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Li X, Wu M, Chen M, Liu R, Tao Q, Hu Y, Yu J, Chen D. The Association Between Neutrophil-Percentage-to-Albumin Ratio (NPAR) and Mortality Among Individuals With Cancer: Insights From National Health and Nutrition Examination Survey. Cancer Med 2025; 14:e70527. [PMID: 39831739 PMCID: PMC11744675 DOI: 10.1002/cam4.70527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 11/27/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Neutrophils interact with tumor cells, potentially exacerbating cancer progression. Additionally, decreased albumin levels are a marker of poor cancer prognosis. The neutrophil-percentage-to-albumin ratio (NPAR) has been used for prognostic assessment in non-cancerous diseases, but its relationship with mortality risk in cancer patients has not been explored. Therefore, we utilized data from the National Health and Nutrition Examination Survey (NHANES) to investigate the correlation between NPAR and the risks of all-cause mortality and cancer-related mortality among cancer patients. METHODS This study leveraged comprehensive NHANES data spanning 2005-2016. We analyzed the relationship between NPAR and the risks of cancer incidence, all-cause mortality, and cancer-related mortality using weighted Logistic and Cox regression models, as well as trend tests. Restricted cubic spline analysis was employed to investigate NPAR's nonlinear relationship with mortality risk. Furthermore, Kaplan-Meier survival analysis was utilized to assess patient prognoses across varying NPAR levels. RESULTS Elevated NPAR was associated with an increased risk of all-cause mortality and cancer-related mortality in cancer patients (p < 0.05), with higher NPAR values correlating with greater risk (p-trend < 0.05). However, no significant association between NPAR and cancer incidence was observed (p > 0.05). Our analysis further identified a non-linear relationship between NPAR and all-cause mortality risk (p-nonlinear < 0.05), while no non-linear relationship was found with cancer-related mortality risk. The relationship is characterized by an optimal NPAR value, correlating with the lowest hazard ratio (HR). Deviations from this optimal NPAR result in increased all-cause mortality risk (p < 0.05). Kaplan-Meier analysis indicated superior survival rates in patients with lower NPAR values compared to those with higher NPAR values (p < 0.05). CONCLUSIONS According to our study, higher NPAR was associated with an increased risk of all-cause mortality and cancer-related mortality in cancer patients.
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Affiliation(s)
- Xinyang Li
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Meng Wu
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Minxin Chen
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Rufei Liu
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Qingxu Tao
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Yun Hu
- Department of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Jinming Yu
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Dawei Chen
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
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Erstad BL. Introduction to the concept of effective albumin concentration. Am J Health Syst Pharm 2024; 82:5-11. [PMID: 39135412 DOI: 10.1093/ajhp/zxae232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024] Open
Abstract
PURPOSE The purpose of this article is to discuss how the structural and presumably functional integrity of albumin, as described by the concept of effective albumin concentration (eAlb), has potentially important clinical implications beyond the total albumin concentration (tAlb) routinely reported by clinical laboratories. SUMMARY Albumin has several functions beyond its oncotic effects, including molecule binding, substance transport, detoxification actions, and serving as an antioxidant. However, there are conformational changes that occur during or following the manufacture of albumin and during its administration to patients with various disease states, such as decompensated liver disease, that often impair these functions. Such impairments are not reflected in tAlb values reported by clinical laboratories and might explain the disconnect often seen between albumin's proposed beneficial mechanistic functions and its less-than-predicted clinical effectiveness as noted in published studies. The concept of eAlb has been introduced to describe albumin with structural and functional integrity. Limited studies have found associations between eAlb values and patient prognostic indicators, but the techniques used to decide these effective concentrations to date are complicated and require specialized equipment and experienced researchers for proper interpretation. CONCLUSION Estimation of eAlb may provide valuable information on the functional ability of albumin beyond the tAlb reported by clinical laboratories, but more research is needed to decide how this information is best used in the clinical setting.
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Affiliation(s)
- Brian L Erstad
- Department of Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA
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Rodríguez-Negrete EV, Gálvez-Martínez M, Sánchez-Reyes K, Fajardo-Felix CF, Pérez-Reséndiz KE, Madrigal-Santillán EO, Morales-González Á, Morales-González JA. Liver Cirrhosis: The Immunocompromised State. J Clin Med 2024; 13:5582. [PMID: 39337069 PMCID: PMC11432654 DOI: 10.3390/jcm13185582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Systemic inflammation and immunodeficiency are important components of cirrhosis-associated immune dysfunction (CAID), the severity of which is dynamic, progressive, and associated with the greater deterioration of liver function. Two inflammation phenotypes have been described: low-grade and high-grade systemic inflammation. Both of these phenotypes are related to liver cirrhosis function; thus, high-grade inflammation is correlated with the severity of hepatic insufficiency, bacterial translocation, and organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation (BT) plays a relevant role in persistent systemic inflammation in patients with cirrhosis, and the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.
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Affiliation(s)
- Elda Victoria Rodríguez-Negrete
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Marisol Gálvez-Martínez
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karina Sánchez-Reyes
- Servicio de Cirugía General, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico;
| | - Carlos Fernando Fajardo-Felix
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karla Erika Pérez-Reséndiz
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | | | - Ángel Morales-González
- Escuela Superior de Cómputo, Instituto Politécnico Nacional, Unidad Profesional “A. López Mateos”, Ciudad de México 07738, Mexico
| | - José Antonio Morales-González
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
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Alukal JJ, Li F, Thuluvath PJ. Older Patients With Acute on Chronic Liver Failure Have a Higher Waitlist Mortality, but Acceptable Post Liver Transplantation Survival When Compared to Younger Patients. Clin Gastroenterol Hepatol 2024; 22:1014-1023.e6. [PMID: 38072285 DOI: 10.1016/j.cgh.2023.11.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 11/19/2023] [Accepted: 11/27/2023] [Indexed: 01/17/2024]
Abstract
BACKGROUND & AIMS There is a paucity of studies on older patients (≥65 years) who develop acute on chronic liver failure (ACLF). The objectives of our study were to determine clinical characteristics and outcomes of older patients listed for liver transplantation (LT). METHODS Adults listed for LT with estimated ACLF (Est-ACLF) between 2005 and 2021 were identified using the United Network for Organ Sharing database and subdivided into older and younger age (18-64 years) groups. Kaplan-Meier survival analyses were used to evaluate survival, and a competing-risk model (Fine-Gray) was used to evaluate risk factors for survival on the waitlist. Logistic regression was done to evaluate risk factors. RESULTS A total of 4313 older (14%) and 26,628 younger (86%) patients were listed for LT, and 2142 (49.6%) and 16,931 (63.5%) were transplanted, respectively. Older patients had a higher 30-day waitlist mortality than younger patients (20.4% vs 16.7%; P < .0001); this was more pronounced in Est-ACLF-2 (23.7% vs 14.8%; P < .0001) and Est-ACLF-3 (43.3% vs 29.9%; P < .0001). One-year post-LT, patient survival in older patients with Est-ACLF grades 1, 2, and 3 were 86.4%, 85.5%, and 77% respectively; younger patients had better survival across all Est-ACLF grades. When adjusted for transplant eras, respiratory failure was the only independent risk factor for increased 1-year post-LT mortality in older patients. CONCLUSION Older patients with Est-CLF had significantly higher waitlist mortality than younger patients, but had acceptable 1-year post-LT survival including those with Est-ACLF-3; therefore, age alone should not be considered as a contraindication for LT. Older patients with respiratory failure should be carefully selected for LT.
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Affiliation(s)
- Joseph J Alukal
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, Maryland; Department of Medicine, University of California Riverside School of Medicine, Riverside, California
| | - Feng Li
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, Maryland
| | - Paul J Thuluvath
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, Maryland; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
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Anouti A, Al Hariri M, VanWagner LB, Lee WM, Mufti A, Pedersen M, Shah J, Hanish S, Vagefi PA, Cotter TG, Patel MS. Early Graft Failure After Living-Donor Liver Transplant. Dig Dis Sci 2024; 69:1488-1495. [PMID: 38381224 DOI: 10.1007/s10620-024-08280-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 01/04/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Living-donor liver transplantation (LDLT) has been increasing in the USA. While data exist on longer-term patient and graft outcomes, a contemporary analysis of short-term outcomes is needed. AIM Evaluate short-term (30-day) graft failure rates and identify predictors associated with these outcomes. METHODS Adult (≥ 18) LDLT recipients from 01/2004 to 12/2021 were analyzed from the United States Scientific Registry of Transplant Recipients. Graft status at 30 days was assessed with graft failure defined as retransplantation or death. Comparison of continuous and categorical variables was performed and a multivariable logistic regression was used to identify risk factors of early graft failure. RESULTS During the study period, 4544 LDLTs were performed with a graft failure rate of 3.4% (155) at 30 days. Grafts from male donors (aOR: 0.63, CI 0.44-0.89), right lobe grafts (aOR: 0.40, CI 0.27-0.61), recipients aged > 60 years (aOR: 0.52, CI 0.32-0.86), and higher recipient albumin (aOR: 0.73, CI 0.57-0.93) were associated with superior early graft outcomes, whereas Asian recipient race (vs. White; aOR: 3.75, CI 1.98-7.10) and a history of recipient PVT (aOR: 2.7, CI 1.52-4.78) were associated with inferior outcomes. LDLTs performed during the most recent 2016-2021 period (compared to 2004-2009 and 2010-2015) resulted in significantly superior outcomes (aOR: 0.45, p < 0.001). CONCLUSION Our study demonstrates that while short-term adult LDLT graft failure is uncommon, there are opportunities for optimizing outcomes by prioritizing right lobe donation, improving candidate nutritional status, and careful pre-transplant risk assessment of candidates with known PVT. Notably, a period effect exists whereby increased LDLT experience in the most recent era correlated with improved outcomes.
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Affiliation(s)
- Ahmad Anouti
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Lisa B VanWagner
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Arjmand Mufti
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Mark Pedersen
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jigesh Shah
- Department of Surgery, UT Southwestern Medical Center, 5959 Harry Hines Blvd, HP04.102, Dallas, TX, 75390, USA
| | - Steven Hanish
- Department of Surgery, UT Southwestern Medical Center, 5959 Harry Hines Blvd, HP04.102, Dallas, TX, 75390, USA
| | - Parsia A Vagefi
- Department of Surgery, UT Southwestern Medical Center, 5959 Harry Hines Blvd, HP04.102, Dallas, TX, 75390, USA
| | - Thomas G Cotter
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Madhukar S Patel
- Department of Surgery, UT Southwestern Medical Center, 5959 Harry Hines Blvd, HP04.102, Dallas, TX, 75390, USA.
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Heybe MA, Mehta KJ. Role of albumin infusion in cirrhosis-associated complications. Clin Exp Med 2024; 24:58. [PMID: 38551716 PMCID: PMC10980629 DOI: 10.1007/s10238-024-01315-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 02/29/2024] [Indexed: 04/01/2024]
Abstract
Cirrhosis is an advanced-stage liver disease that occurs due to persistent physiological insults such as excessive alcohol consumption, infections, or toxicity. It is characterised by scar tissue formation, portal hypertension, and ascites (accumulation of fluid in the abdominal cavity) in decompensated cirrhosis. This review evaluates how albumin infusion ameliorates cirrhosis-associated complications. Since albumin is an oncotic plasma protein, albumin infusion allows movement of water into the intravascular space, aids with fluid resuscitation, and thereby contributes to resolving cirrhosis-induced hypovolemia (loss of extracellular fluid) seen in ascites. Thus, albumin infusion helps prevent paracentesis-induced circulatory dysfunction, a complication that occurs when treating ascites. When cirrhosis advances, other complications such as spontaneous bacterial peritonitis and hepatorenal syndrome can manifest. Infused albumin helps mitigate these by exhibiting plasma expansion, antioxidant, and anti-inflammatory functions. In hepatic encephalopathy, albumin infusion is thought to improve cognitive function by reducing ammonia concentration in blood and thereby tackle cirrhosis-induced hepatocyte malfunction in ammonia clearance. Infused albumin can also exhibit protective effects by binding to the cirrhosis-induced proinflammatory cytokines TNFα and IL6. While albumin administration has shown to prolong overall survival of cirrhotic patients with ascites in the ANSWER trial, the ATTIRE and MACHT trials have shown either no effect or limitations such as development of pulmonary oedema and multiorgan failure. Thus, albumin infusion is not a generic treatment option for all cirrhosis patients. Interestingly, cirrhosis-induced structural alterations in native albumin (which lead to formation of different albumin isoforms) can be used as prognostic biomarkers because specific albumin isoforms indicate certain complications of decompensated cirrhosis.
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Affiliation(s)
- Mohamed A Heybe
- GKT School of Medical Education, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Kosha J Mehta
- Centre for Education, Faculty of Life Sciences and Medicine, King's College London, London, UK.
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Stauber RE, Paar M, Balazs I, Horvath A, Feldbacher N, Posch A, Rainer F, Stadlbauer V, Oettl K. Effect of albumin infusion on oxidative albumin modification and albumin binding capacity in chronic liver failure. Basic Clin Pharmacol Toxicol 2024; 134:375-384. [PMID: 38093476 DOI: 10.1111/bcpt.13973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 11/27/2023] [Accepted: 12/11/2023] [Indexed: 12/28/2023]
Abstract
Oxidative albumin modification and impaired albumin binding function have been described both in chronic liver failure and for therapeutic albumin solutions. The aim of the present study was to evaluate the effect of albumin infusion on redox state and binding function of circulating albumin. We studied 20 patients with cirrhosis who routinely received albumin infusions for prevention of post-paracentesis circulatory dysfunction or treatment of hepatorenal syndrome. We measured albumin fractions by redox state of cysteine-34 and albumin binding properties using dansylsarcosine as site II ligand. Therapeutic albumin solutions showed high contents of human nonmercaptalbumin-1 and human nonmercaptalbumin-2, exceeding the respective values in our patients with decompensated cirrhosis. An initial protocol for the first nine patients sampled at baseline, 24 h and 48 h after albumin infusion revealed no significant changes of oxidized albumin species or albumin binding properties. However, a modified protocol for the remaining 11 patients sampled at baseline, <1 h after and 24 h after albumin infusion revealed short-lived changes of oxidized albumin species while no changes in albumin binding properties were observed. In conclusion, therapeutic albumin infusion transiently changed albumin redox state but did not improve binding function of circulating albumin in chronic liver failure.
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Affiliation(s)
- Rudolf E Stauber
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Margret Paar
- Division of Medicinal Chemistry, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Irina Balazs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- CBmed Center of Biomarker Research in Medicine, Graz, Austria
| | - Angela Horvath
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- CBmed Center of Biomarker Research in Medicine, Graz, Austria
| | - Nicole Feldbacher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- CBmed Center of Biomarker Research in Medicine, Graz, Austria
| | - Andreas Posch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Florian Rainer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Vanessa Stadlbauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- CBmed Center of Biomarker Research in Medicine, Graz, Austria
| | - Karl Oettl
- Division of Medicinal Chemistry, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
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8
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Boss K, Waterstradt K, Schnurr K, Paar M, Stolpe S, Ickerott P, Wieneke U, Spitthöver R, Oettl K, Kribben A. Binding and detoxification efficiency of albumin decline after haemodialysis. Nephrol Dial Transplant 2024; 39:215-221. [PMID: 37558390 PMCID: PMC10828194 DOI: 10.1093/ndt/gfad133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Albumin, as the most abundant plasma protein, represents a target structure for both drug and physicochemical therapeutic approaches to eliminate uraemic toxins more efficiently. Potentially, this approach could reduce mortality of haemodialysis patients. However, little is known about albumin functional properties in these patients and its alteration by haemodialysis treatment. METHODS The binding and detoxification efficiency of albumin were assessed by electron paramagnetic resonance spectroscopy using a spin-labelled fatty acid. Binding efficiency (BE) reflects strength and amount of bound fatty acids under certain ethanol concentration. Detoxification efficiency (DTE) reflects the molecular flexibility of the patient's albumin molecule, thus the ability to change the conformation depending on ethanol concentration. Percentage of BE and DTE are depicted in relation to healthy individuals (100%). RESULTS Fifty-eight patients (59% male, median age 68 years, median time on haemodialysis 32 months) were included in the study. Before haemodialysis treatment, albumin binding and detoxification efficiency were substantially below healthy individuals [median BE 52% (interquartile range, IQR, 45%-59%); median DTE 38% (IQR 32-49%)]. After haemodialysis treatment, median BE and DTE significantly decreased [BE 28% (IQR 20-41%); DTE 11% (IQR 7%-27%; P < .001)]. BE and DTE decline after haemodialysis was not dependent on age, sex or treatment modalities, but was to a certain extent on the level of non-esterified fatty acids. CONCLUSION Albumin binding and detoxification efficiency of fatty acids in maintenance haemodialysis patients were substantially below those in healthy individuals and even declined after dialysis treatment. These findings might be helpful when considering new therapeutic approaches in maintenance haemodialysis patients.
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Affiliation(s)
- Kristina Boss
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | | | | | - Margret Paar
- Division of Medicinal Chemistry, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Susanne Stolpe
- Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Philipp Ickerott
- Gemeinschaftspraxis für Nieren- und Hochdruckkrankheiten Essen-Steele, Essen, Germany
| | | | | | - Karl Oettl
- Division of Medicinal Chemistry, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Andreas Kribben
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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Lakis R, Sauvage FL, Pinault E, Marquet P, Saint-Marcoux F, El Balkhi S. Absolute Quantification of Human Serum Albumin Isoforms by Internal Calibration Based on a Top-Down LC-MS Approach. Anal Chem 2024; 96:746-755. [PMID: 38166371 DOI: 10.1021/acs.analchem.3c03933] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2024]
Abstract
Well-characterized biomarkers using reliable quantitative methods are essential for the management of various pathologies such as diabetes, kidney, and liver diseases. Human serum albumin (HSA) isoforms are gaining interest as biomarkers of advanced liver pathologies. In view of the structural alterations observed for HSA, insights into its isoforms are required to establish them as reliable biomarkers. Therefore, a robust absolute quantification method seems necessary. In this study, we developed and validated a far more advanced top-down liquid chromatography-mass spectrometry (LC-MS) method for the absolute quantification of HSA isoforms, using myoglobin (Mb) as an internal standard for quantification and for mass recalibration. Two different quantification approaches were investigated based on peak integration from the deconvoluted spectrum and extracted ion chromatogram (XIC). The protein mixture human serum albumin/myoglobin eluted in well-shaped separated peaks. Mb allowed a systematic mass recalibration for every sample, resulting in extremely low mass deviations compared to conventional deconvolution-based methods. In total, eight HSA isoforms of interest were quantified. Specific-isoform calibration curves showing good linearity were obtained by using the deconvoluted peaks. Noticeably, the HSA ionization behavior appeared to be isoform-dependent, suggesting that the use of an enriched isoform solution as a calibration standard for absolute quantification studies of HSA isoforms is necessary. Good repeatability, reproducibility, and accuracy were observed, with better sensitivity for samples with low albumin concentrations compared to routine biochemical assays. With a relatively simple workflow, the application of this method for absolute quantification shows great potential, especially for HSA isoform studies in a clinical context, where a high-throughput method and sensitivity are needed.
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Affiliation(s)
- Roy Lakis
- Pharmacology & Transplantation (P&T), Université de Limoges, INSERM U1248, Limoges 87000, France
| | - François-Ludovic Sauvage
- Pharmacology & Transplantation (P&T), Université de Limoges, INSERM U1248, Limoges 87000, France
| | - Emilie Pinault
- Pharmacology & Transplantation (P&T), Université de Limoges, INSERM U1248, Limoges 87000, France
| | - Pierre Marquet
- Pharmacology & Transplantation (P&T), Université de Limoges, INSERM U1248, Limoges 87000, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges 87000, France
| | - Franck Saint-Marcoux
- Pharmacology & Transplantation (P&T), Université de Limoges, INSERM U1248, Limoges 87000, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges 87000, France
| | - Souleiman El Balkhi
- Pharmacology & Transplantation (P&T), Université de Limoges, INSERM U1248, Limoges 87000, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges 87000, France
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10
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El Balkhi S, Rahali MA, Lakis R, Sauvage FL, Martin M, Janaszkiewicz A, Lawson R, Goncalves R, Carrier P, Loustaud-Ratti V, Guyot A, Marquet P, Di Meo F, Saint-Marcoux F. Early detection of liver injuries by the Serum enhanced binding test sensitive to albumin post-transcriptional modifications. Sci Rep 2024; 14:1434. [PMID: 38228668 PMCID: PMC10791642 DOI: 10.1038/s41598-024-51412-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 01/04/2024] [Indexed: 01/18/2024] Open
Abstract
Early and sensitive biomarkers of liver dysfunction and drug-induced liver injury (DILI) are still needed, both for patient care and drug development. We developed the Serum Enhanced Binding (SEB) test to reveal post-transcriptional modifications (PTMs) of human serum albumin resulting from hepatocyte dysfunctions and further evaluated its performance in an animal model. The SEB test consists in spiking serum ex-vivo with ligands having specific binding sites related to the most relevant albumin PTMs and measuring their unbound fraction. To explore the hypothesis that albumin PTMs occur early during liver injury and can also be detected by the SEB test, we induced hepatotoxicity in male albino Wistar rats by administering high daily doses of ethanol and CCl4 over several days. Blood was collected for characterization and quantification of albumin isoforms by high-resolution mass spectrometry, for classical biochemical analyses as well as to apply the SEB test. In the exposed rats, the appearance of albumin isoforms paralleled the positivity of the SEB test ligands and histological injuries. These were observed as early as D3 in the Ethanol and CCl4 groups, whereas the classical liver tests (ALT, AST, PAL) significantly increased only at D7. The behavior of several ligands was supported by structural and molecular simulation analysis. The SEB test and albumin isoforms revealed hepatocyte damage early, before the current biochemical biomarkers. The SEB test should be easier to implement in the clinics than albumin isoform profiling.
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Affiliation(s)
- Souleiman El Balkhi
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France.
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France.
- Pharmacology-Toxicology and Pharmacovigilance Department, Centre de Biologie Et de Recherche en Santé (CBRS), 2, Av. Martin Luther King, 87042, Limoges Cedex, France.
| | - Mohamad Ali Rahali
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France
| | - Roy Lakis
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France
| | | | | | | | - Roland Lawson
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France
| | | | - Paul Carrier
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France
- Department of Liver Disease, CHU Limoges, Limoges, France
| | - Veronique Loustaud-Ratti
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France
- Department of Liver Disease, CHU Limoges, Limoges, France
| | - Anne Guyot
- Department of Pathology, CHU Limoges, Limoges, France
| | - Pierre Marquet
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France
| | | | - Franck Saint-Marcoux
- P&T, UMR1248, Inserm, Univ. Limoges, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France
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11
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Li H, Zou X, Zhang R, Zou S, Qian F, Zheng J, Xiao AY, Guo X. Association of chronic conditions and physical multimorbidity with new-onset incontinence in a nationwide prospective cohort study of older adults ≥ 50 years in China. Age Ageing 2024; 53:afad258. [PMID: 38251743 PMCID: PMC10801828 DOI: 10.1093/ageing/afad258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/22/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND The relationship between multimorbidity (i.e. ≥ 2 chronic conditions) and incontinence (i.e. urinary and/or faecal incontinence) is underexplored. This study investigated the association between multimorbidity and incident incontinence in Chinese adults aged ≥50 years. METHODS Data from the 2011 and 2015 waves of the China Health and Retirement Longitudinal Study were used. The association between 12 chronic conditions, multimorbidity and new-onset incontinence was analysed using weighted logistic regression models. Mediation analysis was conducted to explore the potential mediators (self-reported health, subjective memory, depressive symptoms, disability, cognitive function, handgrip strength, mobility limitations, medications and frailty status) between multimorbidity and incontinence. FINDINGS Among 9,986 individuals aged ≥50 years who were continent at baseline, 5.3% (n = 521) were newly incontinent 4 years later (incident cases). The risk of incident incontinence increased with physical multimorbidity (OR 2.04, 95% CI 1.62-2.57). Compared to no chronic condition, having 1, 2, 3 and ≥ 4 chronic conditions were associated with incident incontinence with OR (95% CI): 1.41 (1.01-1.97), 1.74 (1.24-2.44), 2.82 (1.93-4.12) and 3.99 (2.29-6.95), respectively. The association between multimorbidity and incontinence was mediated by self-reported health (41.2%), medications (26.6%), mobility limitations (20.9%), depressive symptoms (12.8%), disability (11.6%), subjective memory (8.7%) and frailty status (8.3%). CONCLUSION This longitudinal study found that physical multimorbidity and specific chronic conditions may increase the risk of new-onset incontinence among Chinese adults aged ≥50 years. Self-reported health, medications and mobility limitations seemed to be important intermediate conditions between multimorbidity and incident incontinence.
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Affiliation(s)
- Haibin Li
- Department of Cardiac Surgery, Heart Center & Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Xinye Zou
- Cambridge Institute of Public Health, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Ruolin Zhang
- Department of Natural and Applied Science, Duke Kunshan University, No. 8 Duke Ave., Kunshan, Jiangsu 215316, China
| | - Siyu Zou
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
| | - Frank Qian
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jin Zheng
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Angela Y Xiao
- Department of International Studies, Macalester College, 1600 Grand Avenue St. Paul, St Paul, MN 55105, USA
| | - Xiuhua Guo
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China
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12
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Devisetty JV, Mallick B, Praharaj D, Tiwari A, Kumar R, Nath P, Panigrahi SC, Anand AC, Acharya SK, Chawla YK. A Study of Impact of Fixed-Dose Albumin Infusion on Outcome in Patients With Cirrhosis and Infection: A Randomized Open-label Clinical Trial. J Clin Exp Hepatol 2024; 14:101270. [PMID: 38076352 PMCID: PMC10709162 DOI: 10.1016/j.jceh.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/14/2023] [Indexed: 01/05/2025] Open
Abstract
Background and aim Antibiotics and albumin infusion constitute the standard of treatment in patients with decompensated cirrhosis who have spontaneous bacterial peritonitis (SBP). Recent studies have also shown that the use of albumin in patients with advanced liver disease who have infections other than SBP leads to the resolution of acute and chronic liver failure and prevents the development of nosocomial infections. The recommended dose of albumin for these patients is out of reach for many in resource-limited settings like India. The evidence for this recommendation is also scarce. This study aimed to assess the efficacy of a lower dose of albumin infusion in addition to antibiotics on short-term mortality and morbidity in patients with cirrhosis and infections. Patients and methods A prospective, open-label, randomized control study was performed. Consecutive patients with cirrhosis and infections were randomized in a 2:1 ratio into two groups: group A (116) and group B (58) patients. In addition to antibiotics and standard medical therapy, group A was given albumin in a dose of 20 g/day for five days, and group B was given the recommended dose (1.5 g/kg/body weight and 1 g/kg body weight on days one and three, respectively). The primary outcome was in-hospital mortality. Secondary outcomes were improvements in clinical and laboratory parameters. Results Except for etiology, all the baseline clinical and laboratory variables in both groups were comparable. The in-hospital mortality in groups A and B was (11 [10.67%] vs. 6 [10.09%], (P = 0.965). The duration of hospitalization, 30-day mortality, improvement in shock and sensorium, and absolute improvements in serum creatinine, international normalized ratio (INR), and serum bilirubin were also comparable in both groups. Conclusion Low-dose albumin infusion in patients with cirrhosis and infections can have the same results as standard-dose albumin and can be used in resource-limited situations. Clinical trial registration number CTRI/2020/03/023794.
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Affiliation(s)
- Jayadeep V. Devisetty
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Bipadabhanjan Mallick
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Dibyaloahan Praharaj
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Anirudh Tiwari
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Raj Kumar
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Preetam Nath
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Sarat C. Panigrahi
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Anil C. Anand
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Subrat K. Acharya
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Yogesh K. Chawla
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
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13
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Badura K, Frąk W, Hajdys J, Majchrowicz G, Młynarska E, Rysz J, Franczyk B. Hepatorenal Syndrome-Novel Insights into Diagnostics and Treatment. Int J Mol Sci 2023; 24:17469. [PMID: 38139297 PMCID: PMC10744165 DOI: 10.3390/ijms242417469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/09/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS.
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Affiliation(s)
- Krzysztof Badura
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Weronika Frąk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Hajdys
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Gabriela Majchrowicz
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
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14
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Balazs I, Stadlbauer V. Circulating neutrophil anti-pathogen dysfunction in cirrhosis. JHEP Rep 2023; 5:100871. [PMID: 37822786 PMCID: PMC10562928 DOI: 10.1016/j.jhepr.2023.100871] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/16/2023] [Accepted: 07/22/2023] [Indexed: 10/13/2023] Open
Abstract
Neutrophils are the largest population of leucocytes and are among the first cells of the innate immune system to fight against intruding pathogens. In patients with cirrhosis, neutrophils exhibit altered functionality, including changes in phagocytic ability, bacterial killing, chemotaxis, degranulation, reactive oxygen species production and NET (neutrophil extracellular trap) formation. This results in their inability to mount an adequate antibacterial response and protect the individual from infection. Prognosis and survival in patients with cirrhosis are greatly influenced by the development of infectious complications. Multidrug-resistant bacterial infections in patients with cirrhosis are currently a growing problem worldwide; therefore, alternative methods for the prevention and treatment of bacterial infections in cirrhosis are urgently needed. The prevention and treatment of neutrophil dysfunction could be a potential way to protect patients from bacterial infections. However, the reasons for changes in neutrophil function in cirrhosis are still not completely understood, which limits the development of efficient therapeutic strategies. Both cellular and serum factors have been proposed to contribute to the functional impairment of neutrophils. Herein, we review the current knowledge on features and proposed causes of neutrophil dysfunction in cirrhosis, with a focus on current knowledge gaps and limitations, as well as opportunities for future investigations in this field.
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Affiliation(s)
- Irina Balazs
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
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15
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Saeidinejad M, Elshabrawi A, Sriphoosanaphan S, Andreola F, Mehta G, Agarwal B, Jalan R. Novel Therapeutic Approaches in Treatment of Acute-on-Chronic Liver Failure. Semin Liver Dis 2023; 43:429-445. [PMID: 38101419 PMCID: PMC10723941 DOI: 10.1055/s-0043-1776773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.
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Affiliation(s)
- MohammadMahdi Saeidinejad
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Ahmed Elshabrawi
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Endemic Hepatology and Gastroenterology Department, Mansoura University, Mansoura, Egypt
| | - Supachaya Sriphoosanaphan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok
| | - Fausto Andreola
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Gautam Mehta
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Banwari Agarwal
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Royal Free Hospital, London, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Hepatology Department, Royal Free Hospital, London, United Kingdom
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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16
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Pompili E, Zaccherini G, Baldassarre M, Iannone G, Caraceni P. Albumin administration in internal medicine: A journey between effectiveness and futility. Eur J Intern Med 2023; 117:28-37. [PMID: 37423819 DOI: 10.1016/j.ejim.2023.07.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/11/2023]
Abstract
Albumin is the most abundant circulating protein and provides about 70% of the plasma oncotic power. The molecule also carries many other biological functions (binding, transport and detoxification of endogenous and exogenous compounds, antioxidation, and modulation of inflammatory and immune responses). Hypoalbuminemia is a frequent finding in many diseases, representing usually only a biomarker of poor prognosis rather than a primary pathophysiological event. Despite that, albumin is prescribed in many conditions based on the assumption that correction of hypoalbuminemia would lead to clinical benefits for the patients. Unfortunately, many of these indications are not supported by scientific evidence (or have been even disproved), so that a large part of albumin use is nowadays still inappropriate. Decompensated cirrhosis is the clinical area where albumin administration has been extensively studied and solid recommendations can be made. Besides prevention and treatment of acute complications, long-term albumin administration in patients with ascites has emerged in the last decade has a potential new disease-modifying treatment. In non-hepatological settings, albumin is widely used for fluid resuscitation in sepsis and critical illnesses, with no clear superiority over crystalloids. In many other conditions, scientific evidence supporting albumin prescription is weak or even absent. Thus, given its high cost and limited availability, action is needed to avoid the use of albumin for inappropriate and futile indications to ensure its availability in those conditions for which albumin has been demonstrated to have a real effectiveness and an advantage for the patient.
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Affiliation(s)
- Enrico Pompili
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Maurizio Baldassarre
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Centre for Applied Biomedical Research (CRBA), Alma Mater Studiorum of Bologna, Italy
| | - Giulia Iannone
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy.
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17
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Gagliardi R, Zeni N, Piano S. Intravenous albumin in cirrhosis: Updated clinical uses and novel perspectives. Ann Hepatol 2023; 28:101150. [PMID: 37659473 DOI: 10.1016/j.aohep.2023.101150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 08/08/2023] [Indexed: 09/04/2023]
Affiliation(s)
- Roberta Gagliardi
- Department of Medicine (DIMED), Unit of Internal Medicine and Hepatology (UIMH), University and Hospital of Padova, Italy
| | - Nicola Zeni
- Department of Medicine (DIMED), Unit of Internal Medicine and Hepatology (UIMH), University and Hospital of Padova, Italy
| | - Salvatore Piano
- Department of Medicine (DIMED), Unit of Internal Medicine and Hepatology (UIMH), University and Hospital of Padova, Italy.
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18
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Butt MF, Jalan R. Review article: Emerging and current management of acute-on-chronic liver failure. Aliment Pharmacol Ther 2023; 58:774-794. [PMID: 37589507 DOI: 10.1111/apt.17659] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/02/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a clinically and pathophysiologically distinct condition from acutely decompensated cirrhosis and is characterised by systemic inflammation, extrahepatic organ failure, and high short-term mortality. AIMS To provide a narrative review of the diagnostic criteria, prognosis, epidemiology, and general management principles of ACLF. Four specific interventions that are explored in detail are intravenous albumin, extracorporeal liver assist devices, granulocyte-colony stimulating factor, and liver transplantation. METHODS We searched PubMed and Cochrane databases for articles published up to July 2023. RESULTS Approximately 35% of hospital inpatients with decompensated cirrhosis have ACLF. There is significant heterogeneity in the criteria used to diagnose ACLF; different definitions identify different phenotypes with varying mortality. Criteria established by the European Association for the Study of the Liver were developed in prospective patient cohorts and are, to-date, the most well validated internationally. Systemic haemodynamic instability, renal dysfunction, coagulopathy, neurological dysfunction, and respiratory failure are key considerations when managing ACLF in the intensive care unit. Apart from liver transplantation, there are no accepted evidence-based treatments for ACLF, but several different approaches are under investigation. CONCLUSION The recognition of ACLF as a distinct entity from acutely decompensated cirrhosis has allowed for better patient stratification in clinical settings, facilitating earlier engagement with the intensive care unit and liver transplantation teams. Research priorities over the next decade should focus on exploring novel treatment strategies with a particular focus on which, when, and how patients with ACLF should be treated.
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Affiliation(s)
- Mohsin F Butt
- Centre for Neuroscience, Trauma and Surgery, Wingate Institute of Neurogastroenterology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottinghamshire, UK
| | - Rajiv Jalan
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium, Barcelona, Spain
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19
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Lakis R, Sauvage FL, Pinault E, Marquet P, Saint-Marcoux F, El Balkhi S. Semi-synthetic human albumin isoforms: Production, structure, binding capacities and influence on a routine laboratory test. Int J Biol Macromol 2023; 250:126239. [PMID: 37572814 DOI: 10.1016/j.ijbiomac.2023.126239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/02/2023] [Accepted: 08/07/2023] [Indexed: 08/14/2023]
Abstract
Human Serum Albumin (HSA) undergoes Post-Translational-Modifications (PTMs) leading to isoforms affecting its oncotic and non-oncotic properties. HSA is comprised of several isoforms whose abundance may vary with pathologies such as diabetes, kidney and liver diseases. Studying their impact separately may help to understand their sources and potential pathogenicity and further their evaluation as biomarkers. The present study examined semi-synthetic HSA isoforms to investigate independently their structure by means of advanced mass spectrometry techniques (LC-TOF-MS and ICP-MS), influence on the HSA binding/antioxidant activities using a binding capacity test, and potential impact on albumin quantification by a routine immunoturbidimetric assay. Applying different chemical reactions to a commercial HSA solution, we obtained different solutions enriched up to 53 % of native HSA, 78 % of acetylated HSA, 71 % of cysteinylated HSA, 94 % of oxidized HSA, 58 % of nitrosylated HSA and 96 % of glycated HSA, respectively. Moreover, the semi-synthetic isoforms showed differently altered binding capacities for a panel of ligands (Cu, Cd, Au, Ds and L-T4). Furthermore, immunoturbidimetry was found to be insensitive to the presence and abundance of the different isoforms. The fully characterized semi synthetic HSA isoforms obtained should be useful to further investigate their pathogenicity and potential roles as biomarkers.
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Affiliation(s)
- Roy Lakis
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France
| | - François-Ludovic Sauvage
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France
| | - Emilie Pinault
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France
| | - Pierre Marquet
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France; Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France
| | - Franck Saint-Marcoux
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France; Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France
| | - Souleiman El Balkhi
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France; Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France.
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20
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Klinkmann G, Waterstradt K, Klammt S, Schnurr K, Schewe JC, Wasserkort R, Mitzner S. Exploring Albumin Functionality Assays: A Pilot Study on Sepsis Evaluation in Intensive Care Medicine. Int J Mol Sci 2023; 24:12551. [PMID: 37628734 PMCID: PMC10454468 DOI: 10.3390/ijms241612551] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/03/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Human serum albumin (HSA) as the most abundant plasma protein carries multifunctional properties. A major determinant of the efficacy of albumin relies on its potent binding capacity for toxins and pharmaceutical agents. Albumin binding is impaired in pathological conditions, affecting its function as a molecular scavenger. Limited knowledge is available on the functional properties of albumin in critically ill patients with sepsis or septic shock. A prospective, non-interventional clinical trial assessed blood samples from 26 intensive care patients. Albumin-binding capacity (ABiC) was determined by quantifying the unbound fraction of the fluorescent marker, dansyl sarcosine. Electron paramagnetic resonance fatty acid spin-probe evaluated albumin's binding and detoxification efficiencies. Binding efficiency (BE) reflects the strength and amount of bound fatty acids, and detoxification efficiency (DTE) indicates the molecular flexibility of patient albumin. ABiC, BE, and DTE effectively differentiated control patients from those with sepsis or septic shock (AUROC > 0.8). The diagnostic performance of BE showed similarities to procalcitonin. Albumin functionality correlates with parameters for inflammation, hepatic, or renal insufficiency. Albumin-binding function was significantly reduced in critically ill patients with sepsis or septic shock. These findings may help develop patient-specific algorithms for new diagnostic and therapeutic approaches.
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Affiliation(s)
- Gerd Klinkmann
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Medical Center Rostock, Schillingallee 35, 18057 Rostock, Germany
- Fraunhofer Institute for Cell Therapy and Immunology, Department of Extracorporeal Therapy Systems, Schillingallee 68, 18057 Rostock, Germany
| | - Katja Waterstradt
- Department of Research and Development, MedInnovation GmbH, 12487 Berlin, Germany
| | - Sebastian Klammt
- Division of Nephrology, Department of Internal Medicine, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany
| | - Kerstin Schnurr
- Department of Research and Development, MedInnovation GmbH, 12487 Berlin, Germany
| | - Jens-Christian Schewe
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Medical Center Rostock, Schillingallee 35, 18057 Rostock, Germany
| | - Reinhold Wasserkort
- Fraunhofer Institute for Cell Therapy and Immunology, Department of Extracorporeal Therapy Systems, Schillingallee 68, 18057 Rostock, Germany
- Division of Nephrology, Department of Internal Medicine, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany
| | - Steffen Mitzner
- Fraunhofer Institute for Cell Therapy and Immunology, Department of Extracorporeal Therapy Systems, Schillingallee 68, 18057 Rostock, Germany
- Division of Nephrology, Department of Internal Medicine, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany
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21
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Paar M, Fengler VH, Reibnegger G, Schnurr K, Waterstradt K, Schwaminger SP, Stauber RE, Oettl K. Determination of binding characteristics as a measure for effective albumin using different methods. Biochim Biophys Acta Gen Subj 2023:130427. [PMID: 37454915 DOI: 10.1016/j.bbagen.2023.130427] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/13/2023] [Accepted: 07/13/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND & AIMS Transport functions of albumin are of clinical and pharmacological interest and are determined by albumin's properties like posttranslational modifications or bound ligands. Both are affected in pathological conditions and in therapeutic grade albumin solutions. The term effective albumin concentration was introduced as a measure of functionally intact albumin. Our aim was to evaluate the impact of ligands and modifications with different approaches as a measure of effective albumin. APPROACH & RESULTS We used a spin labelled fatty acid and dansylsarcosine to characterize binding properties of albumin i) prepared from plasma of patients and healthy control donors, ii) measured directly out of plasma, iii) research grade albumin, iv) in vitro modified albumin, and v) therapeutic infusion solutions before and after removal of stabilizers. Bilirubin is the main determinant for binding function in patients' albumin. In in vitro prepared albumin bound fatty acids correlated with impaired binding. Human nonmercaptalbumin1, not human nonmercaptalbumin2, showed reduced binding properties. Binding and transport function of therapeutic albumin was severely impaired and restored by filtration. Glycation of research grade albumin had no effect on the binding of dansylsarcosine and only a minor effect on fatty acid binding. CONCLUSIONS Our results suggest that effective albumin -in terms of binding properties- is primarily determined by bound ligands and only to a minor extent by posttranslational modifications. Characterizing albumin directly from plasma better reflects the physiological situation whereas in the case of therapeutic grade albumin stabilizers should be removed to make its binding properties accessible.
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Affiliation(s)
- Margret Paar
- Medical University of Graz, Otto Loewi Research Center, Division of Medicinal Chemistry, Neue Stiftingtalstrasse 6, 8010, Graz, Austria
| | - Vera H Fengler
- University of Graz, Institute of Molecular Biosciences, Humboldtstrasse 50, 8010, Graz, Austria
| | - Gilbert Reibnegger
- Medical University of Graz, Otto Loewi Research Center, Division of Medicinal Chemistry, Neue Stiftingtalstrasse 6, 8010, Graz, Austria
| | - Kerstin Schnurr
- MedInnovation GmbH, Wissenschaftsstandort Berlin-Adlershof (WISTA), Groß-Berliner Damm 151, 12487 Berlin, Germany
| | - Katja Waterstradt
- MedInnovation GmbH, Wissenschaftsstandort Berlin-Adlershof (WISTA), Groß-Berliner Damm 151, 12487 Berlin, Germany
| | - Sebastian P Schwaminger
- Medical University of Graz, Otto Loewi Research Center, Division of Medicinal Chemistry, Neue Stiftingtalstrasse 6, 8010, Graz, Austria; BioTechMed-Graz, Mozartgasse 12, 8010 Graz, Austria
| | - Rudolf E Stauber
- Medical University of Graz, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Auenbruggerplatz 15, 8036 Graz, Austria
| | - Karl Oettl
- Medical University of Graz, Otto Loewi Research Center, Division of Medicinal Chemistry, Neue Stiftingtalstrasse 6, 8010, Graz, Austria.
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22
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Agarwal B, Cañizares RB, Saliba F, Ballester MP, Tomescu DR, Martin D, Stadlbauer V, Wright G, Sheikh M, Morgan C, Alzola C, Lavin P, Green D, Kumar R, Sacleux SC, Schilcher G, Koball S, Tudor A, Minten J, Domenech G, Aragones JJ, Oettl K, Paar M, Waterstradt K, Bode-Boger SM, Ibáñez-Samaniego L, Gander A, Ramos C, Chivu A, Stange J, Lamprecht G, Sanchez M, Mookerjee RP, Davenport A, Davies N, Pavesi M, Andreola F, Albillos A, Cordingley J, Schmidt H, Carbonell-Asins JA, Arroyo V, Fernandez J, Mitzner S, Jalan R. Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure. J Hepatol 2023; 79:79-92. [PMID: 37268222 DOI: 10.1016/j.jhep.2023.03.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/01/2023] [Accepted: 03/07/2023] [Indexed: 06/04/2023]
Abstract
BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER NCT03065699.
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Affiliation(s)
- Banwari Agarwal
- Intensive Care Unit, Royal Free Hospital, London, UK; Institute for Liver & Digestive Health, University College London, London, UK
| | - Rafael Bañares Cañizares
- Department of Gastroenterology and Hepatology, Gregorio Marañón General University Hospital, Spain; Health Research Institute Gregorio Marañón, Department of Medicine Complutense University of Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Faouzi Saliba
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM unit N° 1193, Université Paris-Saclay, France
| | - Maria Pilar Ballester
- INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, Spain; Digestive Disease Department, Hospital Clínico Universitario de Valencia, Spain
| | - Dana Rodica Tomescu
- Carol Davila University of Medicine and Pharmacy, Romania; Fundeni Clinical Institute Bucharest, Romania
| | - Daniel Martin
- Peninsula Medical School, University of Plymouth, UK
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Division of Gastroenterology und Hepatology, Medical University of Graz, Austria
| | - Gavin Wright
- Basildon and Thurrock University Hospital, Mid and South Essex NHS Foundation Trust, Basildon, UK
| | - Mohammed Sheikh
- Institute for Liver & Digestive Health, University College London, London, UK
| | | | | | - Phillip Lavin
- Boston Biostatistics Research Foundation, Inc, Framingham MA, USA
| | | | | | - Sophie Caroline Sacleux
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM unit N° 1193, Université Paris-Saclay, France
| | - Gernot Schilcher
- Department of Internal Medicine, Division of Gastroenterology und Hepatology, Medical University of Graz, Austria
| | | | | | | | - Gema Domenech
- Medical Statistics Core Facility IDIBAPS - Hospital Clinic, Barcelona, USA
| | - Juan Jose Aragones
- Medical Statistics Core Facility IDIBAPS - Hospital Clinic, Barcelona, USA
| | - Karl Oettl
- Division of Medicinal Chemistry, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Margret Paar
- Division of Medicinal Chemistry, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | | | | | - Luis Ibáñez-Samaniego
- Department of Gastroenterology and Hepatology, Gregorio Marañón General University Hospital, Spain; Health Research Institute Gregorio Marañón, Department of Medicine Complutense University of Madrid, Spain
| | - Amir Gander
- Tissue Access for Patient Benefit, Royal Free Hospital, UK
| | - Carolina Ramos
- Department of Surgical Biotechnology, Division of Surgery and Interventional Science, University College London, United Kingdom
| | - Alexandru Chivu
- Department of Surgical Biotechnology, Division of Surgery and Interventional Science, University College London, United Kingdom
| | - Jan Stange
- University Hospital Rostock, Germany; Fraunhofer IZI, Germany
| | - Georg Lamprecht
- Department of Medicine II, Division of Gastroenterology and Endocrinology, Rostock University, Medical Center, Rostock, Germany
| | | | | | - Andrew Davenport
- Institute for Liver & Digestive Health, University College London, London, UK
| | - Nathan Davies
- Institute for Liver & Digestive Health, University College London, London, UK
| | - Marco Pavesi
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, USA
| | - Fausto Andreola
- Institute for Liver & Digestive Health, University College London, London, UK
| | - Agustin Albillos
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain; Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Madrid, Spain; Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
| | - Jeremy Cordingley
- Perioperative Medicine - Critical Care, St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Hartmut Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, 45147 Essen, Germany
| | | | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, USA
| | | | - Steffen Mitzner
- Fraunhofer IZI, Germany; Department of Medicine II, Division of Gastroenterology and Endocrinology, Rostock University, Medical Center, Rostock, Germany
| | - Rajiv Jalan
- Institute for Liver & Digestive Health, University College London, London, UK; European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, USA.
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23
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Muñoz AE, Pollarsky F, Marino M, Cartier M, Míguez C, Rodger EG, Vázquez H, Salgado P, Álvarez D, Romero G. Baseline Severity and Inflammation Would Influence the Effect of Simvastatin on Clinical Outcomes in Cirrhosis Patients. Dig Dis Sci 2023:10.1007/s10620-023-07969-3. [PMID: 37213003 DOI: 10.1007/s10620-023-07969-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 05/08/2023] [Indexed: 05/23/2023]
Abstract
BACKGROUND Simvastatin administration to decompensated cirrhosis patients improved Child-Pugh (CP) at the end of a safety trial (EST). AIM To evaluate whether simvastatin reduces cirrhosis severity through a secondary analysis of the safety trial. METHODS Thirty patients CP class (CPc) CPc A (n = 6), CPc B (n = 22), and CPc C (n = 2) received simvastatin for one year. PRIMARY ENDPOINT cirrhosis severity. Secondary endpoints: health-related quality of life (HRQoL) and hospitalizations for cirrhosis complications. RESULTS Cirrhosis severity decreased baseline versus EST only across CP score (7.3 ± 1.3 versus 6.7 ± 1.7, P = 0.041), and CPc: 12 patients lessened from CPc B to CPc A, and three patients increased from CPc A to CPc B (P = 0.029). Due to cirrhosis severity changes and differences in clinical outcomes, 15 patients completed the trial as CPc AEST and another 15 as CPc B/C. At baseline, CPc AEST showed greater albumin and high-density lipoprotein cholesterol concentrations than CPc B/C (P = 0.036 and P = 0.028, respectively). Comparing EST versus baseline, only in CPc AEST, there was a reduction in white-cell blood (P = 0.012), neutrophils (P = 0.029), monocytes (P = 0.035), and C-reactive protein (P = 0.046); an increase in albumin (P = 0.011); and a recovery in HRQoL (P < 0.030). Finally, admissions for cirrhosis complications decreased in CPc AEST versus CPc B/C (P = 0.017). CONCLUSIONS Simvastatin would reduce cirrhosis severity only in CPc B at baseline in a suitable protein and lipid milieu, possibly due to its anti-inflammatory effects. Furthermore, only in CPc AEST would improve HRQoL and reduce admissions by cirrhosis complications. However, as these outcomes were not primary endpoints, they require validation.
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Affiliation(s)
- Alberto E Muñoz
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Av. Caseros 2061 (1264), Ciudad Autónoma de Buenos Aires, Argentina.
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Marcelo T. Alvear 2142 (1122), Ciudad Autónoma de Buenos Aires, Argentina.
| | - Florencia Pollarsky
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Av. Caseros 2061 (1264), Ciudad Autónoma de Buenos Aires, Argentina
| | - Mónica Marino
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Av. Caseros 2061 (1264), Ciudad Autónoma de Buenos Aires, Argentina
| | - Mariano Cartier
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Av. Caseros 2061 (1264), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos Míguez
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Av. Caseros 2061 (1264), Ciudad Autónoma de Buenos Aires, Argentina
| | - Enrique G Rodger
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Av. Caseros 2061 (1264), Ciudad Autónoma de Buenos Aires, Argentina
| | - Horacio Vázquez
- Unidad Clínica, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Av. Caseros 2061 (1264). Investigador Asociado del Gobierno de La Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Pablo Salgado
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Marcelo T. Alvear 2142 (1122), Ciudad Autónoma de Buenos Aires, Argentina
| | - Daniel Álvarez
- Servicio de Ecografía, Fundación Favaloro, Facultad de Medicina, Universidad Favaloro, Av. Belgrano 1782 (1093), Ciudad Autónoma de Buenos Aires, Argentina
| | - Gustavo Romero
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Av. Caseros 2061 (1264), Ciudad Autónoma de Buenos Aires, Argentina
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24
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Chamroonkul N, Rujeerapaiboon N, Sripongpun P, Kaewdech A, Piratvisuth T. The efficacy of branched-chain amino acid granules to restore phagocytic activity in cirrhosis patients, a randomized controlled trial. Front Nutr 2023; 10:1142206. [PMID: 37252239 PMCID: PMC10213217 DOI: 10.3389/fnut.2023.1142206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND Infection is a detrimental complication among cirrhotic patients, leading to major morbidity and mortality. Reduction in phagocytic activation, as part of immunoparesis, is a distinctive key component of cirrhosis-associated immune dysfunction (CAID) and predicts the development of infection. However, there are limited data on immunotherapeutic approaches to restore phagocytosis. AIMS We aimed to determine the effect of branched-chain amino acid (BCAA) granules on phagocytic activity in patients with CAID. METHODS In this double-blind randomized controlled trial, Participants were randomly assigned (1:1 ratio stratified by Child-Pugh status) to receive either BCAA granules or placebo. In the 3rd and 6th months, phagocytic activity was assessed by flow cytometry. The primary endpoint was the restoration of innate immunity at the 6th month, defined as ≥75% phagocytic activity; the secondary endpoints were the accretion of phagocytic activity and hospitalization due to infection. RESULTS A total of 37 patients were included. There were no differences among the patients in the baseline characteristics and phagocytic activity. At the 6th month, a higher proportion of patients with phagocytic restoration was observed in the BCAA granule group compared to the placebo group (68 vs. 5.6%, p < 0.001). The mean phagocytic activity was 75.4 and 63.4% in the BCAA granule and placebo groups, respectively (p < 0.001). Progressive accretion of phagocytic activity was observed during the 3rd and 6th months. There was no difference in hospitalization due to infection (3 vs. 2 events, p = 0.487). CONCLUSION Our results suggest that BCAA granules significantly restore phagocytic activity across various stages of cirrhosis. A longer follow-up period is required to demonstrate infection prevention.Clinical Trial Registration: www.clinicaltrials.in.th, TCTR20190830005.
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Affiliation(s)
- Naichaya Chamroonkul
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Natthapat Rujeerapaiboon
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
- Gastroenterology Endoscopy and Motility Center, Ramathibodi Hospital, Mahidol University, Ratchathewi, Thailand
| | - Pimsiri Sripongpun
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Songkhla, Thailand
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25
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Rahali MA, Lakis R, Sauvage FL, Pinault E, Marquet P, Saint-Marcoux F, El Balkhi S. Posttranslational-modifications of human-serum-albumin analysis by a top-down approach validated by a comprehensive bottom-up analysis. J Chromatogr B Analyt Technol Biomed Life Sci 2023; 1224:123740. [PMID: 37182409 DOI: 10.1016/j.jchromb.2023.123740] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/03/2023] [Accepted: 05/05/2023] [Indexed: 05/16/2023]
Abstract
The posttranslational modifications (PTM) of human serum albumin (HSA) can result in the development of isoforms that have been identified as potential biomarkers for advanced hepatic diseases. However, previous approaches using top-down (TD) analysis to identify isoforms based on molecular weight may have resulted in misidentifications. The nature of the identified isoforms has never been confirmed in previous works. Here, we aimed to critically evaluate TD for the characterization and determination of HSA isoforms in patients and make an inventory of HSA-PTM. Serum samples from control subjects and patients with liver dysfunctions were analyzed using both top-down (TD) and bottom-up (BU) approaches. TD analysis involved using a LC-TOF-MS system to obtain a multicharged spectrum of HSA, which was deconvoluted to identify isoforms. Spectra were then used for relative quantitation analysis of albumin isoform abundances based on trapezoidal integration. For BU analysis, serums were reduced +/- alkylated, digested with trypsin and analyzed in the Q-TOF, data-dependent acquisition (DDA) mode to generate a SWATH-MS high-resolution mass spectral library of all HSA peptides. Tryptic digests of another set of serum samples were then analyzed using data-independent acquisition (DIA) mode to confirm the presence of HSA isoforms and their modification sites. TD detected 15 isoforms corresponding to various modifications, including glycation, cysteinylation, nitrosylation, and oxidation (di- and tri-). In BU, the spectral library containing 127 peptides allowed for the characterization of the important isoforms with their modified sites, including some modifications that were only characterized in BU (carbamylation, deamidation, and amino-acid substitution). The method used for determining isoforms offered acceptable reproducibility (intra-/inter-assay CVs < 15%) for all isoforms present at relative abundances higher than 2%. Overall, the study found that several isoforms could be missed or misidentified by TD. However, all HSA isoforms identified by TD and reported to be relevant in liver dysfunctions were confirmed by BU. This critical evaluation of TD approach helped design an adequate and reliable method for the characterization of HSA isoforms in patients and offers the possibility to estimate isoform abundances within 3 min. These findings have significant implications for the diagnosis and treatment of liver dysfunctions.
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Affiliation(s)
- Mohamad-Ali Rahali
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France
| | - Roy Lakis
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France
| | - François-Ludovic Sauvage
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France
| | - Emilie Pinault
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France
| | - Pierre Marquet
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France; Department of pharmacology, toxicology and pharmacovigilance, CHU Limoges, Limoges, France
| | - Franck Saint-Marcoux
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France; Department of pharmacology, toxicology and pharmacovigilance, CHU Limoges, Limoges, France
| | - Souleiman El Balkhi
- P&T, UMR1248, University of Limoges, National Institute for Health and Medical Research (INSERM), Limoges, France; Department of pharmacology, toxicology and pharmacovigilance, CHU Limoges, Limoges, France.
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26
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Effective albumin – A novel paradigm in the management of decompensated liver cirrhosis. J Transl Int Med 2023; 11:11-14. [DOI: 10.2478/jtim-2022-0070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023] Open
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27
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Jones GAL, Eaton S, Orford M, Ray S, Wiley D, Ramnarayan P, Inwald D, Grocott MPW, Griksaitis M, Pappachan J, O'Neill L, Mouncey PR, Harrison DA, Rowan KM, Peters MJ. Randomization to a Liberal Versus Conservative Oxygenation Target: Redox Responses in Critically Ill Children. Pediatr Crit Care Med 2023; 24:e137-e146. [PMID: 36728001 DOI: 10.1097/pcc.0000000000003175] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
RATIONALE Optimal systemic oxygenation targets in pediatric critical illness are unknown. A U-shaped relationship exists between blood oxygen levels and PICU mortality. Redox stress or iatrogenic injury from intensive treatments are potential mechanisms of harm from hyperoxia. OBJECTIVES To measure biomarkers of oxidative status in children admitted to PICU and randomized to conservative (oxygen-hemoglobin saturation [Sp o2 ] 88-92%) versus liberal (Sp o2 > 94%) peripheral oxygenation targets. DESIGN Mechanistic substudy nested within the Oxygen in PICU (Oxy-PICU) pilot randomized feasibility clinical trial ( ClinicalTrials.gov : NCT03040570). SETTING Three U.K. mixed medical and surgical PICUs in university hospitals. PATIENTS Seventy-five eligible patients randomized to the Oxy-PICU randomized feasibility clinical trial. INTERVENTIONS Randomization to a conservative (Sp o2 88-92%) versus liberal (Sp o2 > 94%) peripheral oxygenation target. MEASUREMENTS AND MAIN RESULTS Blood and urine samples were collected at two timepoints: less than 24 hours and up to 72 hours from randomization in trial participants (March 2017 to July 2017). Plasma was analyzed for markers of ischemic/oxidative response, namely thiobarbituric acid-reactive substances (TBARS; lipid peroxidation marker) and ischemia-modified albumin (protein oxidation marker). Total urinary nitrate/nitrite was measured as a marker of reactive oxygen and nitrogen species (RONS). Blood hypoxia-inducible factor (HIF)-1a messenger RNA (mRNA) expression (hypoxia response gene) was measured by reverse transcription- polymerase chain reaction. Total urinary nitrate/nitrite levels were greater in the liberal compared with conservative oxygenation group at 72 hours (median difference 32.6 μmol/mmol of creatinine [95% CI 13.7-93.6]; p < 0.002, Mann-Whitney test). HIF-1a mRNA expression was increased in the conservative group compared with liberal in less than 24-hour samples (6.0-fold [95% CI 1.3-24.0]; p = 0.032). There were no significant differences in TBARS or ischemia-modified albumin. CONCLUSIONS On comparing liberal with conservative oxygenation targets, we show, first, significant redox response (increase in urinary markers of RONS), but no changes in markers of lipid or protein oxidation. We also show what appears to be an early hypoxic response (increase in HIF-1a gene expression) in subjects exposed to conservative rather than liberal oxygenation targets.
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Affiliation(s)
- Gareth A L Jones
- Respiratory Critical Care and Anaesthesia Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Simon Eaton
- Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Michael Orford
- Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Samiran Ray
- Respiratory Critical Care and Anaesthesia Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Daisy Wiley
- Clinical Trials Unit, Intensive Care National Audit and Research Centre (ICNARC), London, United Kingdom
| | - Padmanabhan Ramnarayan
- Children's Acute Transport Service, Great Ormond Street Hospital, London, United Kingdom
- Paediatric Intensive Care Unit, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - David Inwald
- Paediatric Intensive Care Unit, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Michael P W Grocott
- Anaesthesia Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton/ University of Southampton, Southampton, United Kingdom
| | - Michael Griksaitis
- Anaesthesia Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton/ University of Southampton, Southampton, United Kingdom
- Paediatric Intensive Care Unit, Southampton Children's Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - John Pappachan
- Anaesthesia Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton/ University of Southampton, Southampton, United Kingdom
- Paediatric Intensive Care Unit, Southampton Children's Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Lauran O'Neill
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Paul R Mouncey
- Clinical Trials Unit, Intensive Care National Audit and Research Centre (ICNARC), London, United Kingdom
| | - David A Harrison
- Clinical Trials Unit, Intensive Care National Audit and Research Centre (ICNARC), London, United Kingdom
| | - Kathryn M Rowan
- Clinical Trials Unit, Intensive Care National Audit and Research Centre (ICNARC), London, United Kingdom
| | - Mark J Peters
- Respiratory Critical Care and Anaesthesia Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, United Kingdom
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Jeng LB, Chan WL, Teng CF. Prognostic Significance of Serum Albumin Level and Albumin-Based Mono- and Combination Biomarkers in Patients with Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15041005. [PMID: 36831351 PMCID: PMC9953807 DOI: 10.3390/cancers15041005] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the most life-threatening human cancers worldwide. Therefore, it is vitally important and urgently needed to develop valuable and independent prognostic biomarkers for the early prediction of poor prognosis in HCC patients, allowing more time for more timely and appropriate treatment to improve the survival of patients. As the most abundant protein in plasma, human serum albumin (ALB) is predominantly expressed by the liver and exhibits a wide variety of essential biological functions. It has been well recognized that serum ALB level is a significant independent biomarker for a broad spectrum of human diseases including cancer. Moreover, ALB has been commonly used as a potent biomaterial and therapeutic agent in clinical settings for the treatment of various human diseases. This review provides a comprehensive summary of the evidence from the up-to-date published literature to underscore the prognostic significance of serum ALB level and various ALB-based mono- and combination biomarkers in the prediction of the prognosis of HCC patients after treatment with different surgical, locoregional, and systemic therapies.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan
- Department of Surgery, China Medical University Hospital, Taichung 404, Taiwan
- Cell Therapy Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Wen-Ling Chan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 413, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Program for Cancer Biology and Drug Development, China Medical University, Taichung 404, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung 404, Taiwan
- Correspondence: ; Tel.: +886-4-2205-2121; Fax: +886-4-2202-9083
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Canillas L, Pelegrina A, Álvarez J, Colominas-González E, Salar A, Aguilera L, Burdio F, Montes A, Grau S, Grande L, Carrión JA. Clinical Guideline on Perioperative Management of Patients with Advanced Chronic Liver Disease. LIFE (BASEL, SWITZERLAND) 2023; 13:life13010132. [PMID: 36676081 PMCID: PMC9860873 DOI: 10.3390/life13010132] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023]
Abstract
(1) Background: Patients with advanced chronic liver disease (ACLD) are living longer with more comorbidities because of improved medical and surgical management. However, patients with ACLD are at increased risk of perioperative morbidity and mortality; (2) Methods: We conducted a comprehensive review of the literature to support a narrative clinical guideline about the assessment of mortality risk and management of perioperative morbidity in patients with ACLD undergoing surgical procedures; (3) Results: Slight data exist to guide the perioperative management of patients with ACLD, and most recommendations are based on case series and expert opinion. The severity of liver dysfunction, portal hypertension, cardiopulmonary and renal comorbidities, and complexity of surgery and type (elective versus emergent) are predictors of perioperative morbidity and mortality. Expert multidisciplinary teams are necessary to evaluate and manage ACLD before, during, and after surgical procedures; (4) Conclusions: This clinical practice document updates the available data and recommendations to optimize the management of patients with advanced chronic liver disease who undergo surgical procedures.
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Affiliation(s)
- Lidia Canillas
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- Liver Section, Gastroenterology Department, Hospital del Mar, 08003 Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
| | - Amalia Pelegrina
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
- Department of Surgery, Hospital del Mar, 08003 Barcelona, Spain
| | - Juan Álvarez
- IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
- Anesthesia Department, Hospital del Mar, 08003 Barcelona, Spain
| | - Elena Colominas-González
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- Pharmacy Department, Hospital del Mar, 08003 Barcelona, Spain
| | - Antonio Salar
- Haematology Department, Hospital del Mar, 08003 Barcelona, Spain
| | - Lluís Aguilera
- IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
- Anesthesia Department, Hospital del Mar, 08003 Barcelona, Spain
| | - Fernando Burdio
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
- Department of Surgery, Hospital del Mar, 08003 Barcelona, Spain
| | - Antonio Montes
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
- Anesthesia Department, Hospital del Mar, 08003 Barcelona, Spain
| | - Santiago Grau
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- Pharmacy Department, Hospital del Mar, 08003 Barcelona, Spain
| | - Luis Grande
- Department of Surgery, Hospital del Mar, 08003 Barcelona, Spain
- Department de Medicina, Universitat Autònoma de Barcelona, 08003 Barcelona, Spain
| | - José A. Carrión
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- Liver Section, Gastroenterology Department, Hospital del Mar, 08003 Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
- Correspondence: ; Tel.: +93-248-3220; Fax: +93-221-8644
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de Mattos ÂZ, Simonetto DA, Terra C, Farias AQ, Bittencourt PL, Pase THS, Toazza MR, de Mattos AA. Albumin administration in patients with cirrhosis: Current role and novel perspectives. World J Gastroenterol 2022; 28:4773-4786. [PMID: 36156923 PMCID: PMC9476855 DOI: 10.3748/wjg.v28.i33.4773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 06/05/2022] [Accepted: 07/05/2022] [Indexed: 02/06/2023] Open
Abstract
Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.
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Affiliation(s)
- Ângelo Zambam de Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Douglas Alano Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55902, United States
| | - Carlos Terra
- Department of Gastroenterology, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil
| | | | | | - Tales Henrique Soares Pase
- Internal Medicine Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Marlon Rubini Toazza
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Angelo Alves de Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
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Simicic D, Cudalbu C, Pierzchala K. Overview of oxidative stress findings in hepatic encephalopathy: From cellular and ammonium-based animal models to human data. Anal Biochem 2022; 654:114795. [PMID: 35753389 DOI: 10.1016/j.ab.2022.114795] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/26/2022] [Accepted: 06/15/2022] [Indexed: 11/30/2022]
Abstract
Oxidative stress is a natural phenomenon in the body. Under physiological conditions intracellular reactive oxygen species (ROS) are normal components of signal transduction cascades, and their levels are maintained by a complex antioxidants systems participating in the in-vivo redox homeostasis. Increased oxidative stress is present in several chronic diseases and interferes with phagocytic and nervous cell functions, causing an up-regulation of cytokines and inflammation. Hepatic encephalopathy (HE) occurs in both acute liver failure (ALF) and chronic liver disease. Increased blood and brain ammonium has been considered as an important factor in pathogenesis of HE and has been associated with inflammation, neurotoxicity, and oxidative stress. The relationship between ROS and the pathophysiology of HE is still poorly understood. Therefore, sensing ROS production for a better understanding of the relationship between oxidative stress and functional outcome in HE pathophysiology is critical for determining the disease mechanisms, as well as to improve the management of patients. This review is emphasizing the important role of oxidative stress in HE development and documents the changes occurring as a consequence of oxidative stress augmentation based on cellular and ammonium-based animal models to human data.
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Affiliation(s)
- D Simicic
- CIBM Center for Biomedical Imaging, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland
| | - C Cudalbu
- CIBM Center for Biomedical Imaging, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - K Pierzchala
- CIBM Center for Biomedical Imaging, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland.
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32
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Bera C, Wong F. Management of hepatorenal syndrome in liver cirrhosis: a recent update. Therap Adv Gastroenterol 2022; 15:17562848221102679. [PMID: 35721838 PMCID: PMC9201357 DOI: 10.1177/17562848221102679] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 05/07/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatorenal syndrome (HRS) is a serious form of renal dysfunction in patients with cirrhosis and ascites. It is an important component of the acute-on-chronic liver failure (ACLF) syndrome. Significant recent changes in the understanding of the pathophysiology of renal dysfunction in cirrhosis include the role of inflammation in addition to hemodynamic changes. The term acute kidney injury (AKI) is now adopted to include all functional and structural forms of acute renal dysfunction in cirrhosis, with various stages describing the severity of the condition. Type 1 hepatorenal syndrome (HRS1) is renamed HRS-AKI, which is stage 2 AKI [doubling of baseline serum creatinine (sCr)] while fulfilling all other criteria of HRS1. Albumin is used for its volume expanding and anti-inflammatory properties to confirm the diagnosis of HRS-AKI. Vasoconstrictors are added to albumin as pharmacotherapy to improve the hemodynamics. Terlipressin, although not yet available in North America, is the most common vasoconstrictor used worldwide. Patients with high grade of ACLF treated with terlipressin are at risk for respiratory failure if there is pretreatment respiratory compromise. Norepinephrine is equally effective as terlipressin in reversing HRS1. Recent data show that norepinephrine may be administered outside the intensive care setting, but close monitoring is still required. There has been no improvement in overall or transplant-free survival shown with vasoconstrictor use, but response to vasoconstrictors with reduction in sCr is associated with improvement in survival. Non-responders to vasoconstrictor plus albumin will need liver transplantation as definite treatment with renal replacement therapy as a bridge therapy. Combined liver and kidney transplantation is recommended for patients with prolonged history of AKI, underlying chronic kidney disease or with hereditary renal conditions. Future developments, such as the use of biomarkers and metabolomics, may help to identify at risk patients with earlier diagnosis to allow for earlier treatment with improved outcomes.
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Affiliation(s)
- Chinmay Bera
- Division of Gastroenterology and Hepatology,
Department of Medicine, Toronto General Hospital, University Health Network,
University of Toronto, Toronto, ON, Canada
| | - Florence Wong
- Division of Gastroenterology and Hepatology,
Department of Medicine, Toronto General Hospital, University Health Network,
University of Toronto, 9EN/222 Toronto General Hospital, 200 Elizabeth
Street, 9EN222, Toronto, ON M5G2C4, Canada
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33
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Caraceni P, O'Brien A, Gines P. Long-term albumin treatment in patients with cirrhosis and ascites. J Hepatol 2022; 76:1306-1317. [PMID: 35589252 DOI: 10.1016/j.jhep.2022.03.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 03/02/2022] [Accepted: 03/14/2022] [Indexed: 01/29/2023]
Abstract
Although proposed for the first time several decades ago, the possibility that long-term human albumin could be effective for the treatment of patients with cirrhosis and ascites has become a topic of scientific and clinical discussion in the last decade. Long-term albumin administration represents a completely different treatment perspective compared to acute or short-term uses of albumin. Results from the ANSWER and the MACHT studies indicate that long-term albumin treatment can be effective, safe and able to modify the course of the disease provided that albumin is given at a sufficient dose and for a sufficient time to restore physiological levels and functions of the circulating molecule, which are compromised, at least partially, in patients with decompensated cirrhosis. Further clinical studies and randomised trials are warranted to confirm the clinical benefits of long-term albumin therapy. Important areas for further research include determining the precise target population, the biomarkers of response, the optimal dose and frequency of albumin infusions, the stopping rules, and the cost-effectiveness of treatment in different healthcare systems across the world, particularly in those where the logistical issues and costs related to the periodic intravenous infusions may represent an important limitation to the implementation of this innovative approach in clinical practice. In this review, we will critically analyse the available data on long-term albumin treatment, focusing on the differences that exist between studies, the controversial issues and the future perspectives.
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Affiliation(s)
- Paolo Caraceni
- IRCCS Azienda Ospedaliera-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences and Center for Biomedical Applied Research, Alma Mater Studiorum University of Bologna, Italy.
| | - Alastair O'Brien
- UCL Institute for Liver and Digestive Health, Upper 3rd Floor, Division of Medicine, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Pere Gines
- Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Catalonia, Spain
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34
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Artru F, McPhail MJW, Triantafyllou E, Trovato FM. Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids. Front Immunol 2022; 13:867261. [PMID: 35432367 PMCID: PMC9008479 DOI: 10.3389/fimmu.2022.867261] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/08/2022] [Indexed: 12/30/2022] Open
Abstract
Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.
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Affiliation(s)
- Florent Artru
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Mark J W McPhail
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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35
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Albillos A, Martin-Mateos R, Van der Merwe S, Wiest R, Jalan R, Álvarez-Mon M. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 2022; 19:112-134. [PMID: 34703031 DOI: 10.1038/s41575-021-00520-7] [Citation(s) in RCA: 202] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 02/08/2023]
Abstract
The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.
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Affiliation(s)
- Agustín Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. .,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
| | - Rosa Martin-Mateos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Schalk Van der Merwe
- Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, University Inselspital, Bern, Switzerland
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Melchor Álvarez-Mon
- Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Department of Internal Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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Cao J, Qiu W, Yu Y, Li N, Wu H, Chen Z. The association between serum albumin and depression in chronic liver disease may differ by liver histology. BMC Psychiatry 2022; 22:5. [PMID: 34983435 PMCID: PMC8729006 DOI: 10.1186/s12888-021-03647-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 12/06/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND There are conflicting results regarding the association between chronic liver disease (CLD) and depression and the underlying biological mechanisms are lack of investigation. To address the impact of depression and its effects on the management of CLD, its biological marker is critical to be identified. The present study explored the association between serum albumin and depression in CLD patients and whether the association varied in different liver histological stages. METHODS Based on the United States National Health and Nutrition Examination Survey 2017-2018, the data of serum albumin and depressive symptoms from 627 participants with CLD were used. Depression symptoms were assessed with the nine-item Patient Health Questionnaire (PHQ-9). We used multivariate linear regression to evaluate the association between serum albumin and PHQ-9 scores. Stratified analysis was performed according to the liver histology examined by vibration controlled transient elastography. RESULTS Serum albumin level was inversely associated with PHQ-9 scores in the multivariate regression model after adjusting for mainly potential confounders (β = - 1.113, 95% CI: - 2.065 to - 0.162, P = 0.0221). In the subgroup analysis stratified by gender, controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), the inverse association remained significant in female (β = - 2.002, 95% CI: - 3.515 to - 0.489, P = 0.0100), patients with CAP < 274 dB/m (β = - 2.215, 95% CI: - 3.621 to - 0.808, P = 0.0023) and patients with LSM ≥8.2 kPa (β = - 4.074, 95% CI: - 6.237 to - 1.911, P = 0.0003). Moreover, the association was much stronger when the serum albumin was higher than 3.4 g/dL among patients with LSM ≥8.2 kPa (β = - 4.835, 95% CI: - 7.137 to - 2.533, P < 0.0001). CONCLUSION Our study revealed an inverse association between serum albumin and depression in CLD patients and this association differed according to liver histological changes. Serum albumin could be a warning marker for depressive symptoms in CLD patients. It is essential for taking corresponding intervention strategies.
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Affiliation(s)
- Junyan Cao
- grid.412558.f0000 0004 1762 1794Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630 China
| | - Weihong Qiu
- grid.412558.f0000 0004 1762 1794Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630 China
| | - Yong Yu
- grid.412558.f0000 0004 1762 1794Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630 China
| | - Na Li
- grid.412558.f0000 0004 1762 1794Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630 China
| | - Huixiang Wu
- grid.412558.f0000 0004 1762 1794Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630 China
| | - Zhaocong Chen
- Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China.
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37
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Simonetti RG, Perricone G, Gluud C. Albumin for people with liver cirrhosis and bacterial infections. Hippokratia 2021. [DOI: 10.1002/14651858.cd014636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Rosa G Simonetti
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research; Capital Region, Rigshospitalet, Copenhagen University Hospital; Copenhagen Denmark
| | | | - Christian Gluud
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research; Capital Region, Rigshospitalet, Copenhagen University Hospital; Copenhagen Denmark
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38
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Grüngreiff K, Gottstein T, Reinhold D, Blindauer CA. Albumin Substitution in Decompensated Liver Cirrhosis: Don't Forget Zinc. Nutrients 2021; 13:4011. [PMID: 34836265 PMCID: PMC8618355 DOI: 10.3390/nu13114011] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/12/2022] Open
Abstract
Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2-4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes.
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Affiliation(s)
- Kurt Grüngreiff
- Clinic of Gastroenterology, City Hospital Magdeburg GmbH, 39130 Magdeburg, Germany;
| | - Thomas Gottstein
- Clinic of Gastroenterology, City Hospital Magdeburg GmbH, 39130 Magdeburg, Germany;
| | - Dirk Reinhold
- Medical Faculty, Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, 39120 Magdeburg, Germany;
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Jagdish RK, Maras JS, Sarin SK. Albumin in Advanced Liver Diseases: The Good and Bad of a Drug! Hepatology 2021; 74:2848-2862. [PMID: 33772846 DOI: 10.1002/hep.31836] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 02/13/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022]
Abstract
Human serum albumin is the most abundant plasma protein, and it regulates diverse body functions. In patients with advanced and decompensated cirrhosis, serum albumin levels are low because of a reduction in the hepatocyte mass due to disease per se and multiple therapeutic interventions. Because of their oncotic and nononcotic properties, administration of human albumin solutions (HAS) have been found to be beneficial in patients undergoing large-volume paracentesis or who have hepatorenal syndrome or spontaneous bacterial peritonitis. Albumin also improves the functionality of the immune cells and mitigates the severity and risk of infections in advanced cirrhosis. Its long-term administration can modify the course of decompensated cirrhosis patients by reducing the onset of new complications, improving the quality of life, and probably providing survival benefits. There is, however, a need to rationalize the dose, duration, and frequency of albumin therapy in different liver diseases and stages of cirrhosis. In patients with acute-on-chronic liver failure, potentially toxic oxidized isoforms of albumin increase substantially, especially human nonmercaptalbumin and 2, and nitrosoalbumin. The role of administration of HAS in such patients is unclear. Determining whether removal of the pathological and dysfunctional albumin forms in these patients by "albumin dialysis" is helpful, requires additional studies. Use of albumin is not without adverse events. These mainly include allergic and transfusion reactions, volume overload, antibody formation and coagulation derangements. Considering their cost, limited availability, need for a health care setting for their administration, and potential adverse effects, judicious use of HAS in liver diseases is advocated. There is a need for new albumin molecules and economic alternatives in hepatologic practice.
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Affiliation(s)
- Rakesh Kumar Jagdish
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Jaswinder Singh Maras
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Nongnuch A, Kitiyakara C, Sappadungsuk S, Sathirapongsasuti N, Vipattawat K, Zhang P, Davies N, Davenport A. Pilot study to investigate differences in middle molecules, oxidative stress and markers of peripheral vascular disease in patients treated by high flux haemodialysis and haemodiafiltration. PLoS One 2021; 16:e0258223. [PMID: 34614018 PMCID: PMC8494338 DOI: 10.1371/journal.pone.0258223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
Background Dialysis patients have an increased risk of mortality. Recently treatment with haemodiafiltration (HDF) has been reported to reduce mortality, particularly cardiovascular mortality, compared to standard high-flux haemodialysis (HD). However, why HDF may offer a survival advantage remains to be determined. So, we conducted a pilot study to explore differences in middle-molecules, inflammation and markers of vascular disease in patients treated by HD and HDF. Methods Observational cross-sectional study measuring serum β2-microglobulin (β2M), Advanced Glycosylation End Products (AGEs) by skin autofluorescence (SAF), oxidative stress with ischaemia modified albumin ratio (IMAR) and peripheral vascular disease assessment using Ankle-Brachial Index (ABI), and arterial stiffness using Cardio-Ankle Vascular Index (CAVI). Results We studied 196 patients, mean age 69.1 ± 12.4 years, 172 (87.8%) treated by HD and 24 (12.2%) by HDF. Age, body mass index, co-morbidity and dialysis vintage were not different between HD and HDF groups. Middle molecules; β2M (31±9.9 vs 31.2±10 ug/mL) and SAF (2.99±0.72 vs 3.0±0.84 AU), ABI (1.06±0.05 vs 1.07±0.10) and CAVI (9.34±1.55 vs 9.35±1.23) were not different, but IMAR was higher in the HD patients (38.4±14.8 vs 31.3 ± 17.4, P = 0.035) Conclusions In this pilot observational study, we found patients treated by HDF had lower oxidative stress as measured by IMAR, with no differences in middle molecules. Lower oxidative stress would be expected to have diverse protective effects on the cardiovascular system Although we found no differences in ABI and CAVI, future studies are required to determine whether reduced oxidative stress translates into clinically relevant differences over time.
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Affiliation(s)
- Arkom Nongnuch
- Renal Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- * E-mail:
| | - Chagriya Kitiyakara
- Renal Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Supawadee Sappadungsuk
- Renal Unit, Department of Medicine, Faculty of Medicine, Chakri Naruebodindra Medical Institute, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nuankanya Sathirapongsasuti
- Section of Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Pin Zhang
- Department of Medicine, University College London, London, United Kingdom
| | - Nathan Davies
- Department of Medicine, University College London, London, United Kingdom
| | - Andrew Davenport
- UCL Centre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom
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Maruyama H, Shiina S. Connection between HPS and ACLF: a solution of chaos? Hepatol Int 2021; 15:1049-1052. [PMID: 34606063 PMCID: PMC8488067 DOI: 10.1007/s12072-021-10255-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/11/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Hitoshi Maruyama
- Department of Gastroenterology, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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Mehta G, Jalan R. The "Alter Ego" of Albumin in Cirrhosis. Hepatology 2021; 74:1734-1736. [PMID: 34009686 DOI: 10.1002/hep.31908] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/20/2021] [Accepted: 04/28/2021] [Indexed: 01/05/2023]
Affiliation(s)
- Gautam Mehta
- UCL Institute for Liver and Digestive Health, Royal Free Campus, London, United Kingdom
| | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Royal Free Campus, London, United Kingdom
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Baldassarre M, Naldi M, Zaccherini G, Bartoletti M, Antognoli A, Laggetta M, Gagliardi M, Tufoni M, Domenicali M, Waterstradt K, Paterini P, Baldan A, Leoni S, Bartolini M, Viale P, Trevisani F, Bernardi M, Caraceni P. Determination of Effective Albumin in Patients With Decompensated Cirrhosis: Clinical and Prognostic Implications. Hepatology 2021; 74:2058-2073. [PMID: 33710623 PMCID: PMC8518406 DOI: 10.1002/hep.31798] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/21/2021] [Accepted: 02/11/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Circulating albumin in cirrhosis can be dysfunctional because of accumulating structural damages, leading to the concept of effective albumin concentration (eAlb), referring to the albumin portion presenting structural and functional integrity. We aimed to estimate eAlb in patients with decompensated cirrhosis and analyze its relationships with albumin function and clinical outcomes as compared to total albumin concentration (tAlb). APPROACH AND RESULTS We evaluated 319 patients with cirrhosis hospitalized for acute decompensation (AD) with and without acute-on-chronic liver failure (ACLF) and 18 age- and sex-comparable outpatients with compensated cirrhosis. tAlb was quantified by standard assay, whereas eAlb was estimated combining liquid chromatography/electrospray ionization/mass spectrometry and standard methods. Albumin binding and detoxification efficiency were evaluated by electron paramagnetic resonance analysis. Circulating albumin in patients with decompensated cirrhosis displayed multiple structural abnormalities, with reversible oxidation and glycation being the most frequent. As a result, eAlb progressively declined with the worsening of cirrhosis and was superior to tAlb in stratifying patients between compensated cirrhosis, AD, and ACLF, as well as patients with and without complications. Moreover, eAlb, but not tAlb, was closely associated with binding capacities in ACLF. Finally, eAlb at admission predicted the occurrence of ACLF within 30 days and mortality at 90 days better than tAlb. CONCLUSIONS This large, observational study provides the evidence in patients with decompensated cirrhosis that eAlb can be quantified and differentiated from tAlb routinely measured in clinical practice. As compared to tAlb, eAlb is more closely associated with disease severity and albumin dysfunction and carries a greater prognostic power. These results prompt future research assessing eAlb as a biomarker for predicting prognosis and treatment response.
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Affiliation(s)
- Maurizio Baldassarre
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Centre for Applied Biomedical Research–CRBAAlma Mater Studiorum University of BolognaSt. Orsola HospitAlbolognaItaly
| | - Marina Naldi
- Centre for Applied Biomedical Research–CRBAAlma Mater Studiorum University of BolognaSt. Orsola HospitAlbolognaItaly,Department of Pharmacy and BiotechnologyAlma Mater Studiorum University of BolognaBolognaItaly
| | - Giacomo Zaccherini
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Michele Bartoletti
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Agnese Antognoli
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Maristella Laggetta
- Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Martina Gagliardi
- Centre for Applied Biomedical Research–CRBAAlma Mater Studiorum University of BolognaSt. Orsola HospitAlbolognaItaly,Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Manuel Tufoni
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly
| | - Marco Domenicali
- Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly,Department of Internal MedicineS. Maria delle Croci HospitalAUSL RomagnaRavennaItaly
| | | | - Paola Paterini
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Centre for Applied Biomedical Research–CRBAAlma Mater Studiorum University of BolognaSt. Orsola HospitAlbolognaItaly
| | - Anna Baldan
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly
| | - Simona Leoni
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly
| | - Manuela Bartolini
- Department of Pharmacy and BiotechnologyAlma Mater Studiorum University of BolognaBolognaItaly
| | - Pierluigi Viale
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Franco Trevisani
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Mauro Bernardi
- Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
| | - Paolo Caraceni
- IRCSS Azienda Ospedaliero–Universitaria di BolognaBolognaItaly,Department of Medical and Surgical SciencesAlma Mater Studiorum University of BolognaBolognaItaly
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Li Y, Liu H, Chen K, Wu X, Wu J, Yang Z, Yao L, Wen G, Zhang C, Chen X, Chen X, Tang D, Wang X, Liu J. Pathological Significance and Prognostic Roles of Indirect Bilirubin/Albumin Ratio in Hepatic Encephalopathy. Front Med (Lausanne) 2021; 8:706407. [PMID: 34527681 PMCID: PMC8435674 DOI: 10.3389/fmed.2021.706407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/10/2021] [Indexed: 11/27/2022] Open
Abstract
Background and Aim: Hepatic encephalopathy (HE) is a neurological disease caused by severe liver disease. Early identification of the risk factor is beneficial to the prevention and treatment of HE. Free bilirubin has always been considered to be the culprit of neonatal kernicterus, but there is no research to explore its role in HE. In this study, we aim to study the clinical significance of the indirect bilirubin-albumin ratio in HE. Methods: A retrospective case-control study of 204 patients with liver failure was conducted. Human serum albumin (HSA) or heme oxygenase-1 (HO-1) inhibitor SnPP (Tin protoporphyrin IX dichloride) was injected intraperitoneally into Ugt1−/− mice to establish a treatment model for endogenous hyperbilirubinemia. Results: IBil/albumin ratio (OR = 1.626, 95% CI1.323–2.000, P < 0.001), white blood cell (WBC) (OR = 1.128, 95% CI 1.009–1.262, P = 0.035), ammonia (OR = 1.010, 95% CI 1.001–1.019, P = 0.027), platelet (OR=1.008, 95% CI 1.001–1.016, P = 0.022), Hb (OR = 0.977, 95% CI 0.961–0.994, P = 0.007), and PTA (OR = 0.960, 95% CI 0.933–0.987, P = 0.005) were independent factors of HE. Patients with a history of liver cirrhosis and severe HE (OR = 12.323, 95% CI 3.278–47.076, P < 0.001) were more likely to die during hospitalization. HSA or SnPP treatment improved cerebellum development and reduced apoptosis of cerebellum cells. Conclusion: The IBil/albumin ratio constitutes the most powerful risk factor in the occurrence of HE, and reducing free bilirubin may be a new strategy for HE treatment.
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Affiliation(s)
- Yanling Li
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Huiyuan Liu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Keng Chen
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xueheng Wu
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jiawen Wu
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Zhenjun Yang
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Leyi Yao
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Institute of Digestive Disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Guanmei Wen
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Change Zhang
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xin Chen
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xiaohui Chen
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Xuejun Wang
- Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD, United States
| | - Jinbao Liu
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Institute of Digestive Disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
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Jeng LB, Li TC, Hsu SC, Chan WL, Teng CF. Association of Low Serum Albumin Level with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection. J Clin Med 2021; 10:jcm10184187. [PMID: 34575311 PMCID: PMC8464848 DOI: 10.3390/jcm10184187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/11/2021] [Accepted: 09/14/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is, globally, one of the most prevalent and deadly human cancers; despite curative surgical resection, its high recurrence rate after surgery remains a large threat, resulting in poor patient survival. The hepatitis B virus (HBV) pre-S2 mutant that harbors deletions spanning the pre-S2 gene segment has emerged as an important oncoprotein for HCC development and a valuable prognostic biomarker for HCC recurrence; however, its relationship with clinicopathological factors is largely unexplored. In this study, the correlation of the deletion spanning the pre-S2 gene segment with clinicopathological factors and the association of such correlation with HCC recurrence after curative surgical resection were examined in HBV-related HCC patients. Inverse correlation between serum albumin level and the deletion spanning the pre-S2 gene segment was identified. HCC patients with the presence of the deletion spanning the pre-S2 gene segment and a low serum albumin level were associated with higher HCC recurrence than patients with either factor alone or neither factor were. Moreover, a combination of the serum albumin level and the deletion spanning the pre-S2 gene segment exhibited better performance than that of either factor alone in predicting HCC recurrence. Collectively, this study shows an association of low serum albumin level with pre-S2 mutant-positive HCC patients, and validates the prognostic value of this association in identifying patients with higher HCC recurrence after curative surgical resection.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung City 404, Taiwan; (L.-B.J.); (S.-C.H.)
- Department of Surgery, China Medical University Hospital, Taichung City 404, Taiwan
- School of Medicine, China Medical University, Taichung City 404, Taiwan
| | - Tsai-Chung Li
- Department of Public Health, College of Public Health, China Medical University, Taichung City 404, Taiwan;
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung City 404, Taiwan
| | - Shih-Chao Hsu
- Organ Transplantation Center, China Medical University Hospital, Taichung City 404, Taiwan; (L.-B.J.); (S.-C.H.)
- Department of Surgery, China Medical University Hospital, Taichung City 404, Taiwan
- School of Medicine, China Medical University, Taichung City 404, Taiwan
| | - Wen-Ling Chan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung City 404, Taiwan;
- Epigenome Research Center, China Medical University Hospital, Taichung City 404, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung City 404, Taiwan; (L.-B.J.); (S.-C.H.)
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung City 404, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung City 404, Taiwan
- Correspondence: ; Tel.: +886-4-2205-2121; Fax: +886-4-2202-9083
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Marquez V. Albumin infusions and decompensated cirrhosis: No longer the elixir of life? CANADIAN LIVER JOURNAL 2021; 4:338-339. [DOI: 10.3138/canlivj-2021-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/06/2021] [Indexed: 11/20/2022]
Affiliation(s)
- Vladimir Marquez
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
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47
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Transition to decompensation and acute-on-chronic liver failure: Role of predisposing factors and precipitating events. J Hepatol 2021; 75 Suppl 1:S36-S48. [PMID: 34039491 DOI: 10.1016/j.jhep.2020.12.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022]
Abstract
The transition from compensated to decompensated cirrhosis results from a complex interplay of predisposing and precipitating factors and represents an inflection point in the probability of a patient surviving. With the progression of cirrhosis, patients accumulate multiple disorders (e.g. altered liver architecture, portal hypertension, local and systemic inflammation, bacterial translocation, gut dysbiosis, kidney vasoconstriction) that predispose them to decompensation. On the background of these factors, precipitating events (e.g. bacterial infection, alcoholic hepatitis, variceal haemorrhage, drug-induced liver injury, flare of liver disease) lead to acute decompensation (ascites, hepatic encephalopathy, variceal bleeding, jaundice) and/or organ failures, which characterise acute-on-chronic liver failure. In this review paper, we will discuss the current hypotheses and latest evidences regarding predisposing and precipitating factors associated with the transition to decompensated liver disease.
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48
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Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021; 75 Suppl 1:S49-S66. [PMID: 34039492 PMCID: PMC9272511 DOI: 10.1016/j.jhep.2021.01.002] [Citation(s) in RCA: 203] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acute-on-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure(s). The pathomechanisms involved in decompensation and disease progression are still not well understood, and as specific disease-modifying treatments do not exist, research to identify novel therapeutic targets is of the utmost importance. This review amalgamates the latest knowledge on disease mechanisms that lead to tissue injury and extrahepatic organ failure - such as systemic inflammation, mitochondrial dysfunction, oxidative stress and metabolic changes - and marries these with the classical paradigms of acute decompensation to form a single paradigm. With this detailed breakdown of pathomechanisms, we identify areas for future research. Novel disease-modifying strategies that break the vicious cycle are urgently required to improve patient outcomes.
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Affiliation(s)
- Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany; Institute for Liver and Digestive Health, University College London, London, United Kingdom; Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain,Biochemistry and Molecular Genetics Service, Hospital ClínicIDIBAPS and CIBERehd, Spain,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
| | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Jaume Bosch
- IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain,Department for Biomedical Research (DBMR), Bern University, Bern, Switzerland
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences; Alma Mater Studiorum – University of Bologna; Italy
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Diagnostic Potential of Low Serum Platelet, Albumin and Prolong PT-INR for Overactive Bladder and Nocturia in Chronic Hepatitis-Related Liver Cirrhosis. J Clin Med 2021; 10:jcm10132838. [PMID: 34198972 PMCID: PMC8268050 DOI: 10.3390/jcm10132838] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/10/2021] [Accepted: 06/24/2021] [Indexed: 01/16/2023] Open
Abstract
Overactive bladder (OAB) is defined as urgency, usually with frequency, nocturia, and incontinence. Patients with liver cirrhosis often present with urinary complaints. The possible reason for this is fluid redistribution, which may induce OAB resulting from portal hypertension and ascites. We conducted this study to investigate predictors of OAB in cirrhotic patients. A total of 164 patients with chronic viral hepatitis-related liver cirrhosis were enrolled and 158 (96.3%) completed the Overactive Bladder Symptoms Score (OABSS) questionnaire. Age, severity of liver cirrhosis, comorbidities, serum sodium level, use of diuretics, body mass index and renal function were also recorded. In the study cohort, the prevalence of OAB was 31.01% and the prevalence of urge incontinence (OAB wet) was 18.3%. Patients with an urgency score ≥2 in OABSS had a significantly lower platelet level (p = 0.025) regardless of the use of diuretics. In addition, 98 patients (62%) with nocturia and 29 patients (18%) with urge incontinence had significantly lower levels of serum albumin (p = 0.028 and 0.044, respectively). In conclusion, patients with liver cirrhosis have a high prevalence of overactive bladder. A low platelet and low serum albumin level in these patients may be predictors for overactive bladder. And longer PT-INR is also a possible biomarker for nocturia.
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Paar M, Fengler VH, Rosenberg DJ, Krebs A, Stauber RE, Oettl K, Hammel M. Albumin in patients with liver disease shows an altered conformation. Commun Biol 2021; 4:731. [PMID: 34127764 PMCID: PMC8203801 DOI: 10.1038/s42003-021-02269-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 05/27/2021] [Indexed: 12/14/2022] Open
Abstract
Human serum albumin (HSA) constitutes the primary transporter of fatty acids, bilirubin, and other plasma compounds. The binding, transport, and release of its cargos strongly depend on albumin conformation, which is affected by bound ligands induced by physiological and pathological conditions. HSA is both highly oxidized and heavily loaded with fatty acids and bilirubin in chronic liver disease. By employing small-angle X-ray scattering we show that HSA from the plasma of chronic liver disease patients undergoes a distinct opening compared to healthy donors. The extent of HSA opening correlates with clinically relevant variables, such as the model of end-stage liver disease score, bilirubin, and fatty acid levels. Although the mild oxidation of HSA in vitro does not alter overall structure, the alteration of patients’ HSA correlates with its redox state. This study connects clinical data with structural visualization of albumin dynamicity in solution and underlines the functional importance of albumin’s inherent flexibility. Paar et al. propose a SAXS-based approach to study conformations of human serum albumin (HSA) from patients with liver disease and a structural understanding of HSA dynamicity and its correlation with clinical variables are provided. Using it on real clinical samples, this study has concrete practical implications too.
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Affiliation(s)
- Margret Paar
- Division of Physiological Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Vera H Fengler
- Division of Physiological Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Daniel J Rosenberg
- Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.,Graduate Group in Biophysics, University of California, Berkeley, CA, USA
| | - Angelika Krebs
- Science Technology Interface-Structural Biology, Center for Medical Research, Medical University of Graz, Graz, Austria
| | - Rudolf E Stauber
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Karl Oettl
- Division of Physiological Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria.
| | - Michal Hammel
- Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
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