Von Willebrand factor processing in patients with advanced chronic liver disease and its relation to portal hypertension and clinical outcome

Background and aims: Endothelial dysfunction and portal hypertension (PH) are reflected by increased von Willebrand factor antigen (VWF-Ag) levels in advanced chronic liver disease (ACLD). This study investigated VWF release and cleavage and their association with PH and clinical outcomes.Methods: Levels of VWF-Ag, VWF-N (VWF-propeptide), and VWF-A (VWF processed by the main VWF-cleaving protease ADAMTS13) were assessed in 229 patients with clinically stable ACLD (hepatic venous pressure gradient [HVPG] ≥ 6 mmHg; absence of bacterial infections or acute decompensation) undergoing HVPG-measurement. Liver-healthy individuals served as controls (n = 24).Results: VWF-Ag and VWF-N were similarly accurate for the identification of clinically significant PH (CSPH; HVPG ≥ 10 mmHg) in compensated ACLD (AUROC: VWF-Ag 0.748; VWF-N 0.728). ADAMTS13 activity was similar between patients with ACLD and controls and did not correlate with PH and disease severity, whereas VWF cleavage decreased in patients with CSPH (i.e., VWF-Ag/-A-ratio increased). In vitro VWF activity strongly reflected VWF-Ag levels (Spearman’s r = 0.874, p &lt; 0.001), but decreased (vs. controls) in patients with CSPH when normalized to VWF-Ag levels (VWF-activity/-Ag-ratio). VWF-Act/-Ag ratio correlated negatively with ADAMTS13 activity (r =– 0.256, p &lt; 0.001). ADAMTS13 activity was independently predictive for (i) portal vein thrombosis (PVT) and (ii) hepatic decompensation or liver-related death.Conclusions: VWF-Ag levels and its propeptide are similarly suitable surrogates of PH in patients with compensated ACLD. ADAMTS13-Act was not linked to disease and PH severity, however, when normalized to VWF-Ag, both VWF cleavage and VWF activity were decreased in patients with CSPH, as compared to liver-healthy individuals. Low ADAMTS13-Act was associated with presumably more procoagulant VWF and adverse outcomes. Clinical trial number: NCT03267615.</p

Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD

Background & Aims: It has been suggested that the ratio of procoagulant factor VIII to anticoagulant protein C (FVIII/PC) reflects the hemostatic equilibrium. Moreover, FVIII/PC predicted decompensation/death in a small study not accounting for portal hypertension severity. We investigated (i) the prognostic value of FVIII/PC (outcome-cohort) and (ii) whether FVIII/PC reflects the hypercoagulable state (assessed by thrombomodulin-modified thrombin generation assay [TM-TGA]) or the risk of bleeding/thrombotic events in patients undergoing hepatic venous pressure gradient (HVPG) measurement during follow-up. Methods: (i) The outcome-cohort comprised 576 patients with evidence of advanced chronic liver disease (liver stiffness measurement ≥10 kPa and/or HVPG ≥6 mmHg). (ii) TM-TGA-cohort patients (n = 142) were recruited from the prospective VIenna CIrrhosis Study (VICIS: NCT03267615). Results: (i) FVIII/PC significantly increased across clinical stages (p <0.001) as well as HVPG (p <0.001) and MELD score (p <0.001) strata and remained independently associated with decompensation/liver-related death (adjusted hazard ratio 1.06; 95% CI 1.01–1.11; p = 0.013), even after multivariable adjustment. It was also associated with acute-on-chronic liver failure (ACLF) development (adjusted hazard ratio 1.10; 95% CI 1.02-1.19; p = 0.015) in patients with decompensated cirrhosis. (ii) FVIII/PC showed a weak positive correlation with endogenous thrombin potential (Spearman's ρ = 0.255; p = 0.002), but this association disappeared after adjusting for the severity of liver disease. FVIII/PC was not associated with the development of bleeding (p = 0.272) or thrombotic events (p = 0.269). However, FVIII/PC correlated with biomarkers of different pathophysiological mechanisms that promote liver disease progression. Conclusion: FVIII/PC provides prognostic information regarding hepatic decompensation/death and ACLF, independently of established prognostic indicators. However, this is not evidence that hypercoagulability drives disease progression, as the correlation between FVIII/PC and thrombin generation is confounded by liver disease severity and FVIII/PC was not associated with thrombosis. Therefore, FVIII/PC does not reflect coagulation and results from previous studies on FVIII/PC require re-interpretation. Clinical trial number: NCT03267615 (in part). Lay summary: A balanced coagulation system is essential for preventing bleeding episodes and blood clot formation (thrombosis). Blood of patients with advanced liver disease may have increased coagulation potential, possibly promoting the worsening of liver disease via thrombosis in the blood vessels of the liver. The ratio between the results of 2 blood tests (procoagulant factor VIII to anticoagulant protein C) has been suggested to reflect these increases in coagulation potential. Our study demonstrates, on the one hand, that this ratio is a versatile predictor of the development of complications of cirrhosis, yet on the other hand, that it is unrelated to coagulation

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination

Codoni G, Kirchner T, Engel B, Villamil AM, Efe C, Stättermayer AF, Weltzsch JP, Sebode M, Bernsmeier C, Lleo A, Gevers TJ, Kupčinskas L, Castiella A, Pinazo J, De Martin E, Bobis I, Sandahl TD, Pedica F, Invernizzi F, Del Poggio P, Bruns T, Kolev M, Semmo N, Bessone F, Giguet B, Poggi G, Ueno M, Jang H, Elpek GÖ, Soylu NK, Cerny A, Wedemeyer H, Vergani D, Mieli-Vergani G, Lucena MI, Andrade RJ, Zen Y, Taubert R, Beretta-Piccoli BT, Histological and serological features of acute liver injury after SARS-CoV-2 vaccination, JHEP Reports (2022), doi: https://doi.org/10.1016/j.jhepr.2022.100605.Liver injury with autoimmune features after vaccination against Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of patients with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features

Journal für Gastroenterologische und Hepatologische Erkrankungen / Autoimmunhepatitis : Klinik, Diagnostik, Therapie

Die Autoimmunhepatitis (AIH) ist eine seltene chronische entzündliche Lebererkrankung, die alle Altersgruppen betrifft und ohne adäquate Behandlung zum Leberversagen führen kann. Die frühzeitige Diagnose und Behandlung sind ausschlaggebend für die günstige Prognose der AIH. Allerdings kann die Diagnose durch das heterogene Spektrum klinischer, laborchemischer und histologischer Manifestationen erschwert sein. Erhöhte Transaminasen und Immunglobulin-G-Spiegel, positive Autoantikörper, charakteristische morphologische Veränderungen in der Leberhistologie und nicht zuletzt gutes Ansprechen auf eine immunsuppressive Behandlung zählen zu den wichtigsten diagnostischen Kriterien und sollten bei einem Verdacht evaluiert werden. Als Therapieziel sollte das Erreichen der kompletten klinischen, biochemischen und histologischen Remission angestrebt werden. Dies kann durch die immunsuppressive Therapie mit Kortikosteroiden und Azathioprin bei einem Großteil der Patienten erzielt werden. Aber auch wenn viele Patienten anfänglich auf eine immunsuppressive Standardtherapie ansprechen, stellen die Nebenwirkungen oder unzureichendes Therapieansprechen weiterhin eine Herausforderung in der Therapie der AIH dar. Dies unterstreicht die Notwendigkeit prospektiver Studien für effektive alternative Behandlungsmöglichkeiten.Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease that affects all age groups and, without adequate treatment, can lead to liver failure. Early diagnosis and treatment are crucial for a favorable prognosis of AIH. However, the diagnosis may be complicated by the heterogeneous spectrum of clinical, laboratory, and histological manifestations. Increased transaminases and immunoglobulin G levels, positive autoantibodies, characteristic morphological changes in liver histology, and finally, good response to immunosuppressive treatment are among the most important diagnostic criteria and should be evaluated if suspected. The goal of therapy should be to achieve complete clinical, biochemical and histologic response. This can be achieved by immunosuppressive therapy with corticosteroids and azathioprine in most of the patients. However, while many patients initially respond well to standard immunosuppressive therapy, side effects or inadequate treatment response continue to be a challenge in the treatment of AIH. This underscores the need for prospective studies for effective alternative treatment.(VLID)358453

European Journal of Clinical Investigation / The dilemma to diagnose Wilson disease by genetic testing alone

Background Wilson disease (WD) is an autosomal recessive disorder of hepatic copper excretion. About sixty per cent of patients present with liver disease. WD is considered a fatal disease if undiagnosed and/or untreated but recent data indicate that disease penetrance may not be 100%. Materials and Methods All patients underwent liver biopsy as part of the diagnostic workup. Genetic testing for ATP7B was performed by Sanger sequencing. Results We report on a large family with multiple affected siblings. The first patient (male, 31 years) underwent orthotopic liver transplantation (OLT) because of fulminant WD. He was homozygous for p.G710A. One asymptomatic brother (37 years) had the same mutation. He is doing well on chelation therapy. Fifteen years later, a seconddegree sibling (female, 16 years) presented with fulminant WD and underwent OLT. She was compound heterozygote (p.G710A/p.G710S). Further family screening revealed a third mutation (p.V536A) in a female (21 years) and male (16 years) compoundheterozygote sibling (p.G710A/p.V536A). In both, serum ceruloplasmin and 24hour urinary copper excretion were normal. Liver biopsy showed normal histology and a quantitative hepatic copper content within the normal range or only slightly elevated (19 and 75 g/g dry weight, respectively). No decoppering treatment was initiated so far. Conclusion Genetic testing alone is not always sufficient to diagnose WD in asymptomatic patients, and human mutation databases should be used with caution. Even patients carrying two diseasecausing mutations do not necessarily have demonstrable alteration of copper metabolism. Asymptomatic siblings diagnosed by genetic screening require further testing before initiating treatment.(VLID)510163