HepQuant SHUNT Detects Portal Hypertension in Early Stages of Clinically Compensated Chronic Liver Disease

Wieland, Amanda; Etzion, Ohad; Ali, Rabab; Levy, Elliot; Kleiner, David E.; Helmke, Steve M.; Heller, Theo; Everson, Gregory T.

doi:10.1016/j.cgh.2021.04.030

Cited by 15 publications

(12 citation statements)

References 8 publications

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“…Noninvasive fibrous diagnoses are evolving rapidly. [79][80][81][82] The broad classes of noninvasive assessment tools include (1) serum assays, using either standard laboratory tests (e.g., Fibrosis-4), proprietary assays for matrix components (e.g., enhanced liver fibrosis, [83] N-terminal type III collagen propeptide [ProC3]/ProC5), proteomics, [84] lipidomics, [85] microRNAs, [86,87] and components of the microbiome [88] ; (2) imaging tests (CT, MRI, or positron emission tomography) that can quantify liver fat, inflammation, fibrosis, as well as liver stiffness as a surrogate for matrix content (reviewed in Besutti et al [89] and Ajmena and Loomba [90] )-techniques for image collagen content directly using collagen-specific probes are also under development [91] -(3) microbiome assessment because the pattern and diversity of the microbiome evolve with disease progression for bacteria, viruses, and fungi [92][93][94][95] ; and (4) functional tests, which measure either intrahepatic shunting, [96] microsomal activity, [97,98] or proteolytic activity in either liver or circulation. [99] Despite the substantial progress and significant investment in developing noninvasive markers of hepatic fibrosis, none has yet been able to supplant biopsy.…”

Section: Noninvasi Ve Assessment Of Hepatic Fibrosismentioning

confidence: 99%

Hepatic fibrosis 2022: Unmet needs and a blueprint for the future

2022

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Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease.Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.

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Section: Noninvasi Ve Assessment Of Hepatic Fibrosismentioning

confidence: 99%

Hepatic fibrosis 2022: Unmet needs and a blueprint for the future

2022

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“… 26 This test is also capable of the early, noninvasive detection of PH, with a reliability similar to that of HVPG. 27 However, while HVPG remains the gold standard method for assessing PH, and its use is encouraged in clinical trials, it is invasive and requires considerable resources and expertise. 28 Therefore, HepQuant SHUNT and other noninvasive biomarkers (eg, spleen stiffness measurements 28 ) may complement HVPG in the short term and perhaps replace it in the future.…”

Section: Discussionmentioning

confidence: 99%

Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study

Lawitz,

Reiberger,

Schattenberg

et al. 2023

Hepatology Communications

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Background: Portal hypertension is a severe complication of cirrhosis. This Phase Ib study (NCT03842761) assessed the safety, tolerability, and pharmacokinetics of soluble guanylyl cyclase activator BI 685509 in patients with mild or moderate hepatic impairment (Child–Pugh [CP] A or B cirrhosis) and healthy volunteers (HVs). Methods: In this single-center, randomized, placebo-controlled study, patients received BI 685509 (maximum doses: 1, 2, or 3 mg, twice daily [BID]) or placebo for 28 days. HVs received one 0.5 mg dose of BI 685509 or placebo. Results: In total, 64 participants (CP-A, n=24; CP-B, n=25; HVs, n=15) were included; most commonly with NAFLD (36.7%), alcohol-associated (30.6%), or chronic viral hepatitis-related cirrhosis (28.6%). In patients with CP-A cirrhosis, drug-related adverse events (AEs) occurred in 5.6% of BI 685509-treated patients and 16.7% of placebo recipients. In patients with CP-B cirrhosis, drug-related AEs occurred in 26.3% of BI 685509-treated patients only. No serious AEs occurred in patients with CP-A cirrhosis; in patients with CP-B cirrhosis, serious AEs (not drug-related) occurred in 10.5% of BI 685509-treated patients and 16.7% of patients receiving placebo. BI 685509 was rapidly absorbed; exposure increased with dosage and was similar between etiologies and between patients with CP-A cirrhosis and patients with CP-A cirrhosis but lower in HVs. The mean percentage portal–systemic shunt fraction was measured in patients with CP-A cirrhosis and decreased at the end of treatment in the 2 mg BID (–11.2 ± 11.9%) and 3 mg BID (–14.0 ± 8.4%) BI 685509 dose groups, but not in the placebo group (+1.0 ± 27.3%). Conclusion: BI 685509 was generally well tolerated, with 3 serious, not drug-related AEs reported in patients with CP-B cirrhosis. In patients with CP-A cirrhosis, portal–systemic shunt fraction in the exploratory efficacy analysis was reduced by 2 mg BID and 3 mg BID BI 685509.

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“…The more recent HepQuant SHUNT trial has used double clearance of cholates after oral and intravenous administration to quantify hepatic perfusion without the effects of total plasma volume. A study ( 29 ) of early clinical compensatory chronic liver disease in 42 patients found that patients with portal hypertension had lower portal hepatic filtration rates and higher portal-systemic spillover of oral d4-cholate percentage (SHUNT%), which presented the increasing portal-systemic flow and the decreasing intrahepatic flow. When evaluated CSPH, using HVPG > 10 mmHg or direct portal pressure (dPP) > 22 mmHg as gold standards, the sensitivity and specificity of SHUNT% > 0.35 was 76.9 and 89.6%, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The injury of liver parenchyma was the feature of liver fibrosis, related liver function indices including single platelet count (PLT), aspartate aminotransferase to alanine aminotransferase (AAR) ratio, aspartate aminotransferase to platelet count ratio index (APRI), fibrosis index based on 4 factors (FIB-4 consists of PLT, AST, ALT, and age), glutamyl transpeptidase to platelet (GPR), King's score (consists of Age, AST, INR, and PLT), Lok score (consists of PLT, AST, ALT, and INR), and the CSPH risk score (consists of ALB, INR, and ALT) have been validated to evaluate PH. Using HVPG ≥ 10 mmHg as the golden standard, the area under the receiver operating characteristic curve (AUROC) of the above indices to diagnose CSPH was 0.6-0.8 and hardly exceeds 0.8 (27)(28)(29).…”

Section: Blood Test the Indicators Of Liver Functionmentioning

confidence: 99%