared with the reference value according to the length of the biopsy specimen. By using image analysis, the coefficient of variation of fibrosis measurement with 15-mm long biopsy specimens was 55%; and for biopsy specimens of 25-mm length it was 45%. By using the METAVIR scoring system, 65% of biopsies 15 mm in length were categorized correctly according to the reference value. This increased to 75% for a 25-mm liver biopsy specimen without any substantial benefit for longer biopsy specimens. Sampling variability of fibrosis is a significant limitation in the assessment of fibrosis with liver biopsy. In conclusion, this study suggests that a length of at least 25 mm is necessary to evaluate fibrosis accurately with a semiquantitative score. Sampling variability becomes a major limitation when using more accurate methods such as automated image analysis. (Hepatology 2003;38:1449-1457.)
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A common clinical concern in patients with NAFLD is whether they have NASH or simple steatosis and, more importantly, what the stage of fibrosis is and whether the level of fibrosis has increased over time. Such concern is based on the fact that patients with NAFLD with advanced fibrosis are at greatest risk of developing complications of end-stage liver disease. Although it lacks sensitivity, ultrasonography is an accepted tool for steatosis screening. The controlled attenuation parameter or CAP seems a promising screening technique, but requires further validation. Cytokeratin-18 has been extensively validated, but it is an imperfect serum marker of NASH. Ultrasonography-based transient elastography can exclude advanced fibrosis and cirrhosis, but its main limitation is its reduced applicability in patients with NAFLD, which is not completely solved by use of the XL probe. Of the noninvasive serum markers, the NAFLD fibrosis score is the most validated and has appropriate accuracy in distinguishing patients with and without advanced fibrosis. Although noninvasive methods require further validation, they could be useful for selecting those patients with NAFLD who require a liver biopsy. This Review discusses the advantages and limitations of noninvasive methods for the management of adults with NAFLD, including diagnosis and quantification of steatosis, diagnosis of NASH and staging of hepatic fibrosis.
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& Aims: Liver stiffness measurements (LSMs), made by elastography, could independently predict outcomes of patients with chronic liver diseases (CLD). However, there is much variation in reporting and consistency of findings. We performed a systematic review and meta-analysis to evaluate the association between LSM and outcomes of patients with CLD. We performed a systematic review of the literature, through February 2013, for studies that followed patients with CLD prospectively for at least 6 months and reported the association between baseline LSM and development of decompensated cirrhosis or hepatocellular carcinoma (HCC), as well as mortality. Summary adjusted relative risk (RR) estimates per unit of LSM and 95% confidence intervals (CI) were estimated using the random effects model. Our final analysis included 17 studies, reporting on 7058 patients with CLD. Baseline LSMs were significantly associated with risk of hepatic decompensation (6 studies; RR, 1.07; 95% CI, 1.03-1.11), HCC (9 studies; RR, 1.11; 95% CI, 1.05-1.18), death (5 studies; RR, 1.22; 95% CI, 1.05-1.43) or a composite of these outcomes (7 studies; RR, 1.32; 95% CI, 1.16-1.51). We observed considerable heterogeneity among studies-primarily in the magnitude of effect, rather than the direction of effect. This heterogeneity could not be a result of the meta-regression analysis based on study location, etiology and stage of CLD, technique of LSM, or whether studies adjusted for covariates and method of imputing relationship. Based on meta-analysis of cohort studies, degree of liver stiffness is associated with risk of decompensated cirrhosis, HCC, and death in patients with CLD. LSMs might therefore be used in risk stratification.
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Interquartile range/median value (IQR/M) of liver stiffness measurement (LSM) is a factor in chronic hepatitis C (CHC) leading to over estimation of fibrosis by Fibroscan. To investigate factors that affect the accuracy of LSM in chronic hepatitis B (CHB). One hundred and ninety-nine patients were enrolled. Only procedures yielding > or =10 valid measurements were considered reliable. Liver fibrosis was evaluated using the Batts and Ludwig system. Liver biopsy (LB) specimens <15 mm were considered ineligible. The mean age (142 men and 57 women) was 40.1 years. A significant discordance (discordance of at least two stages between LB and LSM) was identified in 38 (19.1%) and 47 (23.6%) patients respectively, according to Marcellin et al. and Chan et al.'s cutoff values. In multivariate analyses, BMI and fibrosis stage (F0-2 vs. F3-4) were identified as independent predictors for significant discordance (P = 0.040; hazard ratio [HR], 1.126; 95% confidence interval [CI], 1.005-1.261 and P = 0.036; HR, 0.450; 95% CI, 0.213-0.949 respectively) with Marcellin et al.'s cutoffs, whereas fibrosis stage was the only independent predictor (P = 0.004; HR, 0.300; 95% CI, 0.131-0.685) with Chan's cutoffs. Success rate and IQR/M were not predictive factors of the accuracy for diagnosing liver fibrosis by Fibroscan in CHB. Fibrosis stage (F0-2) was the only factor to predict significant discordance between LB and LSM.
Article
Unlabelled: Transient elastography (TE) is increasingly employed in clinical practice for the noninvasive detection of tissue fibrosis in patients with chronic liver disease (CLD), and particularly chronic hepatitis C virus (HCV)-related hepatitis. The present study was designed to provide a definitive characterization of the "confounding" increase in liver stiffness (LS) following a standardized meal in a consecutive population of 125 patients with chronic HCV infection at different stages of fibrotic evolution. LS values were obtained after overnight fasting and 15, 30, 45, 60, and 120 minutes following the onset of a standardized liquid meal (400 mL, 600 Kcal, 16.7% protein, 53.8% carbohydrates, 29.5% fat). An evident increase in LS values was observed 15 to 45 minutes after the onset of the meal with return to baseline premeal levels within 120 minutes in all patients. The peak postmeal delta increase in LS was progressively more marked with increasing stages of fibrosis (P < 0.001), becoming maximal in patients with cirrhosis. However, the probability of identifying the Metavir stage of fibrosis, the Child-Pugh class, or the presence/absence of esophageal varices with the postmeal delta increase in LS was inferior to that obtained with baseline LS values. Conclusion: The results of the present study provide definitive evidence of the confounding effect of a meal on the accuracy of LS measurements for the prediction of fibrosis stage in patients with chronic HCV hepatitis and suggest that a fasting period of 120 minutes should be observed before the performance of TE.
Article
Background: Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of clinical conditions, actually representing an emerging disease of great clinical interest. Currently, its diagnosis requires liver biopsy, an invasive procedure not free from potential complications. However, several non-invasive diagnostic strategies have been proposed as potential diagnostic alternatives, each with different sensitivities and accuracies. Aim: To review non-invasive diagnostic parameters and tools for NAFLD diagnosis and to formulate a diagnostic and prognostic algorithm for a better classification of patients. Methods: A literature search was carried out on MEDLINE, EMBASE, Web of Science and Scopus for articles and abstracts in English. The search terms used included 'NAFLD', 'non invasive method and NAFLD', 'transient elastography' and 'liver fibrosis'. The articles cited were selected based on their relevancy to the objective of the review. Results: Ultrasonography still represents the first-line diagnostic tool for simple liver steatosis; its sensitivity could be enhanced by the complex biochemical score SteatoTest. Serum cytokeratin-18 is a promising and accurate non-invasive parameter (AUROCs: 0.83; 0.91) for the diagnosis of non-alcoholic steatohepatitis (NASH). The staging of liver fibrosis still represents the most important prognostic problem: the most accurate estimating methods are FibroMeter, FIB-4, NAFLD fibrosis score (AUROCs: 0.94; 0.86; 0.82) and transient elastography (AUROC: 0.84-1.00). Conclusions: Different non-invasive parameters are available for the accurate diagnosis and prognostic stratification of non-alcoholic fatty liver disease which, if employed in a sequential algorithm, may lead to a reduced use of invasive methods, i.e. liver biopsy.
Article
Background & aims: Liver biopsy is the standard for assessing hepatic fibrosis. Ultrasound transient elastography (TE) and the aspartate aminotransferase to platelet ratio index (APRI) are validated, noninvasive tests for identifying patients with cirrhosis. We evaluated discordance among TE, APRI, and histology diagnoses of cirrhosis. Methods: We analyzed findings from 109 patients with chronic hepatitis C who underwent TE within 6 months of liver biopsy at the US National Institutes of Health from 2006 to 2011. Fibrosis was scored using the Ishak scale (0-6). APRI scores were calculated using data collected on the day of the biopsy. Area under receiver operator characteristic curves for TE and APRI were calculated to distinguish patients with cirrhosis (Ishak scores, 5-6) from those without cirrhosis (Ishak scores, 0-4). The best cut-off value and corresponding positive predictive value (PPV) and negative predictive value (NPV) were selected. Results: Based on biopsy analysis, 18% of the patients had no fibrosis, 52% had mild fibrosis, 17% had bridging fibrosis, and 13% had cirrhosis. A TE cut-off value of 13.1 kPa identified patients with cirrhosis with the highest level of accuracy (100% sensitivity, 89% specificity, 58% PPV, 100% NPV), as did an APRI cut-off value of 1.0 (79% sensitivity, 78% specificity, 34% PPV, 96% NPV). Results from TE and APRI were discordant for 28% of cases. TE identified all cases of cirrhosis and an additional 10 patients who were not found to have cirrhosis based on histology analysis; 7 of these patients had clinical or radiologic evidence of cirrhosis, indicating that the biopsy sample was not staged correctly. Conclusions: TE increases the accuracies of biopsy and APRI analyses in identifying patients with cirrhosis. TE also might be used to screen patients for cirrhosis and identify those who should be followed up for development of hepatocellular carcinoma and varices.
Article
Transient elastography (TE), as a non-invasive method, has been studied for evaluation of portal hypertension in patients with chronic liver diseases (CLD) with variable results. We studied the performance of TE for detection of significant portal hypertension, oesophageal varices and large oesophageal varices using meta-analysis. PubMed, the Cochrane Library, EMBASE and ISI web of Knowledge were searched. The studies published in English relating to the diagnostic value of TE for significant portal hypertension, oesophageal varices and large oesophageal varices in patients with CLD were collected. A total of 18 studies, which included 3644 patients were analysed. Summary sensitivity and specificity were 0.90 (95% confidence interval (CI), 0.81–0.95) and 0.79 (95% CI, 0.58–0.91) for significant portal hypertension, and 0.87 (95% CI, 0.80–0.92) and 0.53 (95% CI, 0.36–0.69) for oesophageal varices and 0.86 (95% CI, 0.71–0.94) and 0.59 (95% CI, 0.45–0.72) for large oesophageal varices respectively. The HSROCs were 0.93 for significant portal hypertension, 0.84 for oesophageal varices and 0.78 for large oesophageal varices respectively. TE was very informative with 81% probability of correctly detection significant portal hypertension following a ‘positive’ measurement (over the threshold value) and lowering the probability of disease to as low as 11% when ‘negative’ measurement (below the threshold value) when pre-test probability was 50% whereas, for oesophageal varices or large oesophageal varices, the probability of a correct diagnosis following a ‘positive’ measurement did not exceeded 70%. TE could be used as a good screening tool for significant portal hypertension, but only moderate diagnostic utility for the prediction of oesophageal varices or large oesophageal varices.
Article
Several studies investigated the effect of pioglitazone and rosiglitazone on aminotransferases and liver histology in adults with NASH. In an early uncontrolled open-label study117 in 22 subjects with biopsy-proven NASH, rosiglitazone improved aminotransferases and hepatic steatosis, ballooning and inflammation scores, but not fibrosis. But in a subsequent RCT, Ratziu et al.118 observed that rosiglitazone improved aminotransferases and hepatic steatosis, but not necroinflammation or fibrosis and its two-year open-label extension phase also showed similar results.119 Belfort et al.120 conducted a RCT of pioglitazone (45 mg/day) in patients with NASH who had impaired glucose tolerance or T2DM. Although there was a significant weight gain (2.5 ± 0.5 kg) with pioglitazone, it significantly improved aminotransferases, steatosis, ballooning, and inflammation. The NAS improved with pioglitazone in 73% compared to 24% of placebo-treated patients (P
Article
Liver biopsy is used as the “gold standard” for the assessment of the stage and degree of activity in chronic hepatitis C and is of major importance in evaluating the effects of treatment. Because numerous therapeutic trials are undertaken with histological control, the reproducibility of liver biopsy interpretation appears essential. Therefore the aim of this study was to estimate intraobserver and interobserver variations in the assessment of features, classification, and numerical scoring of chronic viral hepatitis C among 10 pathologists specializing in liver diseases. These pathologists independently reviewed 30 liver biopsy specimens of viral hepatitis C and completed a histological form for each of the specimens. Five pairs of pathologists then were randomly designated. They independently reviewed the biopsy specimens and filled out a new coding form. The interobserver variation was calculated for each item among the 10 individuals and then among the five pairs with the intraclass correlation coefficient or ϰ statistics. Five features showed an almost perfect or a substantial degree of concordance among the 10 observers (i.e., cirrhosis, fibrosis, fibrosis grading of Knodell index, steatosis, portal lymphoid aggregates). The 17 other indicators showed a weaker concordance with, for instance, a moderate degree of concordance for piecemeal necrosis, disease activity, Knodell index, a fair degree of concordance for lobular necrosis, and only a slight degree of concordance for six items. Five items had a higher concordance when viewed by a pair of pathologists than when studied by only one pathologist (i.e., steatosis, periportal necrosis grading of Knodell index, lobular necrosis grading of Knodell index, centrilobular fibrosis, and ductular proliferation). Two showed a significant decrease, and the others were unchanged. This study reveals that certain features of major importance in assessing disease activity show significant observer variation. The acceptable degree of concordance of the Knodell index was related mainly to the substantial degree of concordance of the fibrosis score, whereas other numerical items displayed substantial observer variations. Simultaneous observation by two pathologists increased the reproducibility of numerical scoring and of certain viral hepatitis C lesions. A classification of chronic hepatitis C based on dissociated semiquantitative assessment of necroinflammatory lesions and fibrosis offered more reproducibility than the use of a global numerical index. (Hepatology 1994;20:15–20.)
Article
The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection.
Article
Nonalcoholic fatty liver disease (NAFLD) results in histologically complex specific and nonspecific injury patterns. In clinical research of NAFLD, the liver biopsy evaluation provides a wealth of information on the architectural arrangement and severity of a variety of histologic changes, including steatosis, inflammation, cellular injury, and fibrosis. This information is summarized as an overall diagnostic category, such steatosis or steatohepatitis and the severity of the injury can be graded and staged. Histopathologic disease classification in NAFLD is related to but separate from evaluation of individual histologic lesions. The patient population under study may affect the prevalence of histologic findings and in particular, pediatric patients with NAFLD may show a higher prevalence of zone 1 steatosis and periportal fibrosis as compared with adult populations. For the purposes of clinical research, it is important to provide the pathologist with biopsies that are adequate to classify the disease process as well as to grade and stage the changes. A current understanding of NAFLD pathologic classification, as well as nuances of grading and staging, is presented in this review.
Article
Hepatic elastography (HE) is a noninvasive technique that measures liver stiffness and is used to diagnose hepatic fibrosis. It can help patients who are thought to have early-stage disease avoid a staging liver biopsy, but only when confounding variables that increase liver stiffness are excluded. Chronic inflammation from hepatitis C virus (HCV) infection is not considered to be one of these variables. We identified 684 patients with HCV and METAVIR fibrosis scores of 0-2 from a prospective, multi-institutional study of liver stiffness in 2880 patients with chronic liver disease. Patients were 49.6 ± 9.0 years old, 64.3% were male, and they had an average body mass index of 26.7 ± 4.1 kg/m(2). In a multivariate analysis, inflammation (based on histologic analysis) and level of alanine aminotransferase (ALT) were associated with liver stiffness. The chances of a patient having a level of stiffness that indicates cirrhosis increased with grade of inflammation and level of ALT. By using a conservative 14.5-kPa cutoff for the diagnosis of cirrhosis, grade 3 inflammation had an odds ratio of 9.10 (95% confidence interval, 2.49-33.4). Likewise, levels of ALT greater than 80 and 120 IU/L had odds ratios of 3.84 (95% confidence interval, 2.10-7.00) and 4.10 (95% confidence interval, 2.18-7.69), respectively. The effect of the level of ALT persisted when analysis was restricted to patients with fibrosis scores of F0 to F1. In patients with HCV infection and early-stage fibrosis, increased levels of ALT correlate with liver stiffness among patients in the lowest strata of fibrosis (METAVIR scores 0-2). Patients without fibrosis but high levels of ALT could have liver stiffness within the range for cirrhosis. Inflammation should be considered a confounding variable in analysis of liver stiffness.
Article
Unlabelled: The development of liver fibrosis markers in primary biliary cirrhosis (PBC) is needed to facilitate the assessment of its progression and the effectiveness of new therapies. Here, we investigated the potential usefulness of transient elastography (TE) in the noninvasive evaluation of liver fibrosis stage and disease progression in PBC. We performed, first, a prospective performance analysis of TE for the diagnosis of METAVIR fibrosis stages in a diagnostic cohort of 103 patients and, second, a retrospective longitudinal analysis of repeated examinations in a monitoring cohort of 150 patients followed-up for up to 5 years. All patients were treated with ursodeoxycholic acid. Diagnostic thresholds of liver stiffness in discriminating fibrosis stages ≥ F1, ≥ F2, ≥ F3, and =F4 were 7.1, 8.8, 10.7, and 16.9 kPa, respectively. TE showed high performance and was significantly superior to biochemical markers (e.g., aspartate aminotransferase [AST]/platelet ratio, FIB-4, hyaluronic acid, AST/alanine aminotransferase ratio, and Mayo score) in diagnosing significant fibrosis, severe fibrosis, or cirrhosis. Analysis of the monitoring cohort data set using generalized linear models showed the following: (1) an overall progression rate of 0.48 ± 0.21 kPa/year (P = 0.02) and (2) no significant progression in patients with F0-F1, F2, or F3 stages, but a significant increase (4.06 ± 0.72 kPa/year; P < 0.0001) in