Toward acquisition protocol standardization for estimating liver fat content using ultrasound attenuation coefficient imaging.

PURPOSE: This study's primary aim was to assess factors affecting ultrasound attenuation coefficient (AC) measurement repeatability using the Canon ultrasound (US) system. The secondary aim was to evaluate whether similar results were obtained with other vendors' AC algorithms. METHODS: This prospective study was performed at two centers from February to November 2022. AC was obtained using two US systems (Aplio i800 of Canon Medical Systems and Arietta 850 of Fujifilm). An algorithm combining AC and the backscatter coefficient was also used (Sequoia US System, Siemens Healthineers). To evaluate inter-observer concordance, AC was obtained by two expert operators using different transducer positions with regions of interest (ROIs) varying in terms of depth and size. Intra-observer concordance was evaluated on measurements performed intercostally, subcostally, and in the left liver lobe. Lin's concordance correlation coefficient was used. RESULTS: Thirty-four participants (mean age, 49.4±15.1 years; 18 females) were studied. AC values progressively decreased with depth. The measurements in intercostal spaces on bestquality US images using a 3-cm ROI with its upper edge 2 cm below the liver capsule during breath-hold showed the highest intra-observer and inter-observer concordance (0.92 [95% confidence interval, 0.88 to 0.95] and 0.89 [0.82 to 0.96], respectively). Measurements in the left lobe showed the lowest intra-observer and inter-observer concordance (0.67 [0.43 to 0.90] and 0.58 [0.12 to 1.00], respectively). Intercostal space measurements also had the highest repeatability for the other two ultrasound systems. CONCLUSION: AC values obtained in intercostal spaces on best-quality images using a 3-cm ROI placed with its top 2 cm below the liver capsule were highly repeatable.

Quantification of Liver Fat Content with the iATT Algorithm: Correlation with Controlled Attenuation Parameter.

Background: The primary aim of our study was to assess the correlation between an improved version of the attenuation coefficient available on the Arietta 850 ultrasound system (iATT, Fujifilm Healthcare, Tokyo, Japan) and controlled attenuation parameter (CAP). The secondary aim was to assess whether focusing only on iATT acquisition without following the strict protocol for liver stiffness measurements would affect iATT measurement. Methods: Consecutive individuals were enrolled. Pearson's r was used to test the correlation between ATT and CAP values. The concordance between iATT and CAP was tested using Lin's concordance correlation coefficient (CCC). Results: 354 individuals (203 males, 151 females) were studied. The overall Pearson correlation between CAP and iATT values obtained following or not following the liver stiffness measurement protocol, respectively, were r = 0.73 and r = 0.71. The correlation was affected by the interquartile range/median (IQR/M) of the 10 measurements: it was r = 0.75 for IQR/M ≤ 15% and r = 0.60 for IQR/M > 15%. CCC showed that there was a moderate to good concordance between iATT and CAP values. Conclusion: iATT shows a strong correlation with CAP that does not decrease when the protocol for liver stiffness acquisition is not followed. The correlation between iATT and CAP values is higher when the IQR/M ≤ 15%.

Conservative Management of Liver Echinococcal Cysts in Pregnant Women: One Center's Experience in Pavia, Italy.

Human cystic echinococcosis (CE) in pregnancy is rarely reported, with approximately one case of CE for every 20,000 to 30,000 pregnant women in endemic areas. Little information on its management is available. We report our experience with a watch-and-wait approach in this group of patients. We retrieved clinical data from pregnant patients with hepatic CE seen at our clinic from 1989 to 2021. All patients had at least one hepatic CE cyst and received no treatment during pregnancy. Ultrasound was used to monitor cyst evolution; outcome and complications of pregnancy and echinococcal infection were evaluated. Twelve patients with 15 pregnancies were included in this study. At the time of pregnancy, nine patients had a single cyst and two patients had multiple hepatic CE cysts. Cysts were in stage CE3a, CE3b, CE4, and CE5, according to the WHO Informal Working Group on Echinococcosis classification. All cysts except one remained stable in stage and size during and after pregnancy. In one patient with a history of multiple treatments with albendazole and with a CE4 cyst at the start of pregnancy, reactivation of the cyst during pregnancy was observed. All pregnancies except three had eutocic delivery. Cesarean sections were performed for reasons unrelated to CE. In our experience, "watch and wait" in pregnant women with uncomplicated transitional and inactive CE of the liver was a safe option in a small cohort of patients. Pooled data from other referral centers, including cases with CE1 and CE2 cysts, are needed to confirm the safety of this approach.

Looking for fever in nursing home residents with COVID-19: A false friend?

OBJECTIVES: Residents in nursing homes represent a frail, elderly population, and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can spread easily in this setting. Despite a frequent severe evolution of coronavirus disease 2019 (COVID-19), these patients often present an atypical course with mild initial symptoms. The aim of this study was to assess the occurrence of fever in elderly patients with COVID-19 residing in nursing homes. METHODS: Two hundred and thirty-one elderly patients from three nursing homes in Pavia and surrounding area were enrolled in April-May 2020. SARS-CoV-2 infection was diagnosed using real-time reverse transcription polymerase chain reaction with nasopharyngeal swab and/or serological assay (LIAISON® SARS-CoV-2 S1/S2 IgG). Patients with a positive result on RT-PCR or serology were classed as positive. RESULTS: In total, 170 patients (74%) were SARS-CoV-2-positive on RT-PCR and/or serology, and 61 patients (26%) had negative results on both tests. Fever (body temperature >37.5 °C) was observed in four patients (1.7%): three in the SARS-CoV-2-positive group (1.8%) and one in the SARS-CoV-2-negative group (1.6%). CONCLUSIONS: The prevalence of fever was extremely low in this population of nursing home residents with COVID-19. This finding must be taken into consideration when screening patients without fever in nursing homes.

Comparison of liver stiffness measurements by a 2D-shear wave technique and transient elastography: results from a European prospective multi-centre study.

OBJECTIVES: To compare liver stiffness measurement (LSM) provided by Canon 2D-shear wave elastography (2D-SWE) and transient elastography (TE), the latter being the reference method. METHODS: Prospective study conducted in four European centres from 2015 to 2016 including patients with various chronic liver diseases who had LSMs with both 2D-SWE and TE on the same day. Median of 10 valid measurements (in kPa) was used for comparison using paired t test, Pearson correlation, intraclass correlation coefficient (ICC) and Bland-Altman plot. The ability of 2D-SWE to stratify patient according to recognised LSM-TE thresholds was assessed by ROC curve analysis. RESULTS: Six hundred forty patients were scanned, where 593 (92.7%), 572 (89.4%) and 537 (83.9%) had reliable LSMs by TE, 2D-SWE and both combined, respectively. In the latter (n = 537, 310 [57.7%] male, mean 55.3 ± 14.8 years), median LSM-TE and LSM-2D-SWE had a mean of 10.1 ± 9.4 kPa (range 2.4-75) and 9.1 ± 6.1 kPa (range 3.6-55.7) (paired t test: p < 0.001), respectively. These were significantly correlated (Pearson r = 0.932, p < 0.001, ICC 0.850 (0.825-0.872), bias 0.99 ± 4.33 kPa [95% limits of agreement - 9.48 to + 7.49] with proportional error towards higher LSM values). LSM-2D-SWE values significantly increased with TE categories (ANOVA: p < 0.001). AUROCs ranged from 0.935 ± 0.010 (95% CI 0.910-0.954) to 0.973 ± 0.009 (95% CI 0.955-0.985), resulting in correct classification of 390/537 (73%) patients. Three 2D-SWE measurements were sufficient for reliable LSMs. CONCLUSION: LSM using 2D-SWE correlates well with TE. It tends to underestimate higher stages of liver fibrosis but correctly classifies the majority of patients. It may be used in TE-derived algorithms to manage patients. KEY POINTS: • Liver stiffness measurement (LSM) by 2D-shear wave elastography (2D-SWE) and transient elastography (TE) are strongly correlated. • 2D-SWE shows proportionately lower LSM values compared to TE, particularly with the higher LSM range. • Three individual measurements by 2D-SWE are sufficient to assess LSM reliably.

Performance of the Attenuation Imaging Technology in the Detection of Liver Steatosis.

OBJECTIVES: The main aim was to assess the performance and cutoff value for the detection of liver steatosis (grade S > 0) with the Attenuation Imaging-Penetration (ATI-Pen) algorithm available on the Aplio i-series ultrasound systems (Canon Medical Systems, Otawara, Japan). The magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) was used as the reference standard. Secondary aims were to compare the results to those obtained with the previous ATI algorithm (Attenuation Imaging-General [ATI-Gen]) and with the controlled attenuation parameter (CAP) and to generate a regression equation between ATI-Pen and ATI-Gen values. METHODS: Consecutive adult patients potentially at risk of liver steatosis were prospectively enrolled. Each patient underwent ultrasound quantification of liver steatosis with ATI-Pen and ATI-Gen and a CAP assessment with the FibroScan system (Echosens, Paris, France). The MRI-PDFF evaluation was performed within a week. The correlations between ATI-Pen, ATI-Gen, the CAP, and the MRI-PDFF were analyzed with the Pearson rank correlation coefficient. The diagnostic performance of ATI-Pen, ATI-Gen, and the CAP was assessed with receiver operating characteristic curves and an area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: Seventy-two individuals (31 male and 41 female) were enrolled. Correlation coefficients of ATI-Pen, ATI-Gen, and the CAP with the MRI-PDFF were 0.78, 0.83, and 0.58, respectively. The AUROCs of ATI-Pen, ATI-Gen, and the CAP for detecting steatosis (S > 0) were 0.90 (95% confidence interval, 0.81-0.96), 0.92 (0.82-0.98), and 0.85 (0.74-0.92), and the cutoffs were greater than 0.69 dB/cm/MHz, greater than 0.62 dB/cm/MHz, and greater than 273 dB/m. The regression equation between ATI-Pen and ATI-Gen was ATI-Pen = 0.88 ATI-Gen + 0.13. CONCLUSIONS: Attenuation Imaging is a reliable tool for detecting liver steatosis, showing an excellent correlation with the MRI-PDFF and high performance with AUROCs of 0.90 or higher.

Performance and cutoffs for liver fibrosis staging of a two-dimensional shear wave elastography technique.

OBJECTIVES: To assess performance and cutoffs of the 2-dimensional shear wave elastography technique available on the Aplio i800 ultrasound system (Canon Medical Systems, Japan), using transient elastography as reference standard, and to assess the correlation of shear-wave-speed dispersion with liver fibrosis or steatosis. METHODS: This was a single-center cross-sectional study. The correlations between values obtained with transient elastography and 2-dimensional-shear wave elastography, and between shear-wave-speed dispersion and fibrosis or steatosis, were assessed with Pearson's r. The diagnostic performance of the 2-dimensional-shear wave elastography for staging significant fibrosis and severe fibrosis compared to transient elastography was assessed using the area under the receiver operating characteristic curve analysis. RESULTS: Three hundred sixty-seven patients (198 males and 169 females) were studied. There was a high correlation between 2-dimensional-shear wave elastography and transient elastography (r = 0.87, P < 0.0001). The area under the receiver operating characteristics of 2-dimensional-shear wave elastography for staging significant fibrosis (F2) and severe fibrosis (F3-F4), respectively, were 0.97 (95% confidence interval, 0.91-0.98) and 0.97 (95% confidence interval, 0.95-0.99). The best cutoffs for significant fibrosis and severe fibrosis, respectively, were > 7 and > 9 kPa. Shear-wave-speed dispersion showed a high correlation with fibrosis (r = 0.85, P < 0.0001), whereas there was a very weak correlation with steatosis. CONCLUSIONS: The results of this study show that this 2-dimensional-shear wave elastography technique is accurate for staging liver fibrosis. Shear-wave-speed dispersion is highly correlated with liver fibrosis but not with steatosis.

Bictegravir/emtricitabine/tenofovir alafenamide-induced acute pancreatitis: a case report.

We report here the case of a 32-year-old male with recent diagnosis of HIV that, 45 days after starting a single tablet regimen co-formulated with bictegravir, emtricitabine and tenofovir alafenamide (BIC/FTC/TAF), experienced severe epigastric pain radiating to the back, nausea, episodes of non-bloody non-bilious vomiting and anorexia. Laboratory examination showed a rise in lipase with no alterations in serum transaminases. Abdominal ultrasound revealed a non-homogeneous structure of the pancreatic parenchyma. A diagnosis of mild drug-related acute pancreatitis was made and BIC/FTC/TAF was immediately stopped. The association between the episode of acute pancreatitis and BIC/FTC/TAF was scored as probable according to the Naranjo causality scale.

Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings.

BACKGROUND AND OBJECTIVES: Liver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART). OBJECTIVE: We aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital. METHODS: We searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month. RESULTS: Ten HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable. CONCLUSIONS: The management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal.

Drug-Drug Interactions Between Antiretrovirals and Carbamazepine/Oxcarbazepine: A Real-Life Investigation.

BACKGROUND: Carbamazepine and oxcarbazepine are potent modulators of metabolic enzymes. Hence, potential drug-drug interactions (DDIs) may occur between these 2 drugs and antiretrovirals. Here, we aimed to assess the relevance of these drug-drug interactions in real-life clinical settings. METHODS: Patients treated concomitantly with carbamazepine or oxcarbazepine and antiretrovirals for at least 3 months were considered. Data on therapeutic drug monitoring (TDM) of both antiepileptic and antiretrovirals as trough concentrations were collected. HIV-infected patients not concomitantly treated with antiepileptic drugs and who underwent TDM for antiretrovirals in the previous 2 years were considered as controls. RESULTS: Eleven HIV-positive patients prescribed carbamazepine or oxcarbazepine were identified. All the TDM evaluations for carbamazepine and oxcarbazepine that resulted were within the therapeutic ranges. TDM results of darunavir measured in these patients were comparable with values usually measured in the control group. Conversely, the trough concentrations for atazanavir and dolutegravir demonstrated significantly lower values when compared with values usually measured in HIV-infected patients not treated with antiepileptic drugs (190 ± 91 versus 546 ± 380 ng/mL; -65%, P < 0.001; 191 ± 78 versus 1096 ± 510 ng/mL; -83%, P < 0.001, respectively). CONCLUSIONS: Co-administration of carbamazepine or oxcarbazepine with atazanavir or dolutegravir should be avoided owing to the potential risk of virological failure; in case of these 2 drugs, the adoption of TDM is strongly advisable, eventually combining with increased antiretroviral doses.

Detection of Liver Steatosis With a Novel Ultrasound-Based Technique: A Pilot Study Using MRI-Derived Proton Density Fat Fraction as the Gold Standard.

OBJECTIVES: The primary aim of this study was to investigate the value of attenuation imaging (ATI), a novel ultrasound technique for detection of steatosis, by comparing the results to that obtained with controlled attenuation parameter (CAP) and by using MRI-derived proton density fat fraction (PDFF) as reference standard. METHODS: From March to November 2018, 114 consecutive adult subjects potentially at risk of steatosis and 15 healthy controls were enrolled. Each subject underwent ATI and CAP assessment on the same day. MRI-PDFF was performed within a week. RESULTS: The prevalence of steatosis, as defined by MRI-PDFF ≥ 5%, was 70.7%. There was a high correlation of ATI with MRI-PDFF (r = 0.81, P < 0.0001). The correlation of CAP with MRI-PDFF and with ATI, respectively, was moderate (r = 0.65, P < 0.0001 and r = 0.61, P < 0.0001). The correlation of ATI or CAP with PDFF was not affected by age, gender, or body mass index. Area under the receiver operating characteristics of ATI and CAP, respectively, were 0.91 (0.84-0.95; P < 0.0001) and 0.85 (0.77-0.91; P < 0.0001) for detecting S > 0 steatosis (MRI-PDFF ≥ 5%); 0.95 (0.89-0.98; P < 0.0001) and 0.88 (0.81-0.93; P < 0.0001) for detecting S > 1 steatosis (MRI-PDFF ≥ 16.3%). The cutoffs of ATI and CAP, respectively, were 0.63 dB/cm/MHz and 258 dB/m for detecting S > 0 liver steatosis; 0.72 dB/cm/MHz and 304 dB/m for detecting S > 1 steatosis. ATI performed better than CAP, and this improvement was statistically significant for S > 1 (P = 0.04). DISCUSSION: This study shows that, in patients with no fibrosis/mild fibrosis, ATI is a very promising tool for the noninvasive assessment of steatosis.

Drug-induced liver steatosis in patients with HIV infection.

Drug-induced liver injury (DILI) due to the use of prescription and non-prescription medication by HIV-positive and HIV-negative patients is one of the main causes of acute liver failure and transplantation in Western countries and, although rare, has to be considered a serious problem because of its unforeseeable nature and possibly fatal course. Drug-induced steatosis (DIS) and steatohepatitis (DISH) are infrequent but well-documented types of DILI. Although a number of commonly used drugs are associated with steatosis, it is not always easy to identify them as causative agents because of the weak temporal relationship between the administration of the drug and the clinical event, the lack of a confirmatory re-challenge, and the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population, which often makes it difficult to make a differential diagnosis of DIS and DISH. The scenario is even more complex in HIV-positive patients not only because of the underlying disease, but also because the various anti-retroviral regimens have different effects on liver steatosis. Given the high prevalence of liver steatosis in HIV-positive patients and the increasing use of drugs associated with a potential steatotic risk, the identification of clinical signs suggesting liver damage should help to avoid the possible misdiagnosis of "primary" NAFLD in a patient with DIS or DISH. This review will therefore initially concentrate on the current diagnostic criteria for DIS/DISH and their differential diagnosis from NAFLD. Subsequently, it will consider the different clinical manifestations of iatrogenic liver steatosis in detail, with specific reference to HIV-positive patients. Finally, the last part of the review will be dedicated to the possible effects of liver steatosis on the bioavailability of antiretroviral and other drugs.

Evaluation of Inter-System Variability in Liver Stiffness Measurements.

AIM: The primary aim of this study was to determine the inter-system variability of liver stiffness measurements (LSMs) in patients with varying degrees of liver stiffness. The secondary aim was to determine the inter-observer variability of measurements. MATERIALS AND METHODS: 21 individuals affected by chronic hepatitis C and 5 healthy individuals were prospectively enrolled. The assessment of LSMs was performed using six ultrasound (US) systems, four of which with point shear wave elastography (p-SWE) and two with 2 D shear wave elastography (2D-SWE) systems. The Fibroscan (Echosens, France) was used as the reference standard. Four observers performed the measurements in pairs (A-B, C-D). The agreement between different observers or methods was calculated using Lin's concordance correlation coefficient. The Bland-Altman limits of agreement (LOA) were calculated as well. RESULTS: There was agreement above 0.80 for all pairs of systems. The mean difference between the values of the systems with 2D-SWE technique was 1.54 kPa, whereas the maximum mean difference between the values of three out of four systems with the pSWE technique was 0.79 kPa. The intra-patient concordance for all systems was 0.89 (95 % CI: 0.83 - 0.94). Inter-observer agreement was 0.96 (95 % CI: 0.94 - 0.98) for the pair of observers A-B and 0.93 (95 % CI: 0.89 - 0.96) for the pair of observers C-D. CONCLUSION: The results of this study show that the agreement between LSMs performed with different US systems is good to excellent and the overall inter-observer agreement in "ideal conditions" is above 0.90 in expert hands.

Ultrasound and Cystic Echinococcosis.

The introduction of imaging techniques in clinical practice 40 years ago changed the clinical management of many diseases, including cystic echinococcosis (CE). For the first time cysts were clearly seen before surgery. Among the available imaging techniques, ultrasound (US) has unique properties that can be used to study and manage cystic echinococcosis. It is harmless, can image almost all organs and systems, can be repeated as often as required, is portable, requires no patient preparation, is relatively inexpensive and guides diagnosis, treatment and follow-up without radiation exposure and harm to the patient. US is the only imaging technique which can be used in field settings to assess CE prevalence because it can be run even on solar power or a small generator in remote field locations. Thanks to US classifications, the concept of stage-specific treatments was introduced and because US is repeatable, the scientific community has gained a clearer understanding of the natural history of the disease. This paper reviews the scope of US in CE, describes its strengths and weaknesses compared to other imaging techniques and its relationship with serodiagnosis and discusses sonographic features that may be helpful in differential diagnosis.

Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: An individual patient data-based meta-analysis.

Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of liver fibrosis in small to moderate-sized clinical trials. We aimed at running a larger-scale meta-analysis of individual data. Centers which have worked with Aixplorer ultrasound equipment were contacted to share their data. Retrospective statistical analysis used direct and paired receiver operating characteristic and area under the receiver operating characteristic curve (AUROC) analyses, accounting for random effects. Data on both 2D-SWE and liver biopsy were available for 1,134 patients from 13 sites, as well as on successful transient elastography in 665 patients. Most patients had chronic hepatitis C (n = 379), hepatitis B (n = 400), or nonalcoholic fatty liver disease (n = 156). AUROCs of 2D-SWE in patients with hepatitis C, hepatitis B, and nonalcoholic fatty liver disease were 86.3%, 90.6%, and 85.5% for diagnosing significant fibrosis and 92.9%, 95.5%, and 91.7% for diagnosing cirrhosis, respectively. The AUROC of 2D-SWE was 0.022-0.084 (95% confidence interval) larger than the AUROC of transient elastography for diagnosing significant fibrosis (P = 0.001) and 0.003-0.034 for diagnosing cirrhosis (P = 0.022) in all patients. This difference was strongest in hepatitis B patients. CONCLUSION: 2D-SWE has good to excellent performance for the noninvasive staging of liver fibrosis in patients with hepatitis B; further prospective studies are needed for head-to-head comparison between 2D-SWE and other imaging modalities to establish disease-specific appropriate cutoff points for assessment of fibrosis stage. (Hepatology 2018;67:260-272).