Validation of liver elastography in patients with primary sclerosing cholangitis and healthy individuals. Normal values and correlation to fibrosis parameters.

Liver elastography applies ultrasound-based measurements of liver stiffness (LS), used as a quantification of liver fibrosis. Correlation between liver stiffness measurements (LSM) and histological stages of liver fibrosis was already established; however, technological and methodological differences between ultrasound equipment and biological differences related to age or liver disease etiology, may influence the interpretation of LSM. Correct assessment of disease relies on a precise definition of normality, but reference values and inter-system differences were lacking for several elastography systems. Data were particularly scarce for children and patients with primary sclerosing cholangitis (PSC). In this rare and complicated liver disease, non-invasive surveillance of fibrosis development is recommended as part of follow-up. Thus, we aimed to establish reference values for LSM in children and adults using several elastography systems and to compare principally different methods such as transient elastography (TE), point shear wave elastography (pSWE), and two-dimensional shear wave elastography (2D-SWE) in a head-to-head setup. We furthermore investigated, for the first time, the feasibility of pSWE and 2D-SWE in PSC patients. In studies II and III, we included 343 healthy individuals aged 4-70 years. Applying two or three elastography systems head-to-head in every participant, we defined age-specific reference values for each system. Reference values were determined for different age groups: 4-7 years, 8-11 years, 12–14 years, 15–17 years, and 20–70 years. We found a gender difference in subjects 12–70 years, with no similar difference in young children. LSM was higher in adolescents and adults compared to younger children. Correlation between different observers was good. In studies I and IV, a cohort of adult PSC patients was followed, collecting clinical data and performing LSM and blood tests. Paper I describes pSWE in PSC for the first time, comparing assessments of both liver lobes and concluding that left liver LSM is unreliable; hence, subsequent measurements forming Paper IV were applied in the right liver lobe only. All PSC patients were examined by pSWE at every visit. For Paper IV, all patients were examined head-to-head by both pSWE, 2D-SWE, and TE: all three systems were feasible in PSC patients, and all were highly correlated with other indications of liver fibrosis (B-mode findings, liver biochemistry, fibrosis scores, and prognostic scores). In conclusion, the results demonstrate that elastography systems representing three principally different methods are feasible and perform well in healthy subjects and PSC patients. We have established reference values for healthy children and adults, with head-to-head inter-system comparisons and descriptions of interobserver differences. Ultrasound elastography of the liver should be adopted broadly in the medical environment; in screening, diagnostics, and clinical patient follow-up of both children and adults.Doktorgradsavhandlin

Factors predicting antibiotic prescription and referral to hospital for children with respiratory symptoms: secondary analysis of a randomised controlled study at out-of-hours services in primary care

Objective: Acute respiratory infections and fever among children are highly prevalent in primary care. It is challenging to distinguish between viral and bacterial infections. Norway has a relatively low prescription rate of antibiotics, but it is still regarded as too high as the antimicrobial resistance is increasing. The aim of the study was to identify predictors for prescribing antibiotics or referral to hospital among children. Design: Secondary analysis of a randomised controlled study. Setting: 4 out-of-hours services and 1 paediatric emergency clinic in Norwegian primary care. Participants: 401 children aged 0–6 years with respiratory symptoms and/or fever visiting the out-of-hours services. Outcomes: 2 main outcome variables were registered: antibiotic prescription and referral to hospital. Results: The total prescription rate of antibiotics was 23%, phenoxymethylpenicillin was used in 67% of the cases. Findings on ear examination (OR 4.62; 95% CI 2.35 to 9.10), parents' assessment that the child has a bacterial infection (OR 2.45; 95% CI 1.17 to 5.13) and a C reactive protein (CRP) value >20 mg/L (OR 3.57; 95% CI 1.43 to 8.83) were significantly associated with prescription of antibiotics. Vomiting in the past 24 hours was negatively associated with prescription (OR 0.26; 95% CI 0.13 to 0.53). The main predictors significantly associated with referral to hospital were respiratory rate (OR 1.07; 95% CI 1.03 to 1.12), oxygen saturation 20 mg/L, findings on ear examination, use of paracetamol and no vomiting in the past 24 hours were significantly associated with antibiotic prescription. Affected respiration was a predictor for referral to hospital. The parents' assessment was also significantly associated with the outcomes.publishedVersio

Liver Elastography in Primary Sclerosing Cholangitis Patients Using Three Different Scanner Systems

The aim of the study described here was to characterize three different liver elastography methods in primary sclerosing cholangitis (PSC) patients, for the first time exploring 2-D shear wave elastography (2-D-SWE) in PSC patients and its putative advantages over point shear wave elastography (pSWE). Sixty-six adult PSC patients (51 males, 77%) underwent liver elastography: Transient elastography (TE), pSWE and 2-D-SWE were applied head-to-head after B-mode ultrasonography and blood tests. Liver stiffness measurements (LSMs) by pSWE yielded lower values than those by TE; 2-D-SWE had less steep slope but was overall not significantly different from TE. Correlation between LSMs by pSWE and TE was excellent (intraclass correlation coefficient = 0.92); correlation for 2-D-SWE with either pSWE or TE was moderate but improved with exclusion of overweight individuals. LSMs correlated with the Enhanced Liver Fibrosis test (ELF) across all scanner systems. Our study indicates that LSM by different systems is feasible in PSC patients and that 2-D-SWE tends to underestimate stiffness compared with TE.publishedVersio

Point Shear Wave Elastography and the Effect of Physical Exercise, Alcohol Consumption, and Respiration in Healthy Adults

Purpose Ultrasound elastography is a noninvasive method for liver stiffness measurement (LSM) with the aim of reflecting approximate liver fibrosis load. Despite minimal evidence, current guidelines recommend 10 min of rest and breath hold prior to measurements and offer no advice concerning recent alcohol consumption, leading to challenges in clinical practice. We aimed to investigate how LSM in healthy adults is influenced by physical exercise, recent alcohol consumption, and respiration. Materials and Methods 42 healthy subjects aged 21–36 years were included. LSM using point shear wave elastography (pSWE) was performed in five stages: baseline, after physical activity, after registration of alcohol consumption, and during breath hold compared to free breathing. Results LSM values were significantly increased following physical exercise compared to baseline values (4.1±0.8 vs. 3.8±0.8 kPa, p=0.01). Alcohol consumption during the last 72 h (0–27 alcohol units) did not significantly affect LSM. There was no significant difference between LSM during breath hold and free breathing. Conclusion In healthy subjects, LSM increased after recent physical exercise, while alcohol consumption 24–72 h prior to examination did not have a significant impact. There was no clinically significant effect of breath hold on LSM. Our study supports present guidelines recommending rest prior to LSM, while indicating that breath hold may not be mandatory. Recent moderate alcohol exposure may affect LSM to a lesser extent than commonly believed.publishedVersio

Controlled Attenuation Parameter in Healthy Individuals Aged 8–70 Years

Purpose Controlled attenuation parameter (CAP) is a non-invasive method to assess the presence of liver steatosis. It has been evaluated in children and adults, mainly in either the obese or in subjects with suspected liver disease. Our aim was to describe CAP in healthy non-obese subjects without suspected liver steatosis and to suggest cutoff levels for steatosis. Materials and Methods We prospectively recruited 187 individuals aged 8–70 years. All underwent clinical examination, including height and weight measurement. Body mass index (BMI) was calculated and converted into z-scores. To exclude liver pathology, B-mode ultrasound and liver stiffness measurements were performed in all prior to CAP measurement. Blood was drawn for liver biochemistry in adults. Results CAP was associated with BMI z-score across all ages. CAP started to rise alongside BMI z-score already in subjects with a BMI below average. CAP values were higher in adults than in children (p<0.001), and higher in adult males than adult females (p=0.014). CAP did not correlate with age within the adult or pediatric cohorts. CAP was highly correlated with the fatty liver index. 18 and 23% of subjects showed CAP above the suggested cutoff value for children and adults, respectively. Conclusion CAP was correlated with BMI z-score, even in individuals with a below-average BMI . We found CAP above published cutoff values in a substantial proportion of presumably healthy, non-obese children and adults, warranting further research to clarify whether this represents non-obese non-alcoholic fatty liver disease or if reference values need adjustment.publishedVersio

Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF

Background & Aims Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. Methods We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. Results At baseline, the median (range) ELF test was 9.3 (7.5–12.9) and median LSM 1.26 m/s (0.66–3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). Conclusions ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC.publishedVersio

Validation of liver elastography in patients with primary sclerosing cholangitis and healthy individuals. Normal values and correlation to fibrosis parameters.

Liver elastography applies ultrasound-based measurements of liver stiffness (LS), used as a quantification of liver fibrosis. Correlation between liver stiffness measurements (LSM) and histological stages of liver fibrosis was already established; however, technological and methodological differences between ultrasound equipment and biological differences related to age or liver disease etiology, may influence the interpretation of LSM. Correct assessment of disease relies on a precise definition of normality, but reference values and inter-system differences were lacking for several elastography systems. Data were particularly scarce for children and patients with primary sclerosing cholangitis (PSC). In this rare and complicated liver disease, non-invasive surveillance of fibrosis development is recommended as part of follow-up. Thus, we aimed to establish reference values for LSM in children and adults using several elastography systems and to compare principally different methods such as transient elastography (TE), point shear wave elastography (pSWE), and two-dimensional shear wave elastography (2D-SWE) in a head-to-head setup. We furthermore investigated, for the first time, the feasibility of pSWE and 2D-SWE in PSC patients. In studies II and III, we included 343 healthy individuals aged 4-70 years. Applying two or three elastography systems head-to-head in every participant, we defined age-specific reference values for each system. Reference values were determined for different age groups: 4-7 years, 8-11 years, 12–14 years, 15–17 years, and 20–70 years. We found a gender difference in subjects 12–70 years, with no similar difference in young children. LSM was higher in adolescents and adults compared to younger children. Correlation between different observers was good. In studies I and IV, a cohort of adult PSC patients was followed, collecting clinical data and performing LSM and blood tests. Paper I describes pSWE in PSC for the first time, comparing assessments of both liver lobes and concluding that left liver LSM is unreliable; hence, subsequent measurements forming Paper IV were applied in the right liver lobe only. All PSC patients were examined by pSWE at every visit. For Paper IV, all patients were examined head-to-head by both pSWE, 2D-SWE, and TE: all three systems were feasible in PSC patients, and all were highly correlated with other indications of liver fibrosis (B-mode findings, liver biochemistry, fibrosis scores, and prognostic scores). In conclusion, the results demonstrate that elastography systems representing three principally different methods are feasible and perform well in healthy subjects and PSC patients. We have established reference values for healthy children and adults, with head-to-head inter-system comparisons and descriptions of interobserver differences. Ultrasound elastography of the liver should be adopted broadly in the medical environment; in screening, diagnostics, and clinical patient follow-up of both children and adults

Liver Elastography in Primary Sclerosing Cholangitis Patients Using Three Different Scanner Systems

The aim of the study described here was to characterize three different liver elastography methods in primary sclerosing cholangitis (PSC) patients, for the first time exploring 2-D shear wave elastography (2-D-SWE) in PSC patients and its putative advantages over point shear wave elastography (pSWE). Sixty-six adult PSC patients (51 males, 77%) underwent liver elastography: Transient elastography (TE), pSWE and 2-D-SWE were applied head-to-head after B-mode ultrasonography and blood tests. Liver stiffness measurements (LSMs) by pSWE yielded lower values than those by TE; 2-D-SWE had less steep slope but was overall not significantly different from TE. Correlation between LSMs by pSWE and TE was excellent (intraclass correlation coefficient = 0.92); correlation for 2-D-SWE with either pSWE or TE was moderate but improved with exclusion of overweight individuals. LSMs correlated with the Enhanced Liver Fibrosis test (ELF) across all scanner systems. Our study indicates that LSM by different systems is feasible in PSC patients and that 2-D-SWE tends to underestimate stiffness compared with TE