Prospective evaluation of liver shearwave elastography measurements with 3 different technologies and same day liver biopsy in patients with chronic liver disease.

BACKGROUND: Most ultrasound-based methods for assessing liver fibrosis still need further validation with liver biopsy used as gold standard to assess their accuracy. AIMS: To assess accuracy of three shear wave elastography (SWE) methods: 1) Philips Elast Point Quantification (ElastPQTM), 2) Siemens Virtual TouchTM Quantification (VTQ) acoustic radiation force impulse (ARFI), and 3) transient elastography (TE) measured by Echosens FibroscanTM. METHODS: 160 patients underwent liver stiffness measurements (LSM) with three SWE methods immediately prior to liver biopsy. RESULTS: The number of LSM required for reliable studies could be reduced to 6 for ElastPQ and to 7 for VTQ from standard recommendations of 10. Significant fibrosis and interquartile range/median (IQR/M)> 30 were independent predictors for lower reliability for detection of liver fibrosis. Ordinal logistic regression corrected for age showed that there was a significant interaction between steatosis (p = 0.008) and lobular inflammation (p = 0.04) and VTQ (ARFI) and between lobular inflammation and TE (p = 0.006). CONCLUSIONS: We showed variations in SWE measurements using different ARFI technologies. TE and ElastPQ achieved good diagnostic performance, whereas VTQ showed lower diagnostic accuracy. The number of measurements required for reliable studies can be reduced to 6 for ElastPQ and to 7 for VTQ, which have important clinical implications.

The Accuracy of Ultrasound Controlled Attenuation Parameter in Diagnosing Hepatic Fat Content.

Purpose: The Controlled Attenuation Parameter (CAP score) is based on ultrasonic properties of retropropagated radiofrequency signals acquired by FibroscanTM (Echosens, Paris, France). Since ultrasound propagation is influenced by the presence of fat, CAP score was developed to quantify steatosis. The aim of this study was to delineate the accuracy of CAP in diagnosing hepatic steatosis, compared to the gold standard of liver biopsy. Patients and Methods: A total of 150 patients underwent same-day liver biopsy and measurement of hepatic steatosis with Fibroscan. Only examinations with 10 satisfactory measurements, and an inter-quartile range of less than 30% of the median liver stiffness values were included for data analysis. Histological staging was then correlated with median values and Spearman correlation calculated. P values of <0.05 were considered statistically significant. Results: For diagnosis of hepatic steatosis (HS), CAP could predict the steatosis S2 with AUROC 0.815 (95% CI 0.741-0.889), sensitivity (0.81) and specificity (0.73) when the optimal cut-off value was set at 288 dB/m. CAP detected histological grade S3 with AUROC 0.735 (95% CI 0.618-0.851), sensitivity (0.71) and specificity (0.74), with a cut-off value of 330 dB/m. The AUROC for steatosis grade S1 was 0.741 (95% CI 0.650-0.824), with a cut-off value of 263 dB/m with sensitivity 0.75 and specificity 0.70. Univariate analysis showed a correlation between CAP and diabetes (p 0.048). Conclusion: The performance of CAP to diagnose steatosis severity decreases as steatosis progresses. CAP is associated with diabetes but not other clinical factors and parameters of the metabolic syndrome.

Acute Antibody-mediated rejection in liver transplantation: Impact and applicability of the Banff working group on liver allograft pathology 2016 criteria.

This study was aimed to examine the clinical utility and impact of the 2016 Banff criteria for acute antibody-mediated rejection (acute AMR) in patients with liver transplantation. Among adult patients with donor-specific antibody (DSA) assays performed between 2015 and 2020, cases with proved DSA (mean fluorescent index >2000) and matched liver biopsy available were reviewed. Among 55 patients identified, 28 (51%) had class I DSA, 45 (82%) had class II DSA and 18 (33%) had both. Mild, moderate and severe microvasculitis were observed in 11 (20%), 2 (4%) and 1 (2%) case, respectively. Diffuse immunoreactivity to C4d on portal microvascular endothelia was confirmed in 5 cases (9%), which met the criteria of definite (n = 2) or suspicious for acute AMR (n = 3). Cases of acute AMR more commonly had class I DSA (100% vs. 46%; p = 0.027) or both class I and II DSA (80% vs. 28%; p = 0.018) than cases of non-acute AMR. One case of pure acute AMR with veno-occlusion was successfully treated with plasma exchange. The remaining 4 cases had features of combined acute AMR/T cell-mediated rejection (TCMR), and two progressed to ductopenic rejection within 3 weeks. In conclusion, only 9% of DSA-positive patients met the Banff criteria for acute AMR, necessitating careful morphological and immunohistochemical assessments of the allograft biopsies according to the proposed standards. Combined acute AMR/TCMR was more common than isolated acute AMR, and additional AMR in TCMR cases may be associated with rapid progression to ductopenic rejection.

Recent advances in liver transplantation.

Liver transplant is a life-saving treatment with 1-year and 5-year survival rates of 90% and 70%, respectively. However, organ demand continues to exceed supply, such that many patients will die waiting for an available organ. This article reviews for the general gastroenterologist the latest developments in the field to reduce waiting list mortality and maximise utilisation of available organs. The main areas covered include legislative changes in organ donation and the new 'opt-out' systems being rolled out in the UK, normothermic machine perfusion to optimise marginal grafts, a new national allocation system to maximise benefit from each organ and developments in patient 'prehabilitation' before listing. Current areas of research interest, such as immunosuppression withdrawal, are also summarised.

Guideline review: British Society of Gastroenterology/UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.

New British Society of Gastroenterology/UK-PSC guidelines have recently discussed the current state-of-the-art on primary sclerosing cholangitis and outlined key elements for the management of this disease. The current lack of effective pharmacological treatments to prevent progression of liver fibrosis to cirrhosis limits our ability to modify the natural history of the disease. However, a personalised approach and structured follow-up could allow earlier diagnosis and management of complications and favour access to liver transplantation, which remains the only available treatment. Our commentary overviews the updates and summarises the key recommendations of the recent guidelines for the management of primary sclerosing cholangitis.

Increased Body Mass Index and Type 2 Diabetes Are the Main Predictors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in Liver Biopsies of Patients With Human Immunodeficiency Virus Monoinfection.

BACKGROUND: Liver disease is an important cause of morbidity and mortality in people living with human immunodeficiency virus (PLWH), of which nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause. There are limited data investigating NAFLD in HIV monoinfection and histologically defined disease. We aimed to identify who is at risk of fibrosis, NAFLD, and nonalcoholic steatohepatitis (NASH) among PLWH and explore the diagnostic accuracy of noninvasive markers of fibrosis. METHODS: This was a retrospective, cross-sectional, international, multicenter study including patients with HIV monoinfection, without chronic viral hepatitis or other known causes of chronic liver disease, who underwent liver biopsy for abnormal liver biochemistry and/or clinical suspicion of liver fibrosis. RESULTS: A total of 116 patients from 5 centers were included. Sixty-three (54%) had NAFLD, of whom 57 (92%) had NASH. Overall, 36 (31%) had advanced fibrosis (≥F3) and 3 (3%) had cirrhosis. Of the 53 cases without NAFLD, 15 (28%) had advanced fibrosis. Collagen proportionate area was similar between cases with and without NAFLD (3% vs 2%). Body mass index was independently associated with NAFLD (aOR, 1.2; 95% CI, 1.08-1.34), and type 2 diabetes was independently associated with advanced fibrosis (aOR, 3.42; 95% CI, 1.00-11.71). The area under the curve for advanced fibrosis was 0.65 and 0.66 for both NAFLD Fibrosis Score (NFS) and FIB-4. Cutoff values of -1.455 (NFS) and 1.3 (FIB-4) have negative-predictive values of 0.80 and 0.82, respectively. CONCLUSIONS: Advanced fibrosis is strongly associated with type 2 diabetes in PLWH. Serological markers require further optimization.

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need.

In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies.

High-Throughput, Machine Learning-Based Quantification of Steatosis, Inflammation, Ballooning, and Fibrosis in Biopsies From Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Liver biopsy is the reference standard for staging and grading nonalcoholic fatty liver disease (NAFLD), but histologic scoring systems are semiquantitative with marked interobserver and intraobserver variation. We used machine learning to develop fully automated software for quantification of steatosis, inflammation, ballooning, and fibrosis in biopsy specimens from patients with NAFLD and validated the technology in a separate group of patients. METHODS: We collected data from 246 consecutive patients with biopsy-proven NAFLD and followed up in London from January 2010 through December 2016. Biopsy specimens from the first 100 patients were used to derive the algorithm and biopsy specimens from the following 146 were used to validate it. Biopsy specimens were scored independently by pathologists using the Nonalcoholic Steatohepatitis Clinical Research Network criteria and digitalized. Areas of steatosis, inflammation, ballooning, and fibrosis were annotated on biopsy specimens by 2 hepatobiliary histopathologists to facilitate machine learning. Images of biopsies from the derivation and validation sets then were analyzed by the algorithm to compute percentages of fat, inflammation, ballooning, and fibrosis, as well as the collagen proportionate area, and compared with findings from pathologists' manual annotations and conventional scoring systems. RESULTS: In the derivation group, results from manual annotation and the software had an interclass correlation coefficient (ICC) of 0.97 for steatosis (95% CI, 0.95-0.99; P < .001); ICC of 0.96 for inflammation (95% CI, 0.9-0.98; P < .001); ICC of 0.94 for ballooning (95% CI, 0.87-0.98; P < .001); and ICC of 0.92 for fibrosis (95% CI, 0.88-0.96; P = .001). Percentages of fat, inflammation, ballooning, and the collagen proportionate area from the derivation group were confirmed in the validation cohort. The software identified histologic features of NAFLD with levels of interobserver and intraobserver agreement ranging from 0.95 to 0.99; this value was higher than that of semiquantitative scoring systems, which ranged from 0.58 to 0.88. In a subgroup of paired liver biopsy specimens, quantitative analysis was more sensitive in detecting differences compared with the nonalcoholic steatohepatitis Clinical Research Network scoring system. CONCLUSIONS: We used machine learning to develop software to rapidly and objectively analyze liver biopsy specimens for histologic features of NAFLD. The results from the software correlate with those from histopathologists, with high levels of interobserver and intraobserver agreement. Findings were validated in a separate group of patients. This tool might be used for objective assessment of response to therapy for NAFLD in practice and clinical trials.

Prediction of Esophageal Varices by Liver Stiffness and Platelets in Persons With Human Immunodeficiency Virus Infection and Compensated Advanced Chronic Liver Disease.

BACKGROUND: People living with human immunodeficiency virus (PLWH) are at increased risk of cirrhosis and esophageal varices. Baveno VI criteria, based on liver stiffness measurement (LSM) and platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for esophageal varices needing treatment (EVNT). This approach has not been validated in PLWH. METHODS: PLWH from 8 prospective cohorts were included if they fulfilled the following criteria: (1) compensated advanced chronic liver disease (LSM >10 kPa); (2) availability of EGD within 6 months of reliable LSM. Baveno VI (LSM <20 kPa and platelets >150 000/µL), expanded Baveno VI (LSM <25 kPa and platelets >110 000/µL), and Estudio de las Hepatitis Víricas (HEPAVIR) criteria (LSM <21 kPa) were applied to identify patients not requiring EGD screening. Criteria optimization was based on the percentage of EGDs spared, while keeping the risk of missing EVNT <5%. RESULTS: Five hundred seven PLWH were divided into a training (n = 318) and a validation set (n = 189). EVNT were found in 7.5%. In the training set, Baveno VI, expanded Baveno VI, and HEPAVIR criteria spared 10.1%, 25.5%, and 28% of EGDs, while missing 0%, 1.2%, and 2.2% of EVNT, respectively. The best thresholds to rule out EVNT were platelets >110 000/µL and LSM <30 kPa (HIV cirrhosis criteria), with 34.6% of EGDs spared and 0% EVNT missed. In the validation set, HEPAVIR and HIV cirrhosis criteria spared 54% and 48.7% of EGDs, while missing 4.9% and 2.2% EVNT, respectively. CONCLUSIONS: Baveno VI criteria can be extended to HEPAVIR and HIV cirrhosis criteria while sparing a significant number of EGDs, thus improving resource utilization for PLWH with compensated advanced chronic liver disease.

Spleen stiffness measurements using point shear wave elastography detects noncirrhotic portal hypertension in human immunodeficiency virus.

To assess the utility of spleen stiffness as a diagnostic tool in individuals with human immunodeficiency virus (HIV) and non-cirrhotic portal hypertension (NCPH).The Philips EPIQ7, a new point shearwave elastography (pSWE) technique, was used to assess liver and spleen stiffness in 3 patient groups. Group 1: HIV and NCPH (n = 11); Group 2: HIV with past didanosine (ddI) exposure without known liver disease or NCPH (n = 5); Group 3: HIV without known liver disease or ddI exposure (n = 9).Groups were matched for age, HIV chronicity, and antiretroviral treatment (including cumulative ddI exposure in Groups 1 and 2). Differences in liver and spleen stiffness (in kPa) between groups were analyzed using the Mann-Whiney U test.Liver and spleen stiffness were both significantly higher in NCPH versus ddI-exposed (P = .019 and P = .006) and ddI-unexposed controls (P = .038 and P < .001). Spleen stiffness was more effective than liver stiffness at predicting NCPH, area under receiver operating characteristic (AUROC) 0.812 versus 0.948. Combining the 2 variables improved the diagnostic performance, AUROC 0.961. The optimal cut-off for predicting NCPH using splenic stiffness was 25.4 kPa, with sensitivity 91%, specificity 93%, positive predictive value (PPV) 91%, negative predictive value (NPV) 93%, positive likelihood ratio 12.73, negative likelihood ratio 0.10. Spleen and liver stiffness scores were strongly correlated (P = .0004, 95% confidence interval [CI] 18, 59).Elevated spleen stiffness is observed in HIV with NCPH and can be quantified easily using pSWE with high diagnostic accuracy. Novel strategies such as pSWE for longitudinal monitoring of patients with HIV and NCPH should be considered.

Precision medicine in primary sclerosing cholangitis.

Primary sclerosing cholangitis is a rare, complex autoimmune disease in relatively young patients. There is currently no treatment for the disease, resulting in high rates of advanced liver disease leading to death or liver transplantation. However, advances have been made in our understanding of the pathophysiological mechanisms of the disease, particularly from breakthroughs in the underlying genetics. Moreover, large international collaborations have generated important clinical data that have given greater detail on the different disease phenotypes and natural history, generating new risk prediction models. As a result, drug development may be designed to target specific disease mechanisms at known points of the disease natural history. Therefore, more drugs are entering phase II and III development, giving hope that soon patient-specific treatments may be available to treat this difficult disease.

Monocyte-macrophage activation is associated with nonalcoholic fatty liver disease and liver fibrosis in HIV monoinfection independently of the gut microbiome and bacterial translocation.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common among people living with HIV. There are limited data available on the pathophysiology of NAFLD and the development of fibrosis in this population. OBJECTIVES: The aim of this study was to investigate the association of bacterial translocation, adipose tissue dysfunction, monocyte activation and gut dysbiosis in patients with HIV monoinfection and NAFLD. METHODS: Cases with biopsy-proven NAFLD and HIV monoinfection were age and sex-matched to HIV-positive and HIV-negative controls. Markers of bacterial translocation [lipopolysaccharide-binding protein (LBP), bacterial DNA and lipopolysaccharide (LPS)], adipose tissue dysfunction (leptin, adiponectin) and monocyte activation (sCD14 and sCD163) were measured by ELISA. Hepatic patterns of macrophage activation were explored with immunohistochemistry. 16 s rRNA sequencing was performed with stool. RESULTS: Thirty-three cases were included (≥F2 fibrosis n = 16), matched to HIV-positive (n = 29) and HIV-negative (n = 17) controls. Cases with NAFLD were more obese (BMI 31.0 ±â€Š4.4 vs. 24.1 ±â€Š2.8 kg/m, P < 0.001) and had significantly increased levels of sCD14, sCD163 and higher leptin to adiponectin ratio vs. HIV-positive controls. Cases with ≥F2 verses < F2 fibrosis had increased sCD14 (1.4 ±â€Š0.4 vs. 1.1 ±â€Š0.3 µg/ml, P = 0.023) and sCD163 (1.0 ±â€Š0.3 vs. 0.8 ±â€Š0.3 µg/ml, P = 0.060), which correlated with waist circumference (sCD14 P = 0.022, sCD163 P = 0.011). Immunohistochemistry showed increased hepatic portal macrophage clusters in patients with fibrosis. No markers of bacterial translocation or changes to the microbiome were associated with NAFLD or fibrosis. CONCLUSION: NAFLD fibrosis stage in HIV monoinfected patients is associated with monocyte activation in the context of obesity, which may be independent of bacterial translocation and gut microbiome.