Normal Liver Stiffness Values in Children: A Comparison of Three Different Elastography Methods.

OBJECTIVES: Noninvasive tests for the evaluation of liver fibrosis are particularly helpful in children to avoid general anesthesia and potential complications of invasive tests. We aimed to establish reference values for 2 different elastography methods in a head-to-head comparison for children and adolescents 4 to 17 years, using transient elastography as common reference in a subset. METHODS: A total of 243 healthy participants aged 4 to 17 years were examined by a single observer with a full liver B-mode scan before elastography, following a minimum of 3 hours fasting. Liver stiffness measurements (LSMs) using 2-dimensional shear wave elastography (2D-SWE, GE Logiq E9) and point shear wave elastography (pSWE, Samsung RS80A with Prestige) were performed in all participants, and compared to transient elastography (TE, FibroScan) in a subset (n = 87). Interobserver agreement was evaluated in 50 children aged 4 to 17 years. RESULTS: Valid measurements were obtained in 242 of 243 (99.6%) subjects for 2D-SWE, 238 of 243 (97.9%) for pSWE, and in 83 of 87 (95.4%) for TE. Median liver stiffness overall was 3.3 (interquartile range [IQR] 2.7-4.3), 4.1 (IQR 3.6-4.7), and 4.1 kPa (IQR 3.5-4.6) for 2D-SWE, pSWE, and TE, respectively. Intraclass correlation coefficients between observers were 0.84 and 0.83 for 2D-SWE and pSWE, respectively. LSM values were significantly lower for 2D-SWE compared to pSWE and TE, and increased with advancing age. Higher LSM values in males were observed in adolescents. CONCLUSIONS: All methods showed excellent feasibility. 2D-SWE showed significantly lower LSM values than pSWE and TE, and lower failure rate compared to TE. Our results further indicate an age and sex effect on LSM values.

Secretin-stimulated ultrasound estimation of pancreatic secretion in cystic fibrosis validated by magnetic resonance imaging.

OBJECTIVES: Secretin-stimulated magnetic resonance imaging (s-MRI) is the best validated radiological modality assessing pancreatic secretion. The purpose of this study was to compare volume output measures from secretin-stimulated transabdominal ultrasonography (s-US) to s-MRI for the diagnosis of exocrine pancreatic failure in cystic fibrosis (CF). METHODS: We performed transabdominal ultrasonography and MRI before and at timed intervals during 15 minutes after secretin stimulation in 21 CF patients and 13 healthy controls. To clearly identify the subjects with reduced exocrine pancreatic function, we classified CF patients as pancreas-sufficient or -insufficient by secretin-stimulated endoscopic short test and faecal elastase. RESULTS: Pancreas-insufficient CF patients had reduced pancreatic secretions compared to pancreas-sufficient subjects based on both imaging modalities (p < 0.001). Volume output estimates assessed by s-US correlated to that of s-MRI (r = 0.56-0.62; p < 0.001). Both s-US (AUC: 0.88) and s-MRI (AUC: 0.99) demonstrated good diagnostic accuracy for exocrine pancreatic failure. CONCLUSIONS: Pancreatic volume-output estimated by s-US corresponds well to exocrine pancreatic function in CF patients and yields comparable results to that of s-MRI. s-US provides a simple and feasible tool in the assessment of pancreatic secretion. KEY POINTS: • Cystic fibrosis patients with affected pancreas have reduced pancreatic secretions. • Secretin-stimulated sonography is a simple and feasible method to assess pancreatic output. • Secretin-simulated MRI is a more precise method to assess pancreatic secretions. • The sonographic and MRI methods yielded comparable pancreatic secretory output estimates.

Enhanced liver fibrosis test predicts transplant-free survival in primary sclerosing cholangitis, a multi-centre study.

BACKGROUND & AIMS: Biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC) have not been firmly established. Enhanced liver fibrosis (ELF) test was previously reported to predict outcome in PSC. We aimed to validate the prognostic utility of ELF test in an independent, multi-centre, retrospective PSC study population. METHODS: We collected serum samples from PSC patients from seven countries. We estimated rates of transplant-free survival by the Kaplan-Meier method, used Cox proportional hazards regression to explore the association between ELF test and clinical outcome and determined prognostic performance of ELF test by computing the area under the receiver operating characteristic (AUC-ROC) curve. RESULTS: The final analysis included 534 PSC patients (61% males). Features of autoimmune hepatitis or concomitant inflammatory bowel disease affected 44 (8%) and 379 (71%) patients respectively. ELF test levels were higher in patients reaching the combined endpoint liver transplantation or death (median 10.9 [Interquartile range (IQR): 9.8-12.1]; n=24 deaths, 79 liver transplantations) compared to those censored (8.8 [IQR: 8.0-9.8]); P<.001. ELF test expressed as mild, moderate and severe fibrosis was significantly associated with the risk of reaching the endpoint (P<.001). ELF test independently predicted clinical outcome (Hazard ratio 1.31; 95% confidence interval [1.05-1.65]; P=.018), and enabled good discrimination between PSC patients with and without endpoint (AUC-ROC: 0.79). CONCLUSION: Our retrospective data validates the predictive utility of ELF test for clinical outcomes in PSC. The clinical utility of biomarkers for fibrosis in patients with PSC should be assessed in prospective patient cohorts.

Automated spectrophotometric bicarbonate analysis in duodenal juice compared to the back titration method.

OBJECTIVES: We have recently evaluated a short endoscopic secretin test for exocrine pancreatic function. Bicarbonate concentration in duodenal juice is an important parameter in this test. Measurement of bicarbonate by back titration as the gold standard method is time consuming, expensive and technically difficult, thus a simplified method is warranted. We aimed to evaluate an automated spectrophotometric method in samples spanning the effective range of bicarbonate concentrations in duodenal juice. We also evaluated if freezing of samples before analyses would affect its results. METHODS: Patients routinely examined with short endoscopic secretin test suspected to have decreased pancreatic function of various reasons were included. Bicarbonate in duodenal juice was quantified by back titration and automatic spectrophotometry. Both fresh and thawed samples were analysed spectrophotometrically. RESULTS: 177 samples from 71 patients were analysed. Correlation coefficient of all measurements was r = 0.98 (p < 0.001). Correlation coefficient of fresh versus frozen samples conducted with automatic spectrophotometry (n = 25): r = 0.96 (p < 0.001) CONCLUSIONS: The measurement of bicarbonate in fresh and thawed samples by automatic spectrophotometrical analysis correlates excellent with the back titration gold standard. This is a major simplification of direct pancreas function testing, and allows a wider distribution of bicarbonate testing in duodenal juice. Extreme values for Bicarbonate concentration achieved by the autoanalyser method have to be interpreted with caution.

Diagnostic accuracy of secretin-stimulated ultrasonography of the pancreas assessing exocrine pancreatic failure in cystic fibrosis and chronic pancreatitis.

OBJECTIVE: Volume output failure is a feature of decreasing exocrine pancreatic function. This parameter is assessed by secretin-stimulated MRI in several studies. Our purpose was to evaluate ultrasonography of the fluid in the descending duodenum and Wirsung duct (WD) after secretin stimulation as a measure of pancreatic fluid flow in patients expected to have severe output failure. MATERIAL AND METHODS: We included subjects with chronic pancreatitis (CP), cystic fibrosis (CF) and a group of healthy controls in a prospective observation study. Transabdominal ultrasonography was performed before and during 15 min after secretin i.v. duodenal juice was collected by endoscopic short test (EST), and bicarbonate concentration measured. Patient groups were classified according to exocrine pancreatic function. RESULTS: Pancreatic insufficient CF (CFI) patients and CP insufficient (CPI) patients showed less duodenal fluid filling compared to other groups (p < 0.001). Measures of the WD diameter could only identify the most severe failure in the CFI group (p < 0.001). CONCLUSION: Secretin-stimulated ultrasonography can be used to assess pancreatic fluid flow and may be combined with EST in the evaluation of exocrine pancreatic function. Fluid filling in the descending part of duodenum was the most accurate predictor of pancreatic insufficiency in both patient groups. The test demonstrated better diagnostic accuracy diagnosing exocrine pancreatic failure in the CF patients than in CP patients.

Development of and Gathering Validity Evidence for a Theoretical Test in Contrast-Enhanced Ultrasound.

Contrast-enhanced ultrasound (CEUS) is an imaging modality applied in a broad field of medical specialties for diagnostic uses, guidance during biopsy procedures and ablation therapies and sonoporation therapy. Appropriate training and assessment of theoretical and practical competencies are recommended before practicing CEUS, but no validated assessment tools exist. This study was aimed at developing a theoretical multiple-choice question-based test for core CEUS competencies and gathering validity evidence for the test. An expert team developed the test via a Delphi process. The test was administered to medical doctors with varying CEUS experience, and the results were used to evaluate test items, internal-consistency reliability, ability to distinguish between different proficiency levels and to establish a pass/fail score. Validity evidence was gathered according to Messick's framework. The final test with 47 test items could distinguish between operators with and without CEUS experience with acceptable reliability. The pass/fail score led to considerable risk of false positives and negatives. The test may be used as an entry test before learning practical CEUS competencies but is not recommended for certification purposes because of the risk of false positives and negatives.

Postprandial Symptoms in Patients With Functional Dyspepsia and Irritable Bowel Syndrome: Relations to Ultrasound Measurements and Psychological Factors.

BACKGROUND/AIMS: Dyspeptic symptoms are common in patients with functional gastrointestinal (GI) disorders, and may be related to visceral hypersensitivity. We aim to explore the relation between visceral hypersensitivity by using an ultrasonographic meal test and questionnaires in patients with irritable bowel syndrome (IBS) and/or functional dyspepsia (FD). METHODS: Patients (FD, n = 94; IBS, n = 88; IBS + FD, n = 66, healthy controls [HC], n = 30) were recruited consecutively and examined with ultrasound of the proximal and distal stomach after drinking 500 mL of a low caloric meat soup, and scored dyspeptic symptoms on a visual analogue scale (0-100 mm) before and after the meal. Psychological symptoms were assessed by Visceral Sensitivity Index (GI specific anxiety, n = 58), and Eysenck's Personality Questionnaire-neuroticism (EPQ-N, n = 203). RESULTS: Patients with IBS and/or FD reported higher levels of nausea, upper GI discomfort, and epigastric pain both before and after a liquid meal compared to HC (P < 0.001), and had a larger antral area in a fasting state, compared to HC. We found impaired accommodation in 33% of the patients with FD, however ultrasound measurements and symptom severity did not correlate. Symptoms of epigastric pain, fullness and upper GI discomfort positively correlated to Visceral Sensitivity Index and EPQ-N in a fasting state, but not postprandially. CONCLUSIONS: Nausea, upper GI discomfort, and epigastric pain was common in patients with IBS and FD. Both patient groups had enlarged antral area in a fasting state compared to HC. Discomfort and pain were associated to GI specific anxiety and neuroticism in a fasting state.

Contrast-Enhanced Ultrasound: Development of Syllabus for Core Theoretical and Practical Competencies.

Contrast-enhanced ultrasound (CEUS) is dependent on the observer's competencies, and thus, appropriate education and testing of individual competency is essential. The current international curriculum in CEUS is methodologically weak and lacks validated competency assessment tests. In this study, we aimed to develop a syllabus for core competencies in CEUS using the Delphi process and an international panel of experts. A core writing group constructed an initial draft of the syllabus based on the existing literature. Eight international experts in CEUS or medical education were recruited as Delphi panelists. The draft underwent iterative and anonymous Delphi rounds until a pre-defined level of consensus was reached. The final syllabus consisted of 16 items, which were indexed in two main domains and in procedural order. An expert-generated proposal for a syllabus of core CEUS competencies has been constructed via the Delphi process and may serve as framework for future development of a CEUS curriculum, including competency assessment tests.

Diagnostic Accuracy of Transabdominal Ultrasound in Chronic Pancreatitis.

The performance of transabdominal ultrasound (US) in chronic pancreatitis (CP) following the advances in US technology made during recent decades has not been explored. Our aim in this prospective study was to evaluate the diagnostic accuracy of modern abdominal US compared with the Mayo score in CP. One hundred thirty-four patients referred for suspected CP were included in the study. Fifty-four patients were assigned the diagnosis CP. After inclusion, transabdominal US was performed. Ductal features (calculi, dilations and caliber variations, side-branch dilations and hyper-echoic duct wall margins) and parenchymal features (calcifications, cysts, hyper-echoic foci, stranding, lobulation and honeycombing) were recorded. Features were counted and scored according to a weighting system defined at the international consensus meeting in Rosemont, Illinois (Rosemont score). Diagnostic performance indices (95% confidence interval) of US were calculated: The unweighted count of features had a sensitivity of 0.69 (0.54-0.80) and specificity of 0.97 (0.90-1). The Rosemont score had a sensitivity of 0.81 (0.69-0.91) and specificity of 0.97 (0.90-1). Exocrine pancreatic failure was most pronounced in Rosemont groups I and II (p < 0.001). We conclude that using both unweighted and weighted scores, the diagnostic accuracy of modern transabdominal US is good. The extent of pancreatic changes detected by the method is correlated with exocrine pancreatic function.

Guanylate Cyclase C Activation Shapes the Intestinal Microbiota in Patients with Familial Diarrhea and Increased Susceptibility for Crohn's Disease.

BACKGROUND: With 25% prevalence of Crohn's disease, Familial GUCY2C diarrhea syndrome (FGDS) is a monogenic disorder potentially suited to study initiating factors in inflammatory bowel disease (IBD). We aimed to characterize the impact of an activating GUCY2C mutation on the gut microbiota in patients with FGDS controlling for Crohn's disease status and to determine whether changes share features with those observed in unrelated patients with IBD. METHODS: Bacterial DNA from fecal samples collected from patients with FGDS (N = 20), healthy relatives (N = 11), unrelated healthy individuals (N = 263), and IBD controls (N = 46) was subjected to sequencing of the V3-V4 region of the 16S rRNA gene to determine gut microbiota composition. Food frequency questionnaires were obtained from patients with FGDS and their relatives. RESULTS: Compared with healthy controls, FGDS displayed prominent changes in many microbial lineages including increase in Enterobacteriaceae, loss of Bifidobacterium and Faecalibacterium prausnitzii but an unchanged intraindividual (alpha) diversity. The depletion of F. prausnitzii is in line with what is typically observed in Crohn's disease. There was no significant difference in the dietary profile between the patients and related controls. The gut microbiota in related and unrelated healthy controls was also similar, suggesting that diet and familial factors do not explain the gut microbiota alterations in FGDS. CONCLUSIONS: The findings support that the activating mutation in GUCY2C creates an intestinal environment with a major influence on the microbiota, which could contribute to the increased susceptibility to IBD in patients with FGDS.

Three-dimensional surface model analysis in the gastrointestinal tract.

The biomechanical changes during functional loading and unloading of the human gastrointestinal (GI) tract are not fully understood. GI function is usually studied by introducing probes in the GI lumen. Computer modeling offers a promising alternative approach in this regard, with the additional ability to predict regional stresses and strains in inaccessible locations. The tension and stress distributions in the GI tract are related to distensibility (tension-strain relationship) and smooth muscle tone. More knowledge on the tension and stress on the GI tract are needed to improve diagnosis of patients with gastrointestinal disorders. A modeling framework that can be used to integrate the physiological, anatomical and medical knowledge of the GI system has recently been developed. The 3-D anatomical model was constructed from digital images using ultrasonography, computer tomography (CT) or magnetic resonance imaging (MRI). Different mathematical algorithms were developed for surface analysis based on thin-walled structure and the finite element method was applied for the mucosa-folded three layered esophageal model analysis. The tools may be useful for studying the geometry and biomechanical properties of these organs in health and disease. These studies will serve to test the structure-function hypothesis of geometrically complex organs.

Ultrasound echo-intensity predicts severe pancreatic affection in cystic fibrosis patients.

BACKGROUND: Pancreatic destruction affects the majority of patients with cystic fibrosis. We aimed to relate ultrasound findings to exocrine pancreatic function and cystic fibrosis genotype. METHODS: Patients with cystic fibrosis and a matched group of healthy controls were included. We performed transabdominal ultrasound, and recorded echo intensities of the pancreas and parenchymal characteristics according to endoscopic ultrasound based Rosemont criteria. RESULTS: We included 39 patients and 29 healthy controls. The cystic fibrosis patients were grouped according to exocrine pancreatic function; Cystic fibrosis, insufficient (n = 20) and sufficient (n = 19). Echo intensity measures and visual score demonstrated hyper-echogenicity in the pancreas insufficient group compared to the pancreas sufficient groups (p<0.001). Ductal and parenchymal changes were not prevalent in any of the groups. CONCLUSION: The hyper-echoic pancreas was the most frequent ultrasonographic finding in exocrine pancreas insufficient cystic fibrosis patients. Pancreatic echo levels correlated to pancreatic phenotype.

Bowel perfusion measured with dynamic contrast-enhanced ultrasound predicts treatment outcome in patients with Crohn's disease.

BACKGROUND: To improve management of patients with Crohn's disease (CD), objective measurements of the degree of local inflammation in the gastrointestinal wall are needed. Increased microvessel density and perfusion are typical features of acute inflammation and can be estimated with contrast-enhanced ultrasound (CEUS). The aim of the study was to investigate whether CEUS can provide prognostic information about patients treated medically for an acute exacerbation of CD. METHODS: Fourteen patients with CD who received medical treatment for acute exacerbation with systemic steroids or tumor necrosis factor-α inhibitors were prospectively recruited. The patients were examined with clinical scoring, blood tests, and CEUS at time 0, 1, 3, and 12 months after initiation of the treatment. Outcome was treatment efficacy or treatment failure defined as change in medical treatment after 1 month or later. The perfusion analysis was performed with a commercially available software program that analyzes the contrast intensity in a selected area, fits the data to a standardized time-intensity curve, and derives several relative perfusion parameters. RESULTS: Six of the 14 patients had treatment failure during the study period. There was a significant difference between the groups for peak contrast enhancement (P = 0.013), rate of wash-in (P = 0.020) and wash-out (P = 0.008), and the area under the time-intensity curve in the wash-in phase (0.013) at the examination 1 month after the start of treatment. CONCLUSIONS: Perfusion analysis of the intestinal wall with CEUS 1 month after starting treatment in patients with CD can provide prognostic information regarding treatment efficacy.

Association between visceral, cardiac and sensorimotor polyneuropathies in diabetes mellitus.

AIMS: Gastrointestinal complaints are common in diabetes mellitus. However, its association to peripheral sensorimotor and autonomic neuropathies is not well investigated. The aim was to assess skin, muscle, bone and visceral sensitivity in diabetes patients with sensorimotor neuropathy, and correlate these with gastrointestinal symptoms and degree of cardiac autonomic neuropathy. METHODS: Twenty patients with sensorimotor neuropathy (65% type 2 diabetes, aged 58.3±12.0 years, diabetes duration 15.8±10.0 years) and 16 healthy controls were recruited. Cutaneous sensitivity to von Frey filaments, mechanical allodynia, muscle/bone/rectosigmoid sensitivities, and heart rate variability were examined. Gastrointestinal symptom scores (PAGI-SYM) and health-related quality of life (SF-36) were also recorded. RESULTS: Patients displayed hypesthesia to von Frey filaments (p=0.028), but no difference to muscle and bone pain sensitivities. Also, patients were hyposensitive to multimodal rectal stimulations (all p<0.05), although they suffered more gastrointestinal complaints. Heart rate variability was reduced in the patient cohort. Rectal mechanical and cutaneous sensitivities correlated (p<0.001), and both were associated with heart rate variability as well as PAGI-SYM and SF-36 scores (p<0.01). CONCLUSIONS: In diabetic sensorimotor neuropathy there is substantial evidence of concomitant cutaneous, cardiac and visceral autonomic neuropathies. The neuropathy may reduce quality of life and explain the higher prevalence of gastrointestinal complaints.

Ultrasound perfusion analysis combining bolus-tracking and burst-replenishment.

A new signal model and processing method for quantitative ultrasound perfusion analysis is presented, called bolus-and-burst. The method has the potential to provide absolute values of blood flow, blood volume, and mean transit time. Furthermore, it provides an estimate of the local arterial input function which characterizes the arterial tree, allowing accurate estimation of the bolus arrival time. The method combines two approaches to ultrasound perfusion analysis: bolus-tracking and burst-replenishment. A pharmacokinetic model based on the concept of arterial input functions and tissue residue functions is used to model both the bolus and replenishment parts of the recording. The pharmacokinetic model is fitted to the data using blind deconvolution. A preliminary assessment of the new perfusion-analysis method is presented on clinical recordings.