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Zhang J, Li Y, Wang Y, Li Z, Li X, Bao H, Li J, Zhou D. Transcriptome Sequencing and Metabolite Analysis Revealed the Single and Combined Effects of Microplastics and Di-(2-ethylhexyl) Phthalate on Mouse Liver. Int J Mol Sci 2025; 26:4943. [PMID: 40430083 PMCID: PMC12112587 DOI: 10.3390/ijms26104943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 05/12/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025] Open
Abstract
The widespread use of plastics has led to a substantial increase in plastic waste, resulting in the dissemination of plastic debris throughout ecosystems and posing significant threats to biota. Bis(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer, enhances plastic flexibility but may also exert subtle toxic effects. This study aimed to investigate the potential toxicological impacts and underlying mechanisms of microplastics (MPs), di-(2-ethylhexyl) phthalate (DEHP), and their combined exposure (MPs + DEHP) on oxidative stress, apoptotic damage, transcriptomic alterations, and metabolic disturbances in mice. The results demonstrated that exposure to MPs, DEHP, and MPs + DEHP impaired the antioxidant defense system and reduced overall antioxidant capacity. Concurrently, all three exposure conditions significantly increased biochemical markers, particularly those associated with liver dysfunction, prompting further analysis of hepatic tissues. Histopathological examination revealed apoptotic damage in hepatocytes. Integrated transcriptomic and metabolomic analyses indicated that exposure to MPs, DEHP, and MPs + DEHP disrupted carbohydrate, amino acid, and lipid metabolism, induced the expression of genes related to hepatocarcinogenesis, and impaired purine metabolism. Moreover, MP and DEHP exposure aggravated hepatic apoptosis and inflammatory responses via activation of the PI3K/AKT signaling pathway, thereby eliciting notable biotoxic effects. These findings provide new scientific evidence regarding the individual and combined toxicological effects of MPs and the plastic additive DEHP on living organisms.
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Affiliation(s)
| | | | | | | | | | | | - Jiakui Li
- College of Animal Medicine, Huazhong Agricultural University, Wuhan 430070, China; (J.Z.); (Y.L.); (Y.W.); (Z.L.); (X.L.); (H.B.)
| | - Donghai Zhou
- College of Animal Medicine, Huazhong Agricultural University, Wuhan 430070, China; (J.Z.); (Y.L.); (Y.W.); (Z.L.); (X.L.); (H.B.)
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Hagenbuch B, Stieger B, Locher KP. Organic anion transporting polypeptides: Pharmacology, toxicology, structure, and transport mechanisms. Pharmacol Rev 2025; 77:100023. [PMID: 40148036 DOI: 10.1016/j.pharmr.2024.100023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 11/12/2024] [Indexed: 03/29/2025] Open
Abstract
Organic anion transporting polypeptides (OATPs) are membrane proteins that mediate the uptake of a wide range of substrates across the plasma membrane of various cells and tissues. They are classified into 6 subfamilies, OATP1 through OATP6. Humans contain 12 OATPs encoded by 11 solute carrier of organic anion transporting polypeptide (SLCO) genes: OATP1A2, OATP1B1, OATP1B3, the splice variant OATP1B3-1B7, OATP1C1, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OATP4C1, OATP5A1, and OATP6A1. Most of these proteins are expressed in epithelial cells, where they mediate the uptake of structurally unrelated organic anions, cations, and even neutral compounds into the cytoplasm. The best-characterized members are OATP1B1 and OATP1B3, which have an important role in drug metabolism by mediating drug uptake into the liver and are involved in drug-drug interactions. In this review, we aimed to (1) provide a historical perspective on the identification of OATPs and their nomenclature and discuss their phylogenic relationships and molecular characteristics; (2) review the current knowledge of the broad substrate specificity and their role in drug disposition and drug-drug interactions, with a special emphasis on human hepatic OATPs; (3) summarize the different experimental systems that are used to study the function of OATPs and discuss their advantages and disadvantages; (4) review the available experimental 3-dimensional structures and examine how they can help elucidate the transport mechanisms of OATPs; and (5) finally, summarize the current knowledge of the regulation of OATP expression, discuss clinically important single-nucleotide polymorphisms, and outline challenges of physiologically based pharmacokinetic modeling and in vitro to in vivo extrapolation. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (OATPs) are a family of 12 uptake transporters in the solute carrier superfamily. Several members, particularly the liver-expressed OATP1B1 and OATP1B3, are important drug transporters. They mediate the uptake of several endobiotics and xenobiotics, including statins and numerous other drugs, into hepatocytes, and their inhibition by other drugs or reduced expression due to single-nucleotide polymorphisms can lead to adverse drug effects. Their recently solved 3-dimensional structures should help to elucidate their transport mechanisms and broad substrate specificities.
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Affiliation(s)
- Bruno Hagenbuch
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas.
| | - Bruno Stieger
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Kaspar P Locher
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
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Pantea R, Bednarsch J, Schmitz S, Meister P, Heise D, Ulmer F, Neumann UP, Lang SA. The assessment of impaired liver function and prognosis in hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2024; 18:779-794. [PMID: 39688572 DOI: 10.1080/17474124.2024.2442573] [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: 10/16/2024] [Revised: 12/05/2024] [Accepted: 12/11/2024] [Indexed: 12/18/2024]
Abstract
INTRODUCTION The impairment of liver function strongly limits the therapeutic options for hepatocellular carcinoma (HCC), and the assessment of liver function is key to finding the appropriate therapy for patients suffering from this disease. Furthermore, preexisting liver dysfunction has a negative impact on the prognosis of patients in addition to the malignant potential of HCC. Hence, defining the optimal treatment of patients with HCC requires a comprehensive examination with liver function being a crucial part of it. AREAS COVERED This review will provide an overview of the currently existing methods for evaluating the liver function in patients with HCC. Assessment of liver function includes scoring systems but also functional and technical methods. In addition, the role of these tests in different treatment facilities such as liver resection, transplantation, interventional and systemic therapy is summarized. EXPERT OPINION A comprehensive pretherapeutic assessment of the liver function includes laboratory-based scoring systems, as well as imaging- and non-imaging-based functional tests. Combining diverse parameters can help to improve the safety and efficacy of HCC therapy particularly in patients with compromised liver function. Future research should focus on optimizing pretherapeutic assessment recommendations for each therapy.
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Affiliation(s)
- Roxana Pantea
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Jan Bednarsch
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Sophia Schmitz
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Phil Meister
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Daniel Heise
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Sven Arke Lang
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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Tabone T, Mooney P, Donnellan C. Intestinal failure-associated liver disease: Current challenges in screening, diagnosis, and parenteral nutrition considerations. Nutr Clin Pract 2024; 39:1003-1025. [PMID: 38245851 DOI: 10.1002/ncp.11116] [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: 07/26/2023] [Revised: 12/19/2023] [Accepted: 12/25/2023] [Indexed: 01/22/2024] Open
Abstract
Intestinal failure-associated liver disease (IFALD) is a serious life-limiting complication that can occur throughout the clinical course of intestinal failure and its management by parenteral nutrition (PN). Despite this, there is a lack of a standardized definition for IFALD, which makes this insidious condition increasingly difficult to screen and diagnose in clinical practice. Attenuating the progression of liver disease before the onset of liver failure is key to improving morbidity and mortality in these patients. This requires timely detection and promptly addressing reversible factors. Although there are various noninvasive tools available to the clinician to detect early fibrosis or cirrhosis in various chronic liver disease states, these have not been validated in the patient population with IFALD. Such tools include biochemical composite scoring systems for fibrosis, transient elastography, and dynamic liver function tests. This review article aims to highlight the existing real need for an accurate, reproducible method to detect IFALD in its early stages. In addition, we also explore the role PN plays in the pathogenesis of this complex multifactorial condition. Various aspects of PN administration have been implicated in the etiology of IFALD, including the composition of the lipid component, nutrient excess and deficiency, and infusion timing. We aim to highlight the clinical relevance of these PN-associated factors in the development of IFALD and how these can be managed to mitigate the progression of IFALD.
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Affiliation(s)
- Trevor Tabone
- Department of Gastroenterology, St James University Hospital, Leeds, United Kingdom
| | - Peter Mooney
- Department of Gastroenterology, St James University Hospital, Leeds, United Kingdom
| | - Clare Donnellan
- Department of Gastroenterology, St James University Hospital, Leeds, United Kingdom
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Ray GS, Streeter SS, Bateman LM, Elliott JT, Henderson ER, NEFARIOUS Study Group. Real-time identification of life-threatening necrotizing soft-tissue infections using indocyanine green fluorescence imaging. JOURNAL OF BIOMEDICAL OPTICS 2024; 29:066003. [PMID: 38745983 PMCID: PMC11092151 DOI: 10.1117/1.jbo.29.6.066003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/02/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
Significance Necrotizing soft-tissue infections (NSTIs) are life-threatening infections with a cumulative case fatality rate of 21%. The initial presentation of an NSTI is non-specific, frequently leading to misdiagnosis and delays in care. No current strategies yield an accurate, real-time diagnosis of an NSTI. Aim A first-in-kind, observational, clinical pilot study tested the hypothesis that measurable fluorescence signal voids occur in NSTI-affected tissues following intravenous administration and imaging of perfusion-based indocyanine green (ICG) fluorescence. This hypothesis is based on the established knowledge that NSTI is associated with local microvascular thrombosis. Approach Adult patients presenting to the Emergency Department of a tertiary care medical center at high risk for NSTI were prospectively enrolled and imaged with a commercial fluorescence imager. Single-frame fluorescence snapshot and first-pass perfusion kinetic parameters-ingress slope (IS), time-to-peak (TTP) intensity, and maximum fluorescence intensity (IMAX)-were quantified using a dynamic contrast-enhanced fluorescence imaging technique. Clinical variables (comorbidities, blood laboratory values), fluorescence parameters, and fluorescence signal-to-background ratios (SBRs) were compared to final infection diagnosis. Results Fourteen patients were enrolled and imaged (six NSTI, six cellulitis, one diabetes mellitus-associated gangrene, and one osteomyelitis). Clinical variables demonstrated no statistically significant differences between NSTI and non-NSTI patient groups (p -value ≥ 0.22 ). All NSTI cases exhibited prominent fluorescence signal voids in affected tissues, including tissue features not visible to the naked eye. All cellulitis cases exhibited a hyperemic response with increased fluorescence and no distinct signal voids. Median lesion-to-background tissue SBRs based on snapshot, IS, TTP, and IMAX parameter maps ranged from 3.2 to 9.1, 2.2 to 33.8, 1.0 to 7.5, and 1.5 to 12.7, respectively, for the NSTI patient group. All fluorescence parameters except TTP demonstrated statistically significant differences between NSTI and cellulitis patient groups (p -value < 0.05 ). Conclusions Real-time, accurate discrimination of NSTIs compared with non-necrotizing infections may be possible with perfusion-based ICG fluorescence imaging.
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Affiliation(s)
- Gabrielle S. Ray
- Dartmouth Health, Department of Orthopaedics, Lebanon, New Hampshire, United States
- Dartmouth College, Geisel School of Medicine, Hanover, New Hampshire, United States
| | - Samuel S. Streeter
- Dartmouth Health, Department of Orthopaedics, Lebanon, New Hampshire, United States
- Dartmouth College, Geisel School of Medicine, Hanover, New Hampshire, United States
| | - Logan M. Bateman
- Dartmouth College, Thayer School of Engineering, Hanover, New Hampshire, United States
| | - Jonathan Thomas Elliott
- Dartmouth Health, Department of Orthopaedics, Lebanon, New Hampshire, United States
- Dartmouth College, Geisel School of Medicine, Hanover, New Hampshire, United States
- Dartmouth College, Thayer School of Engineering, Hanover, New Hampshire, United States
| | - Eric R. Henderson
- Dartmouth Health, Department of Orthopaedics, Lebanon, New Hampshire, United States
- Dartmouth College, Geisel School of Medicine, Hanover, New Hampshire, United States
- Dartmouth College, Thayer School of Engineering, Hanover, New Hampshire, United States
| | - NEFARIOUS Study Group
- Dartmouth Health, Department of Orthopaedics, Lebanon, New Hampshire, United States
- Dartmouth College, Geisel School of Medicine, Hanover, New Hampshire, United States
- Dartmouth College, Thayer School of Engineering, Hanover, New Hampshire, United States
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Gan YX, Yang ZL, Pan YX, Ou-Yang LY, Tang YH, Zhang YJ, Chen MS, Xu L. Change of indocyanine green clearance ability and liver function after transcatheter intra-arterial therapies and its impact on outcomes of resectable hepatocellular carcinoma: a retrospective cohort study. Int J Surg 2024; 110:2832-2844. [PMID: 38363991 DOI: 10.1097/js9.0000000000001156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/26/2024] [Indexed: 02/18/2024]
Abstract
BACKGROUND Indocyanine green (ICG) clearance test is a classical measurement of hepatic reserve, which involves surgical safety and patient recovery of hepatocellular carcinoma (HCC). The authors aim to compare effects of hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization (TACE) on liver function and outcomes of subsequent hepatectomy. MATERIAL AND METHODS HCC patients receiving HAIC/TACE in SYSUCC with repeated ICG clearance tests were retrospectively enrolled. ICG eliminating rate (ICG-K), ICG retention rate at 15 min (ICG-R15) and ordinary laboratory tests were collected. Peri-therapeutic changes of values were compared between the groups. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) were employed to validate findings. Post-hepatectomy liver failure (PHLF), overall survival (OS) and recurrence-free survival (RFS) were analyzed in patients with subsequent curative hepatectomy. RESULTS Two hundred and four patients treated with HAIC ( n =130) and TACE ( n =74) were included. ΔICG-R15 was greater in the HAIC arm before matching (mean, 3.8% vs. 0.7%, P <0.001), after PSM (mean, 4.7% vs. 1.1%, P =0.014) and IPTW (mean, 2.0% vs. -3.6%, P <0.001). No difference was found for ΔALB, ΔALBI, ΔTBIL, ΔALT, ΔAST and ΔPT-INR. Multivariable analyses revealed elder age, cirrhosis, HAIC, greater ΔTBIL and ΔALBI were associated with deteriorating ICG-R15. Among those (105 for HAIC and 48 for TACE) receiving hepatectomy, occurrence of grade B/C PHLF (4.8% vs. 8.3%, P =0.616), OS (median, unreached vs. unreached, P =0.94) and RFS (median, 26.7 vs. 17.1 months, P =0.096) were comparable between the two arms. In subgroup analyses, preoperative HAIC yield superior RFS (median, 26.7 vs. 16.2 months, P =0.042) in patients with baseline ICG-R15 less than or equal to 10%. CONCLUSION Preoperative FOLFOX-HAIC caused apparent impairment of ICG clearance ability than TACE yet comparable impact on liver function and post-hepatectomy outcomes.
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Affiliation(s)
| | | | | | - Li-Ying Ou-Yang
- Intensive Care Unit, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center
| | - Yu-Hao Tang
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | | | | | - Li Xu
- Department of Liver Surgery
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Raoufinia R, Arabnezhad A, Keyhanvar N, Abdyazdani N, Saburi E, Naseri N, Niazi F, Niazi F, Namdar AB, Rahimi HR. Leveraging stem cells to combat hepatitis: a comprehensive review of recent studies. Mol Biol Rep 2024; 51:459. [PMID: 38551743 DOI: 10.1007/s11033-024-09391-y] [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: 10/08/2023] [Accepted: 02/27/2024] [Indexed: 04/02/2024]
Abstract
Hepatitis is a significant global public health concern, with viral infections being the most common cause of liver inflammation. Antiviral medications are the primary treatments used to suppress the virus and prevent liver damage. However, the high cost of these drugs and the lack of awareness and stigma surrounding the disease create challenges in managing hepatitis. Stem cell therapy has arisen as a promising therapeutic strategy for hepatitis by virtue of its regenerative and immunomodulatory characteristics. Stem cells have the exceptional capacity to develop into numerous cell types and facilitate tissue regeneration, rendering them a highly promising therapeutic avenue for hepatitis. In animal models, stem cell therapy has demonstrated worthy results by reducing liver inflammation and improving liver function. Furthermore, clinical trials have been undertaken to assess the safety and effectiveness of stem cell therapy in individuals with hepatitis. This review aims to explore the involvement of stem cells in treating hepatitis and highlight the findings from studies conducted on both animals and humans. The objective of this review is to primarily concentrate on the ongoing and future clinical trials that assess the application of stem cell therapy in the context of hepatitis, including the transplantation of autologous bone marrow-derived stem cells, human induced pluripotent stem cells, and other mesenchymal stem cells. In addition, this review will explore the potential merits and constraints linked to stem cell therapy for hepatitis, as well as its prospective implications in the management of this disease.
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Affiliation(s)
- Ramin Raoufinia
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Arabnezhad
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Keyhanvar
- Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA, 94107, USA
| | - Nima Abdyazdani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Naseri
- Department of Biochemistry, School of medicine, Hamadan University of medical sciences, Hamadan, Iran
| | - Fereshteh Niazi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Niazi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Beheshti Namdar
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Haertel F, Nuding S, Reisberg D, Peters M, Werdan K, Schulze PC, Ebelt H. The Prognostic Value of a Liver Function Test Using Indocyanine Green (ICG) Clearance in Patients with Multiple Organ Dysfunction Syndrome (MODS). J Clin Med 2024; 13:1039. [PMID: 38398351 PMCID: PMC10888702 DOI: 10.3390/jcm13041039] [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: 11/14/2023] [Revised: 01/22/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Multiple organ dysfunction syndrome (MODS) is common in intensive care units (ICUs) and is associated with high mortality. Although there have been multiple investigations into a multitude of organ dysfunctions, little is known about the role of liver dysfunction. In addition, clinical and laboratory findings of liver dysfunction may occur with a significant delay. Therefore, the aim of this study was to investigate whether a liver function test, based on indocyanine green (ICG)-clearance, contains prognostic information for patients in the early phase of MODS. METHODS The data of this analysis were based on the MODIFY study, which included 70 critically ill patients of a tertiary medical ICU in the early phase of MODS (≤24 h after diagnosis by an APACHE II score ≥ 20 and a sinus rhythm ≥ 90 beats per minute, with the following subgroups: cardiogenic (cMODS) and septic MODS (sMODS)) over a period of 18 months. ICG clearance was characterized by plasma disappearance rate = PDR (%/min); it was measured non-invasively by using the LiMON system (PULSION Medical Systems, Feldkirchen, Germany). The PDR was determined on the day of study inclusion (baseline) and after 96 h. The primary endpoint of this analysis was 28-day mortality. RESULTS ICG clearance was measured in 44 patients of the MODIFY trial cohort, of which 9 patients had cMODS (20%) and 35 patients had sMODS (80%). Mean age: 59.7 ± 16.5 years; 31 patients were men; mean APACHE II score: 33.6 ± 6.3; 28-day mortality was 47.7%. Liver function was reduced in the total cohort as measured by a PDR of 13.4 ± 6.3%/min At baseline, there were no relevant differences between survivors and non-survivors regarding ICG clearance (PDR: 14.6 ± 6.1%/min vs. 12.1 ± 6.5%/min; p = 0.21). However, survivors showed better liver function than non-survivors after 96 h (PDR: 21.9 ± 6.3%/min vs. 9.2 ± 6.3%/min, p < 0.05). Consistent with these findings, survivors but not non-survivors show a significant improvement in the PDR (7.3 ± 6.3%/min vs. -2.9 ± 2.6%/min; p < 0.01) within 96 h. In accordance, receiver-operating characteristic curves (ROCs) at 96 h but not at baseline show a link between the PDR and 28-day mortality (PDR at 96 h: AUC: 0.87, 95% CI: 0.76-0.98; p < 0.01. CONCLUSIONS In our study, we found that ICG clearance at baseline did not provide prognostic information in patients in the early stages of MODS despite being reduced in the total cohort. However, improvement of ICG clearance 96 h after ICU admission is associated with reduced 28-day mortality.
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Affiliation(s)
- Franz Haertel
- Department of Internal Medicine I, Cardiology, University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany
| | - Sebastian Nuding
- Department of Internal Medicine III, Cardiology University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle, Germany
- Department of Internal Medicine II, Cardiology, Hospital St. Elisabeth and St. Barbara Halle (Saale), Mauerstraße 5, 06110 Halle (Saale), Germany
| | - Diana Reisberg
- Department of pediatrics, Ameos Hospital Aschersleben, Eislebener Str. 7A, 06449 Aschersleben, Germany
| | - Martin Peters
- Department of Internal Medicine, Helios Hospital Jerichower Land, August-Bebel-Str. 55a, 39288 Burg, Germany
| | - Karl Werdan
- Department of Internal Medicine III, Cardiology University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle, Germany
| | - P. Christian Schulze
- Department of Internal Medicine I, Cardiology, University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany
| | - Henning Ebelt
- Department of Internal Medicine III, Cardiology University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle, Germany
- Department of Internal Medicine II, Cardiology, Catholic Hospital “St. Johann Nepomuk”, Haarbergstr. 72, 99097 Erfurt, Germany
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Yasri S, Wiwanitkit V. Drug elimination and renal excretion of drugs. PHYSICO-CHEMICAL ASPECTS OF DOSAGE FORMS AND BIOPHARMACEUTICS 2024:173-178. [DOI: 10.1016/b978-0-323-91818-3.00006-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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10
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Río Bártulos C, Senk K, Bade R, Schumacher M, Kaiser N, Plath J, Planert M, Stroszczynski C, Woetzel J, Wiggermann P. Using AI and Gd-EOB-DTPA-enhanced MR imaging to assess liver function, comparing the MELIF score with the ALBI score. Sci Rep 2023; 13:13121. [PMID: 37573451 PMCID: PMC10423205 DOI: 10.1038/s41598-023-39954-1] [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: 01/30/2023] [Accepted: 08/02/2023] [Indexed: 08/14/2023] Open
Abstract
Monitoring disease progression is particularly important for determining the optimal treatment strategy in patients with liver disease. Especially for patients with diseases that have a reversible course, there is a lack of suitable tools for monitoring liver function. The development and establishment of such tools is very important, especially in view of the expected increase in such diseases in the future. Image-based liver function parameters, such as the T1 relaxometry-based MELIF score, are ideally suited for this purpose. The determination of this new liver function score is fully automated by software developed with AI technology. In this study, the MELIF score is compared with the widely used ALBI score. The ALBI score was used as a benchmark, as it has been shown to better capture the progression of less severe liver disease than the MELD and Child‒Pugh scores. In this study, we retrospectively determined the ALBI and MELIF scores for 150 patients, compared these scores with the corresponding MELD and Child‒Pugh scores (Pearson correlation), and examined the ability of these scores to discriminate between good and impaired liver function (AUC: MELIF 0.8; ALBI 0.77) and to distinguish between patients with and without cirrhosis (AUC: MELIF 0.83, ALBI 0.79). The MELIF score performed more favourably than the ALBI score and may also be suitable for monitoring mild disease progression. Thus, the MELIF score is promising for closing the gap in the available early-stage liver disease monitoring tools (i.e., identification of liver disease at a potentially reversible stage before chronic liver disease develops).
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Affiliation(s)
- Carolina Río Bártulos
- Institut Für Röntgendiagnostik Und Nuklearmedizin, Städtisches Klinikum Braunschweig gGmbH, 38126, Braunschweig, Germany.
| | - Karin Senk
- Institut Für Röntgendiagnostik, Universitätsklinikum Regensburg, 93053, Regensburg, Germany
| | - Ragnar Bade
- MeVis Medical Solutions AG, 28359, Bremen, Germany
| | | | - Nico Kaiser
- MeVis Medical Solutions AG, 28359, Bremen, Germany
| | - Jan Plath
- MeVis Medical Solutions AG, 28359, Bremen, Germany
| | - Mathis Planert
- Institut Für Röntgendiagnostik Und Nuklearmedizin, Städtisches Klinikum Braunschweig gGmbH, 38126, Braunschweig, Germany
| | | | - Jan Woetzel
- MeVis Medical Solutions AG, 28359, Bremen, Germany
| | - Philipp Wiggermann
- Institut Für Röntgendiagnostik Und Nuklearmedizin, Städtisches Klinikum Braunschweig gGmbH, 38126, Braunschweig, Germany
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Luerken L, Dollinger M, Goetz A, Utpatel K, Doppler MC, Weiss JB, Uller W, Ignee A, Verloh N, Haimerl M. Diagnostic Accuracy of Indocyanine Green Clearance Test for Different Stages of Liver Fibrosis and Cirrhosis. Diagnostics (Basel) 2023; 13:2663. [PMID: 37627922 PMCID: PMC10453681 DOI: 10.3390/diagnostics13162663] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/01/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
(1) Background: This study aimed to correlate the indocyanine green clearance (ICG) test with histopathological grades of liver fibrosis and liver cirrhosis to assess its diagnostic accuracy in differentiating normal liver parenchyma from liver fibrosis and liver cirrhosis. (2) Methods: A total of 82 patients who received a histopathological liver examination, imaging, and ICG test within three months were included in this retrospective study. The histopathological level of fibrosis was graded using the Ishak scoring system, and the patients were divided into five categories: no liver fibrosis (NLF), mild liver fibrosis (MLF), advanced liver fibrosis (ALF), severe liver fibrosis (SLF), and liver cirrhosis (LC). The non-parametric Kruskal-Wallis test with post hoc pairwise comparison utilizing Mann-Whitney U tests and Bonferroni adjustment was used to analyze differences in the ICG test results between the patient groups. Cross correlation between the individual fibrosis/cirrhosis stages and the score of the ICG test was performed, and the sensitivity, specificity, and positive and negative predictive values were calculated for each model predicting liver fibrosis/cirrhosis. (3) Results: A significant difference (p ≤ 0.001) between stages of NLF, LF, and LC was found for the ICG parameters (ICG plasma disappearance rate (ICG-PDR) and ICG retention percentage at 15 min (ICG-R15)). The post hoc analysis revealed that NLF significantly differed from SLF (ICG-PDR: p = 0.001; ICG-R15: p = 0.001) and LC (ICG-PDR: p = 0.001; ICG-R15: p = 0.001). ALF also significantly differed from SLF (ICG-PDR: p = 0.033; ICG-R15: p = 0.034) and LC (ICG-PDR: p = 0.014; ICG-R15: p = 0.014). The sensitivity for detection of an initial stage of liver fibrosis compared to no liver fibrosis (Ishak ≥ 1) was 0.40; the corresponding specificity was 0.80. The differentiation of advanced liver fibrosis or cirrhosis (Ishak ≥ 4) compared to other stages of liver fibrosis was 0.75, with a specificity of 0.81. (4) Conclusions: This study shows that the ICG test, as a non-invasive diagnostic test, is able to differentiate patients with no liver fibrosis from patients with advanced liver fibrosis and liver cirrhosis. The ICG test seems to be helpful in monitoring patients with liver fibrosis regarding compensation levels, thus potentially enabling physicians to both detect progression from compensated liver fibrosis to advanced liver fibrosis and cirrhosis and to initiate antifibrotic treatment at an earlier stage.
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Affiliation(s)
- Lukas Luerken
- Department of Radiology, University Hospital Regensburg, 93053 Regensburg, Germany; (L.L.)
| | - Marco Dollinger
- Department of Radiology, University Hospital Regensburg, 93053 Regensburg, Germany; (L.L.)
| | - Andrea Goetz
- Department of Radiology, University Hospital Regensburg, 93053 Regensburg, Germany; (L.L.)
| | - Kirstin Utpatel
- Department of Pathology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Michael Christian Doppler
- Department of Diagnostic and Interventional Radiology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany
| | - Jakob Benedikt Weiss
- Department of Diagnostic and Interventional Radiology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany
| | - Wibke Uller
- Department of Diagnostic and Interventional Radiology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany
| | - André Ignee
- Department of Gastroenterology, Hospital Wuerzburg Mitte, 97074 Wuerzburg, Germany
| | - Niklas Verloh
- Department of Diagnostic and Interventional Radiology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany
| | - Michael Haimerl
- Department of Diagnostic and Interventional Radiology, Hospital Wuerzburg Mitte, 97074 Wuerzburg, Germany
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12
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Shi X, Hu Z, Gan B, He Y, Zhang L, Chen M, Wang Y, Li X. Multivariate Evaluation of DNA Quality Differences in Different Preanalytical Procedures in Mouse Livers. Biopreserv Biobank 2023; 21:378-387. [PMID: 36067273 DOI: 10.1089/bio.2022.0027] [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: 11/13/2022] Open
Abstract
Successful histogenetic research relies on proper handling of tissue samples to maximize DNA quality. As the largest gland in the body, the liver is particularly sensitive to sample mishandling owing to its enzymatic and transcriptional activity. However, the impact of preanalytical procedures on the quality of extracted liver DNA remains poorly understood. In this study, we assessed the impact of extraction methods, duration of ex vivo liver ischemia, liver storage time, and temperature on extracted DNA quality. Comprehensive parameters such as DNA yields, purity, DNA integrity number, the percentage of double-stranded DNA (%dsDNA), and PCR amplification of the GAPDH gene fragment were assessed to identify the quality of extracted DNA. Our results revealed that these preanalytical processes had little effect on DIN values and PCR efficiency of GAPDH gene fragments for each sample, whereas the DNA yields, purity, and %dsDNAs varied widely across different processes. For liver DNA extraction, RNase is necessary to isolate "pure" DNA, and the presence of RNase could significantly increase the %dsDNA. In addition, significant increases in the yields, purity, and %dsDNA of extracted DNA were observed in the TissueLyser-processed livers compared with the mortar and pestle or shear cell disruption methods. Further investigation revealed that livers experiencing longer periods of ex vivo ischemia resulted in significantly compromised DNA yields, and to obtain sufficient DNA, the ex vivo liver ischemia should be limited to within 30 minutes. Moreover, compared with storage of livers at -80°C, storage of livers in the vapor phase of liquid nitrogen yielded a higher quality of the extracted DNA. Our findings exhibited significant implications for liver-derived DNA quality assessment and management.
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Affiliation(s)
- Xue Shi
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
| | - Zhenyue Hu
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
| | - Baoyu Gan
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
| | - Yinlin He
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
| | - Linpei Zhang
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
| | - Min Chen
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
| | - Yawen Wang
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
| | - Xiaojiao Li
- BioBank, The First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China
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13
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Monti C, Audi SH, Womack J, Hong SK, Yang Y, Kim J, Dash RK. Physiologically-Based Pharmacokinetic Modeling of Blood Clearance of Liver Fluorescent Markers for the Assessment of the Degree of Hepatic Ischemia-Reperfusion Injury . ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2023;2023:1-6. [PMID: 38082711 DOI: 10.1109/embc40787.2023.10340273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
During liver transplantation, ischemia-reperfusion injury (IRI) is inevitable and decreases the overall success of the surgery. While guidelines exist, there is no reliable way to quantitatively assess the degree of IRI present in the liver. Our recent study has shown a correlation between the bile-to-plasma ratio of FDA-approved sodium fluorescein (SF) and the degree of hepatic IRI, presumably due to IRI-induced decrease in the activity of the hepatic multidrug resistance-associated protein 2 (MRP2); however, the contribution of SF blood clearance via the bile is still convoluted with other factors, such as renal clearance. In this work, we sought to computationally model SF blood clearance via the bile. First, we converted extant SF fluorescence data from rat whole blood, plasma, and bile to concentrations using calibration curves. Next, based on these SF concentration data, we generated a "liver-centric", physiologically-based pharmacokinetic (PBPK) model of SF liver uptake and clearance via the bile. Model simulations show that SF bile concentration is highly sensitive to change in the activity of hepatic MPR2. These simulations suggest that SF bile clearance along with the PBPK model can be used to quantify the effect of IRI on the activity of MRP2.Clinical Relevance- This study establishes the theory necessary to generate a model for predicting the degree of IRI during liver transplantation.
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14
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Jovanović M, Kovačević M, Vezmar-Kovačević S, Palibrk I, Bjelanović J, Miljković B, Vučićević K. Lidocaine clearance as pharmacokinetic parameter of metabolic hepatic activity in patients with impaired liver. J Med Biochem 2023; 42:304-310. [PMID: 36987422 PMCID: PMC10040201 DOI: 10.5937/jomb0-38952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 10/10/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND The study aimed to estimate lidocaine (LID) pharmacokinetic parameter values in patients with impaired liver function, level of correlation between the pharmacokinetic parameters and Child-Pugh class and change in pharmacokinetic parameters after liver tumor resection compared to the preoperative value. METHODS Patients with impaired liver function were subject to the LID test 1 day prior to, 3 and 7 days after the intervention. LID was administered in single i.v. dose of 1 mg/kg. Blood samples were collected at 15, 30 and 90 minutes after drug administration. Non-compartmental analysis was applied for calculating the pharmacokinetic parameters. RESULTS The study included 17 patients with the diagnosis of cirrhosis and 41 patients with liver tumor. In both groups of patients, the values of the coefficients of correlation show the best correlation between clearance (CL) and Child-Pugh score (-0.693, p<0.005) over other pharmacokinetic parameters. The results indicate worsening hepatic function on 3rd day after operation in comparison to the values of LID CL prior to operation (mean LID CL for patients with Child-Pugh class A are 25.91 L/h, 41.59 L/h, respectively; while for B class are 16.89 L/h, 22.65 L/h, respectively). On day 7th, the values of LID CL (mean value for patients with Child-Pugh class A and B are 40.98 L/h and 21.46 L/h, respectively) are increased in comparison to 3rd day after. CONCLUSIONS LID pharmacokinetic parameters consequently changed according to the severity of liver impairment, assessed by Child-Pugh score. Values of LID CL and volume of distribution (Vd) coupled with standard biochemical parameters may be used for preoperative assessment of liver function and monitoring of its postoperative recovery.
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Affiliation(s)
- Marija Jovanović
- University of Belgrade, Faculty of Pharmacy, Department of Pharmacokinetics and Clinical Pharmacy, Belgrade
| | - Milena Kovačević
- University of Belgrade, Faculty of Pharmacy, Department of Pharmacokinetics and Clinical Pharmacy, Belgrade
| | - Sandra Vezmar-Kovačević
- University of Belgrade, Faculty of Pharmacy, Department of Pharmacokinetics and Clinical Pharmacy, Belgrade
| | - Ivan Palibrk
- University Clinical Centre of Serbia, Department for Anesthesia and Reanimation, Section at Clinic for Digestive Surgery, Belgrade
| | - Jasna Bjelanović
- University Clinical Centre of Serbia, Center for Medical Biochemistry, Belgrade
| | - Branislava Miljković
- University of Belgrade, Faculty of Pharmacy, Department of Pharmacokinetics and Clinical Pharmacy, Belgrade
| | - Katarina Vučićević
- University of Belgrade, Faculty of Pharmacy, Department of Pharmacokinetics and Clinical Pharmacy, Belgrade
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15
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Abstract
Primary liver cancer and colorectal cancer liver metastases are among the leading causes of cancer-related mortality worldwide. Surgery is one of the main methods of treatment to achieve the best results in overall and recurrence-free survival. The main objectives in this surgery are preoperative planning, assessment of functional viability of liver parenchyma and total resection with low complication rate. Post-resection liver failure is one of the most formidable and often fatal complication following functional failure of liver remnant. Thus, preoperative assessment of liver functional reserves is a necessary step for adequate selection of patients and safe surgery. Passive liver tests, such as biochemical parameters or clinical scales, do not accurately reflect the actual functional component of liver parenchyma. The most accurate method is dynamic quantitative test of liver, such as indocyanine green clearance. The authors discuss the practical aspects of preoperative assessment of liver functional reserves using indocyanine green, as well as the concept and technical foundations of fluorescent imaging in hepatobiliary surgery.
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Affiliation(s)
- A D Kaprin
- National Medical Research Radiology Center, Obninsk, Russia
| | - S A Ivanov
- Tsyb Medical Radiology Research Center, Obninsk, Russia
| | - L O Petrov
- Tsyb Medical Radiology Research Center, Obninsk, Russia
| | - A G Isaeva
- Tsyb Medical Radiology Research Center, Obninsk, Russia
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16
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Immunomodulation by Hemoadsorption—Changes in Hepatic Biotransformation Capacity in Sepsis and Septic Shock: A Prospective Study. Biomedicines 2022; 10:biomedicines10102340. [PMID: 36289602 PMCID: PMC9598581 DOI: 10.3390/biomedicines10102340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/26/2022] Open
Abstract
Background: Sepsis is often associated with liver dysfunction, which is an indicator of poor outcomes. Specific diagnostic tools that detect hepatic dysfunction in its early stages are scarce. So far, the immune modulatory effects of hemoadsorption with CytoSorb® on liver function are unclear. Method: We assessed the hepatic function by using the dynamic LiMAx® test and biochemical parameters in 21 patients with sepsis or septic shock receiving CytoSorb® in a prospective, observational study. Points of measurement: T1: diagnosis of sepsis or septic shock; T2 and T3: 24 h and 48 h after the start of CytoSorb®; T4: 24 h after termination of CytoSorb®. Results: The hepatic biotransformation capacity measured by LiMAx® was severely impaired in up to 95 % of patients. Despite a rapid shock reversal under CytoSorb®, a significant improvement in LiMAx® values appeared from T3 to T4. This decline and recovery of liver function were not reflected by common parameters of hepatic metabolism that remained mostly within the normal range. Conclusions: Hepatic dysfunction can effectively and safely be diagnosed with LiMAx® in ventilated ICU patients under CytoSorb®. Various static liver parameters are of limited use since they do not adequately reflect hepatic dysfunction and impaired hepatic metabolism.
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17
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Thomas CN, Alfahad N, Capewell N, Cowley J, Hickman E, Fernandez A, Harrison N, Qureshi OS, Bennett N, Barnes NM, Dick AD, Chu CJ, Liu X, Denniston AK, Vendrell M, Hill LJ. Triazole-derivatized near-infrared cyanine dyes enable local functional fluorescent imaging of ocular inflammation. Biosens Bioelectron 2022; 216:114623. [PMID: 36029662 DOI: 10.1016/j.bios.2022.114623] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/28/2022] [Accepted: 08/03/2022] [Indexed: 11/26/2022]
Abstract
Near-infrared (NIR) chemical fluorophores are promising tools for in-vivo imaging in real time but often succumb to rapid photodegradation. Indocyanine green (ICG) is the only NIR dye with regulatory approval for ocular imaging in humans; however, ICG, when employed for applications such as labelling immune cells, has limited sensitivity and does not allow precise detection of specific inflammatory events, for example leukocyte recruitment during uveitic flare-ups. We investigated the potential use of photostable novel triazole NIR cyanine (TNC) dyes for detecting and characterising activated T-cell activity within the eye. Three TNC dyes were evaluated for ocular cytotoxicity in-vitro using a MTT assay and optimised concentrations for intraocular detection within ex-vivo porcine eyes after topical application or intracameral injections of the dyes. TNC labelled T-cell tracking experiments and mechanistic studies were also performed in-vitro. TNC-1 and TNC-2 dyes exhibited greater fluorescence intensity than ICG at 10 μM, whereas TNC-3 was only detectable at 100 μM within the porcine eye. TNC dyes did not demonstrate any ocular cell toxicity at working concentrations of 10 μM. CD4+T-cells labelled with TNC-1 or TNC-2 were detected within the porcine eye, with TNC-1 being brighter than TNC-2. Detection of TNC-1 and TNC-2 into CD4+T-cells was prevented by prior incubation with dynole 34-2 (50 μM), suggesting active uptake of these dyes via dynamin-dependent processes. The present study provides evidence that TNC dyes are suitable to detect activated CD4+T-cells within the eye with potential as a diagnostic marker for ocular inflammatory diseases.
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Affiliation(s)
- Chloe N Thomas
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
| | - Nada Alfahad
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Nicholas Capewell
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Jamie Cowley
- Celentyx Ltd, Birmingham Research Park, Vincent Drive, Edgbaston, Birmingham, UK
| | - Eleanor Hickman
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Antonio Fernandez
- Department of Organic Chemistry, Faculty of Chemistry, University of Murcia, Murcia, Spain; Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Neale Harrison
- Celentyx Ltd, Birmingham Research Park, Vincent Drive, Edgbaston, Birmingham, UK
| | - Omar S Qureshi
- Celentyx Ltd, Birmingham Research Park, Vincent Drive, Edgbaston, Birmingham, UK
| | - Naomi Bennett
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Healthcare Technologies Institute, School of Chemical Engineering, University of Birmingham, Birmingham, UK
| | - Nicholas M Barnes
- Neuropharmacology Research Group, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Andrew D Dick
- National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK; Academic Unit of Ophthalmology, Bristol Medical School and School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Colin J Chu
- National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK; Academic Unit of Ophthalmology, Bristol Medical School and School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Xiaoxuan Liu
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK; Health Data Research UK, London, UK
| | - Alastair K Denniston
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK; Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK; Health Data Research UK, London, UK; Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Marc Vendrell
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Lisa J Hill
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
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18
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Kim J, Yang Y, Hong SK, Zielonka J, Dash RK, Audi SH, Kumar SN, Joshi A, Zimmerman MA, Hong JC. Fluorescein clearance kinetics in blood and bile indicates hepatic ischemia-reperfusion injury in rats. Am J Physiol Gastrointest Liver Physiol 2022; 323:G126-G133. [PMID: 35700191 DOI: 10.1152/ajpgi.00038.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Quantitative measurement of the degree of hepatic ischemia-reperfusion injury (IRI) is crucial for developing therapeutic strategies for its treatment. We hypothesized that clearance of fluorescent dye through bile metabolism may reflect the degree of hepatic IRI. In this study, we investigated sodium fluorescein clearance kinetics in blood and bile for quantifying the degree of hepatic IRI. Warm ischemia times (WITs) of 0, 30, or 60 min followed by 1 h or 4 h of reperfusion, were applied to the median and lateral lobes of the liver in Sprague-Dawley rats. Subsequently, 2 mg/kg of sodium fluorescein was injected intravenously, and blood and bile samples were collected over 60 min to measure fluorescence intensities. The bile-to-plasma fluorescence ratios demonstrated an inverse correlation with WIT and were distinctly lower in the 60-min WIT group than in the control or 30-min WIT groups. Bile-to-plasma fluorescence ratios displayed superior discriminability for short versus long WITs when measured 1 h after reperfusion versus 4 h. We conclude that the bile-to-blood ratio of fluorescence after sodium fluorescein injection has the potential to enable the quantification of hepatic IRI severity.NEW & NOTEWORTHY Previous attempts to use fluorophore clearance to test liver function have relied on a single source of data. However, the kinetics of substrate processing via bile metabolism include decreasing levels in blood and increasing levels in bile. Thus, we analyzed data from blood and bile to better reflect fluorescein clearance kinetics.
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Affiliation(s)
- Joohyun Kim
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Yongqiang Yang
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Seung-Keun Hong
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jacek Zielonka
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ranjan K Dash
- Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.,Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Said H Audi
- Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.,Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Suresh N Kumar
- Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Amit Joshi
- Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.,Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Johnny C Hong
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
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19
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MELIF, a Fully Automated Liver Function Score Calculated from Gd-EOB-DTPA-Enhanced MR Images: Diagnostic Performance vs. the MELD Score. Diagnostics (Basel) 2022; 12:diagnostics12071750. [PMID: 35885653 PMCID: PMC9318040 DOI: 10.3390/diagnostics12071750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/07/2022] [Accepted: 07/13/2022] [Indexed: 12/24/2022] Open
Abstract
In the management of patients with chronic liver disease, the assessment of liver function is essential for treatment planning. Gd-EOB-DTPA-enhanced MRI allows for both the acquisition of anatomical information and regional liver function quantification. The objective of this study was to demonstrate and evaluate the diagnostic performance of two fully automatically generated imaging-based liver function scores that take the whole liver into account. T1 images from the native and hepatobiliary phases and the corresponding T1 maps from 195 patients were analyzed. A novel artificial-intelligence-based software prototype performed image segmentation and registration, calculated the reduction rate of the T1 relaxation time for the whole liver (rrT1liver) and used it to calculate a personalized liver function score, then generated a unified score—the MELIF score—by combining the liver function score with a patient-specific factor that included weight, height and liver volume. Both scores correlated strongly with the MELD score, which is used as a reference for global liver function. However, MELIF showed a stronger correlation than the rrT1liver score. This study demonstrated that the fully automated determination of total liver function, regionally resolved, using MR liver imaging is feasible, providing the opportunity to use the MELIF score as a diagnostic marker in future prospective studies.
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20
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Río Bártulos C, Senk K, Schumacher M, Plath J, Kaiser N, Bade R, Woetzel J, Wiggermann P. Assessment of Liver Function With MRI: Where Do We Stand? Front Med (Lausanne) 2022; 9:839919. [PMID: 35463008 PMCID: PMC9018984 DOI: 10.3389/fmed.2022.839919] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/25/2022] [Indexed: 12/12/2022] Open
Abstract
Liver disease and hepatocellular carcinoma (HCC) have become a global health burden. For this reason, the determination of liver function plays a central role in the monitoring of patients with chronic liver disease or HCC. Furthermore, assessment of liver function is important, e.g., before surgery to prevent liver failure after hepatectomy or to monitor the course of treatment. Liver function and disease severity are usually assessed clinically based on clinical symptoms, biopsy, and blood parameters. These are rather static tests that reflect the current state of the liver without considering changes in liver function. With the development of liver-specific contrast agents for MRI, noninvasive dynamic determination of liver function based on signal intensity or using T1 relaxometry has become possible. The advantage of this imaging modality is that it provides additional information about the vascular structure, anatomy, and heterogeneous distribution of liver function. In this review, we summarized and discussed the results published in recent years on this technique. Indeed, recent data show that the T1 reduction rate seems to be the most appropriate value for determining liver function by MRI. Furthermore, attention has been paid to the development of automated tools for image analysis in order to uncover the steps necessary to obtain a complete process flow from image segmentation to image registration to image analysis. In conclusion, the published data show that liver function values obtained from contrast-enhanced MRI images correlate significantly with the global liver function parameters, making it possible to obtain both functional and anatomic information with a single modality.
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Affiliation(s)
- Carolina Río Bártulos
- Institut für Röntgendiagnostik und Nuklearmedizin, Städtisches Klinikum Braunschweig gGmbH, Braunschweig, Germany
| | - Karin Senk
- Institut für Röntgendiagnostik, Universtitätsklinikum Regensburg, Regensburg, Germany
| | | | - Jan Plath
- MeVis Medical Solutions AG, Bremen, Germany
| | | | | | | | - Philipp Wiggermann
- Institut für Röntgendiagnostik und Nuklearmedizin, Städtisches Klinikum Braunschweig gGmbH, Braunschweig, Germany
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21
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Meira Júnior JDD, Fonseca GM, Carvalho Neto FND, Jeismann VB, Kruger JAP, Silva JPM, Coelho FF, Herman P. Platelet-albumin (PAL) score as a predictor of perioperative outcomes and survival in patients with hepatocellular carcinoma undergoing liver resection in a Western center. Surg Oncol 2022; 42:101752. [PMID: 35378376 DOI: 10.1016/j.suronc.2022.101752] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 02/18/2022] [Accepted: 03/25/2022] [Indexed: 11/25/2022]
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22
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Dube T, Kompella UB, Panda JJ. Near infrared triggered chemo-PTT-PDT effect mediated by glioma directed twin functional-chimeric peptide-decorated gold nanoroses. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2022; 228:112407. [PMID: 35189576 DOI: 10.1016/j.jphotobiol.2022.112407] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/02/2022] [Indexed: 12/17/2022]
Abstract
The successful application of nanomedicine against glioma is basically hooked on to the fabrication of specific and efficient glioma targeted multifunctional theranostics. Herein, through an easy synthetic methodology, we fabricated a type of novel multifunctional theranostic nanoplatform comprising of anisotropic gold nanoroses (AuNs) co-loaded with doxorubicin (DOX) and the near-infrared (NIR) active/responsive dye, indocyanine green (ICG). The tailored nanotheranostics upon being exposed to NIR laser helped in achieving combinatorial chemo-phototherapy along with optical cell imaging. BBB/glioma-targeting ability was realized by amalgamating the AuNs with a naive peptide drug with BBB-glioma targeting and anti-glioma twin functionality. Efficacy studies carried out in C6 cells and spheroids demonstrated heightened synergistic glioma chemo-PDT-PTT effect (~85% ablation in C6 cells and ~88% in C6 spheroids) by the AuNDIPs as compared to the individual therapeutic entities. Here, the AuNs derived nanophototheranostics with in force targeting and on-demand drug release nature will further aid in abolishing chemotherapy associated adverse events by adopting a combinatorial approach for synergistic glioma eradication.
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Affiliation(s)
- Taru Dube
- Institute of Nano Science and Technology (INST), Mohali, Punjab 160062, India
| | - Uday B Kompella
- Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Jiban Jyoti Panda
- Institute of Nano Science and Technology (INST), Mohali, Punjab 160062, India.
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Abstract
The liver comprises both parenchymal and non-parenchymal cells with varying functions. Cirrhosis is often complicated by the development of portal hypertension and its associated complications. Hence, assessment of liver in cirrhosis should include assessment of its structural, function of both hepatic and non-hepatic tissue and haemodynamic assessment of portal hypertension. There is no single test that can evaluate all functions of liver and assess prevalence and severity of portal hypertension. Commonly available tests like serum bilirubin, liver enzymes (alanine [ALT] and aspartate aminotransferase [AST], serum alkaline phosphatase [ALP], gamma glutamyl transpeptidase [GGT]), serum albumin and prothrombin time for assessment of liver functions partly assess liver functions. quantitative liver functions like indocyanine clearance tests [ICG-K], methacetin breath test [MBT] were developed to assess dynamic status of liver but has its own limitation and availability. Imaging based assessment of liver by transient elastography, MRI based 99 mTc-coupled asialoglycoprotein mebrofenin scan help the clinician to assess liver function, functional volume of liver left after surgery and portal hypertension [PH]. Hepatic venous pressure gradient still remains the gold standard for the assessment of portal hypertension but is invasive and not available in all centres. Combinations of blood parameters in form of various indices like fibrosis score of 4 [FIB-4], Lok index, scores like model for end stage liver disease (MELD) and Child-Turcotte Pugh score are commonly used for assessing liver function in clinical practice.
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Key Words
- 99mTc-GSA, technetium-99m galactosyl human serum albumin
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- ARFI, Acoustic Radiation Force Impulse
- AST, aspartate aminotransferase
- BUN, blood urea nitrogen
- CLD, chronic liver disease
- ESLD, end-stage liver disease
- FIB-4, fibrosis score of 4
- GGT, gamma glutamyl transpeptidase
- HVPG, Hepatic venous pressure gradient
- ICG-K, indocyanine clearance tests
- INR, International normalised ratio
- LFTs, liver function tests
- MBT, methacetin breath test
- NAFLD, non-alcoholic fatty liver disease
- PBS, primary biliary cholangitis
- PHT, portal hypertension
- PSC, primary Sclerosing cholangitis
- cirrhosis
- liver function tests
- portal hypertension
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Affiliation(s)
- Praveen Sharma
- Address for correspondence: Praveen Sharma, Associate Professor, Department of Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India.
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24
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Mousa OY, Kamath PS. A History of the Assessment of Liver Performance. Clin Liver Dis (Hoboken) 2021; 18:28-48. [PMID: 34745582 PMCID: PMC8555456 DOI: 10.1002/cld.1100] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Interview and Audio Recording.
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Affiliation(s)
- Omar Y. Mousa
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineMayo ClinicRochesterMN
| | - Patrick S. Kamath
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineMayo ClinicRochesterMN
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25
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Pham YL, Beauchamp J. Breath Biomarkers in Diagnostic Applications. Molecules 2021; 26:molecules26185514. [PMID: 34576985 PMCID: PMC8468811 DOI: 10.3390/molecules26185514] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
The detection of chemical compounds in exhaled human breath presents an opportunity to determine physiological state, diagnose disease or assess environmental exposure. Recent advancements in metabolomics research have led to improved capabilities to explore human metabolic profiles in breath. Despite some notable challenges in sampling and analysis, exhaled breath represents a desirable medium for metabolomics applications, foremost due to its non-invasive, convenient and practically limitless availability. Several breath-based tests that target either endogenous or exogenous gas-phase compounds are currently established and are in practical and/or clinical use. This review outlines the concept of breath analysis in the context of these unique tests and their applications. The respective breath biomarkers targeted in each test are discussed in relation to their physiological production in the human body and the development and implementation of the associated tests. The paper concludes with a brief insight into prospective tests and an outlook of the future direction of breath research.
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Affiliation(s)
- Y Lan Pham
- Department of Sensory Analytics and Technologies, Fraunhofer Institute for Process Engineering and Packaging IVV, Giggenhauser Straße 35, 85354 Freising, Germany;
- Department of Chemistry and Pharmacy, Chair of Aroma and Smell Research, Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestraße 9, 91054 Erlangen, Germany
| | - Jonathan Beauchamp
- Department of Sensory Analytics and Technologies, Fraunhofer Institute for Process Engineering and Packaging IVV, Giggenhauser Straße 35, 85354 Freising, Germany;
- Correspondence:
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26
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Huang S, Blutke A, Feuchtinger A, Klemm U, Zachariah Tom R, Hofmann SM, Stiel AC, Ntziachristos V. Functional multispectral optoacoustic tomography imaging of hepatic steatosis development in mice. EMBO Mol Med 2021; 13:e13490. [PMID: 34411447 PMCID: PMC8422073 DOI: 10.15252/emmm.202013490] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 12/14/2022] Open
Abstract
The increasing worldwide prevalence of obesity, fatty liver diseases and the emerging understanding of the important roles lipids play in various other diseases is generating significant interest in lipid research. Lipid visualization in particular can play a critical role in understanding functional relations in lipid metabolism. We investigated the potential of multispectral optoacoustic tomography (MSOT) as a novel modality to non-invasively visualize lipids in laboratory mice around the 930nm spectral range. Using an obesity-induced non-alcoholic fatty liver disease (NAFLD) mouse model, we examined whether MSOT could detect and differentiate different grades of hepatic steatosis and monitor the accumulation of lipids in the liver quantitatively over time, without the use of contrast agents, i.e. in label-free mode. Moreover, we demonstrate the efficacy of using the real-time clearance kinetics of indocyanine green (ICG) in the liver, monitored by MSOT, as a biomarker to evaluate the organ's function and assess the severity of NAFLD. This study establishes MSOT as an efficient imaging tool for lipid visualization in preclinical studies, particularly for the assessment of NAFLD.
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Affiliation(s)
- Shan Huang
- Chair of Biological ImagingSchool of Medicine, Central Institute for Translational Cancer Research (TranslaTUM)Technical University of MunichGermany
- Institute of Biological and Medical ImagingHelmholtz Zentrum München (GmbH)NeuherbergGermany
| | - Andreas Blutke
- Research Unit Analytical PathologyHelmholtz Zentrum München (GmbH)NeuherbergGermany
| | - Annette Feuchtinger
- Research Unit Analytical PathologyHelmholtz Zentrum München (GmbH)NeuherbergGermany
| | - Uwe Klemm
- Chair of Biological ImagingSchool of Medicine, Central Institute for Translational Cancer Research (TranslaTUM)Technical University of MunichGermany
| | - Robby Zachariah Tom
- Institute of Diabetes and Regeneration ResearchHelmholtz Zentrum München (GmbH)NeuherbergGermany
- Medizinische Klinik und Poliklinik IVLudwig‐Maximilians‐Universität MünchenMunichGermany
| | - Susanna M Hofmann
- Institute of Diabetes and Regeneration ResearchHelmholtz Zentrum München (GmbH)NeuherbergGermany
| | - Andre C Stiel
- Chair of Biological ImagingSchool of Medicine, Central Institute for Translational Cancer Research (TranslaTUM)Technical University of MunichGermany
| | - Vasilis Ntziachristos
- Chair of Biological ImagingSchool of Medicine, Central Institute for Translational Cancer Research (TranslaTUM)Technical University of MunichGermany
- Institute of Biological and Medical ImagingHelmholtz Zentrum München (GmbH)NeuherbergGermany
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27
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Almazroo OA, Miah MK, Pillai VC, Shaik IH, Xu R, Dharmayan S, Johnson HJ, Ganesh S, Planinsic RM, Demetris AJ, Al-Khafaji A, Lopez R, Molinari M, Tevar AD, Hughes C, Humar A, Venkataramanan R. An evaluation of the safety and preliminary efficacy of peri- and post-operative treprostinil in preventing ischemia and reperfusion injury in adult orthotopic liver transplant recipients. Clin Transplant 2021; 35:e14298. [PMID: 33764591 PMCID: PMC8243925 DOI: 10.1111/ctr.14298] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 03/17/2021] [Indexed: 12/29/2022]
Abstract
Background Orthotopic liver transplantation (OLT) is the only treatment option for various end‐stage liver diseases. Ischemia and reperfusion (I/R) injury is one of the unavoidable complications/conditions in OLT. In 2019, a total of 8896 livers were transplanted of which >94% organs were procured from deceased donors. An increase in the use of extended criteria donor (ECD) livers for transplantation further unraveled the role of hepatic I/R injury on short‐term and long‐term graft outcomes. Despite promising outcomes with the use of antioxidants, free radical scavengers, and vasodilators; I/R‐mediated liver injury persists and significantly influences the overall clinical outcomes. Treprostinil, a synthetic prostacyclin I2 (PGI2) analog, due to its vasodilatory property, antiplatelet activity, and its ability to downregulate pro‐inflammatory cytokines can potentially minimize I/R injury. Aim We investigated the safety and preliminary efficacy of continuous intravenous infusion of treprostinil in liver transplant recipients in a prospective, single‐center, non‐randomized, interventional study. Material and methods This was a dose escalation (3 + 3 design) phase 1/2 study. Deceased donor liver transplant recipients received 5 ng/kg/min for two days, or 2.5, 5, and 7.5 ng/min/kg for 5 days as a continuous infusion. Multiple blood samples were collected for biochemical parameter assessment and for measuring treprostinil levels. Indocyanine green plasma disappearance rate was used as a measure of hepatic functional capacity. Results Subjects tolerated continuous infusion of treprostinil up to 5 ng/kg/min for 120 h with no occurrence of primary graft non‐function (PNF), minimized need for ventilation support, reduced hospitalization time, 100% graft and patient survival, and improved hepatobiliary excretory function comparable to normal healthy adults. Discussion Treprostinil can be administered to liver transplant patients safely during the perioperative period. Conclusion Based on this phase 1/2 study, further efficacy studies of treprostinil in preventing I/R injury of liver should be conducted to potentially increase the number of livers available for transplantation.
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Affiliation(s)
- Omar Abdulhameed Almazroo
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mohammad Kowser Miah
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Venkateswaran C Pillai
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Imam H Shaik
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ruichao Xu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Stalin Dharmayan
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Heather J Johnson
- Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Swaytha Ganesh
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Raymond M Planinsic
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Anthony J Demetris
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ali Al-Khafaji
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Critical Care Medicine, Univeristy of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Roberto Lopez
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michele Molinari
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Amit D Tevar
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Christopher Hughes
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Abhinav Humar
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.,Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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28
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Exploring Liver Mitochondrial Function by 13C-Stable Isotope Breath Tests: Implications in Clinical Biochemistry. Methods Mol Biol 2021; 2310:179-199. [PMID: 34096004 DOI: 10.1007/978-1-0716-1433-4_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The liver is at the crossroad of key metabolic processes, which include detoxification, glycolipidic storage and export, and protein synthesis. The gut-liver axis, moreover, provides hepatocytes with a series of bacterial products and metabolites, which contribute to maintain liver function in health and disease. Breath tests (BTs) are developed as diagnostic tools for indirect, rapid, noninvasive assessment of several metabolic processes in the liver. BTs monitor the appearance of CO2 in breath as a marker of a specific substrate metabolized in the liver, typically within microsomes, cytosol, or mitochondria. The noninvasiveness of BTs originates from the use of the, nonradioactive, naturally occurring stable isotope 13C marking a specific substrate which is metabolized in the liver, leading to the appearance of 13CO2 in expired air. Some substrates (ketoisocaproic acid, methionine, and octanoic acid) provide information about dynamic liver mitochondrial function in health and disease. In humans, the application of 13C-breath tests ranges from nonalcoholic and alcoholic liver diseases to liver cirrhosis, hepatocarcinoma, preoperative and postoperative assessment of liver function, and drug-induced liver damage. 13C-BTs are an indirect, cost-effective, and easy method to evaluate dynamic liver function and gastric kinetics in health and disease, with ongoing studies focusing on further applications in clinical medicine.
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29
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Salehi E, Mashayekh M, Taheri F, Gholami M, Motaghinejad M, Safari S, Sepehr A. Curcumin Can be Acts as Effective agent for Prevent or Treatment of Alcohol-induced Toxicity in Hepatocytes: An Illustrated Mechanistic Review. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:418-436. [PMID: 34400970 PMCID: PMC8170768 DOI: 10.22037/ijpr.2020.112852.13985] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Previous studies have shown that alcohol abuse can cause serious liver damage and cirrhosis. The main pathway for these types of hepatocellular cell neurodegeneration is mitochondrial dysfunction, which causes lipid peroxidation and dysfunction of the glutathione ring and the defect of antioxidant enzymes in alcoholic hepatic cells. Alcohol can also initiate malicious inflammatory pathways and trigger the initiation and activation of intestinal and extrinsic apoptosis pathways in hepatocellular tissues that lead to cirrhosis. Previous studies have shown that curcumin may inhibit lipid peroxidation, glutathione dysfunction and restore antioxidant enzymes. Curcumin also modulates inflammation and the production of alcohol-induced biomarkers. Curcumin has been shown to play a critical role in the survival of alcoholic hepatocellular tissue. It has been shown that curcumin can induce and trigger mitochondrial biogenesis and, by this mechanism, prevent the occurrence of both intrinsic and extrinsic apoptosis pathways in liver cells that have been impaired by alcohol. According to this mechanism, curcumin may protect hepatocellular tissue from alcohol-induced cell degeneration and may therefore survive alcoholic hepatocellular tissue. . Based on these mechanisms, the protective functions of curcumin against alcohol-induced cell degeneration due to oxidative stress, inflammation, and apoptosis events in hepatocellular tissue have been recorded. Hence, in this research, we have attempted to evaluate and analyze the main contribution mechanism of curcumin cell defense properties against alcohol-induced hepatocellular damage, according to previous experimental and clinical studies, and in this way we report findings from major studies.
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Affiliation(s)
- Elham Salehi
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University (IUAPS), Tehran, Iran.
| | - Mohammad Mashayekh
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University (IUAPS), Tehran, Iran.
| | - Fereshteh Taheri
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Mina Gholami
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Majid Motaghinejad
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Sepideh Safari
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Afrah Sepehr
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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30
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Herrero R, Sánchez G, Asensio I, López E, Ferruelo A, Vaquero J, Moreno L, de Lorenzo A, Bañares R, Lorente JA. Liver-lung interactions in acute respiratory distress syndrome. Intensive Care Med Exp 2020; 8:48. [PMID: 33336286 PMCID: PMC7746785 DOI: 10.1186/s40635-020-00337-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022] Open
Abstract
Patients with liver diseases are at high risk for the development of acute respiratory distress syndrome (ARDS). The liver is an important organ that regulates a complex network of mediators and modulates organ interactions during inflammatory disorders. Liver function is increasingly recognized as a critical determinant of the pathogenesis and resolution of ARDS, significantly influencing the prognosis of these patients. The liver plays a central role in the synthesis of proteins, metabolism of toxins and drugs, and in the modulation of immunity and host defense. However, the tools for assessing liver function are limited in the clinical setting, and patients with liver diseases are frequently excluded from clinical studies of ARDS. Therefore, the mechanisms by which the liver participates in the pathogenesis of acute lung injury are not totally understood. Several functions of the liver, including endotoxin and bacterial clearance, release and clearance of pro-inflammatory cytokines and eicosanoids, and synthesis of acute-phase proteins can modulate lung injury in the setting of sepsis and other severe inflammatory diseases. In this review, we summarized clinical and experimental support for the notion that the liver critically regulates systemic and pulmonary responses following inflammatory insults. Although promoting inflammation can be detrimental in the context of acute lung injury, the liver response to an inflammatory insult is also pro-defense and pro-survival. A better understanding of the liver–lung axis will provide valuable insights into new diagnostic targets and therapeutic strategies for clinical intervention in patients with or at risk for ARDS.
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Affiliation(s)
- Raquel Herrero
- Department of Critical Care Medicine, Hospital Universitario de Getafe, Madrid, Spain. .,CIBER de Enfermedades Respiratorias, Instituto de Investigación Carlos III, Madrid, Spain. .,Fundación de Investigación Biomédica del Hospital Universitario de Getafe, Madrid, Spain.
| | - Gema Sánchez
- Fundación de Investigación Biomédica del Hospital Universitario de Getafe, Madrid, Spain.,Laboratory of Biochemistry, Hospital Universitario de Getafe, Madrid, Spain
| | - Iris Asensio
- Servicio de Aparato Digestivo. HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Investigación Carlos III, Madrid, Spain
| | - Eva López
- Fundación de Investigación Biomédica del Hospital Universitario de Getafe, Madrid, Spain
| | - Antonio Ferruelo
- CIBER de Enfermedades Respiratorias, Instituto de Investigación Carlos III, Madrid, Spain
| | - Javier Vaquero
- Servicio de Aparato Digestivo. HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Investigación Carlos III, Madrid, Spain
| | - Laura Moreno
- CIBER de Enfermedades Respiratorias, Instituto de Investigación Carlos III, Madrid, Spain.,Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Alba de Lorenzo
- Fundación de Investigación Biomédica del Hospital Universitario de Getafe, Madrid, Spain
| | - Rafael Bañares
- Servicio de Aparato Digestivo. HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Investigación Carlos III, Madrid, Spain
| | - José A Lorente
- Department of Critical Care Medicine, Hospital Universitario de Getafe, Madrid, Spain.,CIBER de Enfermedades Respiratorias, Instituto de Investigación Carlos III, Madrid, Spain.,Fundación de Investigación Biomédica del Hospital Universitario de Getafe, Madrid, Spain.,Universidad Europea de Madrid, Madrid, Spain
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31
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Lan R, Wei L, Chang Q, Wu S, Zhihui Z. Effects of dietary chitosan oligosaccharides on oxidative stress and inflammation response in liver and spleen of yellow-feather broilers exposed to high ambient temperature. ITALIAN JOURNAL OF ANIMAL SCIENCE 2020. [DOI: 10.1080/1828051x.2020.1850215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Ruixia Lan
- Department of Animal Science, College of Coastal Agriculture Science, Guangdong Ocean University, Zhanjiang, P.R. China
| | - Linlin Wei
- Department of Animal Science, College of Coastal Agriculture Science, Guangdong Ocean University, Zhanjiang, P.R. China
| | - Qingqing Chang
- Department of Animal Science, College of Coastal Agriculture Science, Guangdong Ocean University, Zhanjiang, P.R. China
| | - Shengnan Wu
- Department of Animal Science, College of Coastal Agriculture Science, Guangdong Ocean University, Zhanjiang, P.R. China
| | - Zhao Zhihui
- Department of Animal Science, College of Coastal Agriculture Science, Guangdong Ocean University, Zhanjiang, P.R. China
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32
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Xu Y, Li W, Chen S, Huang B, Pei W, Niu C. Near-Infrared Responsive Phase-Shifted Nanoparticles for Magnetically Targeted MR/US Imaging and Photothermal Therapy of Cancer. Front Bioeng Biotechnol 2020; 8:599107. [PMID: 33304893 PMCID: PMC7701124 DOI: 10.3389/fbioe.2020.599107] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/26/2020] [Indexed: 01/25/2023] Open
Abstract
Accurate diagnosis, providing guidance for early treatment, can greatly improve the survival rate of cancer patients. However, there are still some difficulties with the existing diagnostic technology and early treatment methods. Here, near-infrared responsive phase-shifted nanoparticles (NRPNs) have been designed for magnetically targeted MR/US imaging and photothermal therapy of tumors. In this study, we fabricated a multifunctional polymer nanoparticle encapsulating indocyanine green (ICG), magnetic Fe3O4 nanoparticles and perfluoropentane (PFP). Under laser irradiation, the NRPNs, which trigger a phase-shifted expansion effect due to the quick conversion from light to heat by ICG and Fe3O4, can be used for ultrasound (US) imaging. At the same time, such nanoparticles can kill cancer cells via photothermal therapy (PTT). As a kind of negative enhancement agent, magnetic Fe3O4 nanoparticles in NRPNs showed high spatial resolution in MR imaging. Moreover, with the help of the magnetic field, the NRPNs nanoparticles showed high cellular uptake and high tumor accumulation, indicating their magnetic targeting property without biosafety concerns. Therefore, we present a strategy for magnetically targeted MR/US imaging guided photothermal therapy for the accurate diagnosis and efficient treatment of tumors.
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Affiliation(s)
- Yan Xu
- Department of Ultrasound Diagnosis, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wang Li
- Department of Ultrasound Diagnosis, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Sijie Chen
- Department of Ultrasound Diagnosis, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Biying Huang
- Department of Ultrasound Diagnosis, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wenjing Pei
- Department of Ultrasound Diagnosis, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chengcheng Niu
- Department of Ultrasound Diagnosis, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, China
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33
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Savchenko E, Kolokolnikov I, Velichko E, Osovskikh V, Kiseleva L, Musakulova Z. Design of Liver Functional Reserve Estimation Technique Based on Optical Densitometry. Diagnostics (Basel) 2020; 10:diagnostics10080599. [PMID: 32824396 PMCID: PMC7460397 DOI: 10.3390/diagnostics10080599] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/11/2020] [Accepted: 08/13/2020] [Indexed: 12/15/2022] Open
Abstract
This work is aimed at creating a modified invasive technique for assessing the liver's functional reserves. A study of the degree of hepatodepression is carried out by measuring the plasma elimination of indocyanine green using the method of optical densitometry. This paper presents test results for an aqueous solution and an albumin solution, as well as the results of measurements of plasma elimination of indocyanine green for patients with liver disease. Perfecting the proposed method will make an important scientific contribution to modern diagnostic medicine. Diagnosing the stages in the progression of the disease and its developing complications can make it possible to rapidly correct the patient's treatment algorithm, achieving positive outcomes in medical practice.
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Affiliation(s)
- Ekaterina Savchenko
- Institute of Physics, Nanotechnology and Telecommunications, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (I.K.); (E.V.)
- Correspondence: ; Tel.: +7-999-245-77-86
| | - Ilya Kolokolnikov
- Institute of Physics, Nanotechnology and Telecommunications, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (I.K.); (E.V.)
| | - Elena Velichko
- Institute of Physics, Nanotechnology and Telecommunications, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (I.K.); (E.V.)
| | - Victor Osovskikh
- Department of Anesthesiology and Resuscitation Russian Research Center for Radiology and Surgical Technologies, 197758 St. Petersburg, Russia; (V.O.); (L.K.)
| | - Lyubov Kiseleva
- Department of Anesthesiology and Resuscitation Russian Research Center for Radiology and Surgical Technologies, 197758 St. Petersburg, Russia; (V.O.); (L.K.)
| | - Zhyldyz Musakulova
- Computer Information Systems, International University of Kyrgyzstan, Bishkek 720007, Kyrgyzstan;
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Alraish R, Wicha SG, Frey OR, Roehr AC, Pratschke J, Stockmann M, Wuensch T, Kaffarnik M. Pharmacokinetics of tigecycline in critically ill patients with liver failure defined by maximal liver function capacity test (LiMAx). Ann Intensive Care 2020; 10:106. [PMID: 32754775 PMCID: PMC7403243 DOI: 10.1186/s13613-020-00707-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 06/26/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND In critically ill patients, tigecycline (TGC) remains an important therapeutic option due to its efficacy against multiresistant Gram-positive and Gram-negative bacteria. TGC is metabolized and eliminated predominantly by the liver. Critical illness-induced liver failure may have a profound impact on the pharmacokinetic of TGC. In the present study, we aimed to establish a link between the degree of liver dysfunction and TGC plasma concentration using the novel maximum liver function capacity (LiMAx) test, as a dynamic liver function test. MATERIALS/METHODS The prospective study included 33 patients from a surgical ICU with the clinical indication for antibiotic therapy with TGC. The patients received 100 mg loading dose of TGC followed by intermittent standard doses of 50 mg q12. Blood samples for TGC plasma concentration were collected at 0.3, 2, 5, 8 and 11.5 h in a steady-state condition after at least 36 h post-standard dosage. The results were analyzed by means of a high-performance liquid chromatography (HPLC) method. Within the same day, the LiMAx test was carried out and routine blood parameters were measured. RESULTS Peak plasma concentrations of TGC were significantly higher in patients with severe liver failure (LiMAx < 100 µg/kg/h) when compared to patients with normal liver function (LiMAx > 300 µg/kg/h). The pharmacokinetic curves revealed higher values in severe liver failure at any measured point. Moreover, LiMAx and total bilirubin were the only liver-related parameters that correlated with TGC Cmax. CONCLUSIONS The present study demonstrates a high variability of TGC plasma concentrations in critically ill patients. The results show a significant correlation between the degree of liver dysfunction, measured by the LiMAx test, and TGC Cmax. LiMAx test may be a helpful tool beyond others for adjusting the required dosage of hepatic metabolized antibiotics in critically ill patients. Trial registry DRKS-German clinical trials register; Trial registration number: DRKS00008888; Date of registration: 07-17-2015; Date of enrolment of the first participant to the trial: 12-10-2015.
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Affiliation(s)
- Rawan Alraish
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Sebastian G Wicha
- Dept. of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146, Hamburg, Germany
| | - Otto R Frey
- Clinical Pharmacy, Klinikum Heidenheim, Schlosshaustraße 100, 89522, Heidenheim, Germany
| | - Anka C Roehr
- Clinical Pharmacy, Klinikum Heidenheim, Schlosshaustraße 100, 89522, Heidenheim, Germany
| | - Johann Pratschke
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum Augustenburger Platz 1, 13353, Berlin, Germany
| | - Martin Stockmann
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum Augustenburger Platz 1, 13353, Berlin, Germany
| | - Tilo Wuensch
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum Augustenburger Platz 1, 13353, Berlin, Germany
| | - Magnus Kaffarnik
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum Augustenburger Platz 1, 13353, Berlin, Germany
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35
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Hindel S, Geisel D, Alerić I, Theilig D, Denecke T, Lüdemann L. Liver function quantification of patients with portal vein embolization using dynamic contrast-enhanced MRI for assessment of hepatocyte uptake and elimination. Phys Med 2020; 76:207-220. [PMID: 32707485 DOI: 10.1016/j.ejmp.2020.07.002] [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: 03/19/2020] [Revised: 06/18/2020] [Accepted: 07/02/2020] [Indexed: 11/30/2022] Open
Abstract
PURPOSE We evaluated pharmacokinetic models which quantify liver function including biliary elimination based on a dynamic Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) technique with sparse data collection feasible in clinical routine. METHODS Twelve patients with embolized liver segments following interventional treatment of primary liver cancer or hepatic metastasis underwent MRI. During Gd-EOB-DTPA bolus administration, a 3D dynamic gradient-echo (GRE) MRI examination was performed over approx. 28 min. Interrupted data sampling was started approx. 5 min after contrast agent administration. Different implementations of dual-inlet models were tested, namely the Euler method (DE) and convolution with residue functions (C). A simple uptake model (U) and an uptake- elimination model (UE) extended by incorporating the biliary contrast agent elimination rate (Ke) were evaluated. RESULTS The uptake-elimination model, calculated via the simple Euler method (UE- DE) and by convolution (UE-C), yielded similar overall estimates in terms of fitting quality and agreement with published values. The Euler method was approx. 50 times faster and yielded a mean elimination rate of Ke=1.8±1.2mL/(min·100 mL) in nonembolized liver tissue, which was significantly higher (p=8.8·10-4) than in embolized tissue Ke=0.4±0.4 mL/(min·100 mL). Fractional hepatocyte volume vh was not significantly higher in nonembolized tissue (52.4 ± 13.4 mL/100 mL) compared to embolized tissue (44.4 ± 26.1 mL/100 mL). CONCLUSIONS Interrupted late enhancement MRI data sampling in conjunction with the uptake-elimination model, deconvolved by integration of the differential rate equation and combined with the simple uptake model implemented with the Euler method (U-DE), turned out to be a stable and practical method for reliable noninvasive assessment of liver function.
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Affiliation(s)
- Stefan Hindel
- Department of Radiotherapy, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany.
| | - Dominik Geisel
- Department of Radiology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ivana Alerić
- Department of Radiotherapy, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany; Department of Physics, University of Osijek, Trg Ljudevita Gaja 6, 31000 Osijek, Croatia
| | - Dorothea Theilig
- Department of Radiology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Timm Denecke
- Clinic and Polyclinic for Diagnostic and Interventional Radiology, University Hospital Leipzig, Liebigstraße 20, 04103 Leipzig, Germany
| | - Lutz Lüdemann
- Department of Radiotherapy, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany
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36
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Sitia L, Sevieri M, Bonizzi A, Allevi R, Morasso C, Foschi D, Corsi F, Mazzucchelli S. Development of Tumor-Targeted Indocyanine Green-Loaded Ferritin Nanoparticles for Intraoperative Detection of Cancers. ACS OMEGA 2020; 5:12035-12045. [PMID: 32548382 PMCID: PMC7271044 DOI: 10.1021/acsomega.0c00244] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/29/2020] [Indexed: 05/13/2023]
Abstract
Indocyanine green (ICG) is a fluorescent dye with a strong emission in the near-infrared spectral range that allows deep signal penetration and minimal interference of tissue autofluorescence. It has been employed in clinics for different applications, among which the more interesting is certainly near-infrared fluorescence image-guided surgery. This technique has found wide application in surgical oncology for lymph node mapping or for laparoscopic surgery. Despite ICG being useful for tracking loco-regional lymph nodes, it does not provide any information about cancer involvement of such lymph nodes or lymphatic vessels, lacking any tumor-targeting specificity. However, the clinical need in surgical oncology is not only a specific tracking of metastatic nodes but also the intraoperative detection of micrometastatic deposits. Here, we have exploited a nanotechnological solution to improve ICG usefulness by its encapsulation in H-ferritin (HFn) nanocages. They are natural protein-based nanoparticles that exhibit some very interesting features as delivery systems in oncological applications because they display specific tumor homing. We show that HFn loaded with ICG exhibits specific uptake into different cancer cell lines and is able to deliver ICG to the tumor more efficiently than the free dye in an in vivo model of TNBC. Our results pave the way for the application of ICG-loaded HFn in fluorescence image-guided surgery of cancer.
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Affiliation(s)
- Leopoldo Sitia
- Nanomedicine
Laboratory, Department of Biomedical and Clinical Sciences “Luigi
Sacco”, Università degli Studi
di Milano, via G.B. Grassi 74, 20157 Milan, Italy
| | - Marta Sevieri
- Nanomedicine
Laboratory, Department of Biomedical and Clinical Sciences “Luigi
Sacco”, Università degli Studi
di Milano, via G.B. Grassi 74, 20157 Milan, Italy
| | - Arianna Bonizzi
- Nanomedicine
Laboratory, Department of Biomedical and Clinical Sciences “Luigi
Sacco”, Università degli Studi
di Milano, via G.B. Grassi 74, 20157 Milan, Italy
| | - Raffaele Allevi
- Nanomedicine
Laboratory, Department of Biomedical and Clinical Sciences “Luigi
Sacco”, Università degli Studi
di Milano, via G.B. Grassi 74, 20157 Milan, Italy
| | - Carlo Morasso
- Nanomedicine
and Molecular Imaging Lab, Istituti Clinici
Scientifici Maugeri IRCCS, via S. Maugeri, 10, 27100 Pavia (PV), Italy
| | - Diego Foschi
- General
Surgery Division, Department of Biomedical and Clinical Sciences “Luigi
Sacco”, Università degli Studi
di Milano, via G.B. Grassi
74, 20157 Milan, Italy
| | - Fabio Corsi
- Nanomedicine
Laboratory, Department of Biomedical and Clinical Sciences “Luigi
Sacco”, Università degli Studi
di Milano, via G.B. Grassi 74, 20157 Milan, Italy
- Nanomedicine
and Molecular Imaging Lab, Istituti Clinici
Scientifici Maugeri IRCCS, via S. Maugeri, 10, 27100 Pavia (PV), Italy
- Breast
Unit, Istituti Clinici Scientifici Maugeri
IRCCS, via S. Maugeri,
10, 27100 Pavia
(PV), Italy
| | - Serena Mazzucchelli
- Nanomedicine
Laboratory, Department of Biomedical and Clinical Sciences “Luigi
Sacco”, Università degli Studi
di Milano, via G.B. Grassi 74, 20157 Milan, Italy
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Assessing Non-Invasive Liver Function in Patients with Intestinal Failure Receiving Total Parenteral Nutrition-Results from the Prospective PNLiver Trial. Nutrients 2020; 12:nu12051217. [PMID: 32357501 PMCID: PMC7282264 DOI: 10.3390/nu12051217] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 04/14/2020] [Accepted: 04/23/2020] [Indexed: 01/21/2023] Open
Abstract
Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB–4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group and a stable parenteral nutrition (SPN) group. While the SPN group (n = 9) had significantly shorter small bowel length and poorer nutritional status at baseline compared to the RPN group (n = 11), no difference in liver function was observed between the distinct groups. Over time, liver function determined by LiMAx did continuously decrease from baseline to 24 months in the SPN group but remained stable in the RPN group. This decrease in liver function assessed with LiMAx in the SPN group preceded deterioration of all other investigated liver function tests during the study period. Our results suggest that the liver function over time is primarily determined by the degree of intestinal failure. Furthermore, the LiMAx test appeared more sensitive in detecting early changes in liver function in comparison to other liver function tests.
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Theilig D, Tsereteli A, Elkilany A, Raabe P, Lüdemann L, Malinowski M, Stockmann M, Pratschke J, Hamm B, Denecke T, Geisel D. Gd-EOB-DTPA-enhanced MRI T1 relaxometry as an imaging-based liver function test compared with 13C-methacetin breath test. Acta Radiol 2020; 61:291-301. [PMID: 31324131 DOI: 10.1177/0284185119861314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) can be used as an imaging-based liver function test. This study aims to further corroborate its validity. Purpose To compare Gd-EOB-DTPA-enhanced MRI as an imaging-based liver function test with the 13C-methacetin breath test. Material and Methods Fifty-three patients who underwent Gd-EOB-DTPA-enhanced MRI T1 relaxometry before and 20 min after intravenous Gd-EOB-DTPA administration as well as a 13C-methacetin breath test (LiMAx test) were retrospectively analyzed. T1 relaxation times of liver parenchyma, total liver volume (TLV), and functional liver volume (FLV) were determined. Pearson correlations, multiple linear regression analysis, and receiver operating characteristic curve analysis were performed with indices derived from T1 relaxometry, liver volumetry, and laboratory parameters to identify the best predictor of liver function as determined by the LiMAx test. Results T1 reduction rate (T1 RR), T1 RR × TLV, T1 RR × FLV, and T1 relaxation time 20 min after intravenous Gd-EOB administration showed a statistically significant correlation with LiMAx and discriminatory capacity between patients with LiMAx of > and < 315 µg/kg/h. Of the indices investigated, T1 RR showed the best discriminatory capacity and proved to be the only statistically significant parameter in multiple linear regression analysis. Conclusion Gd-EOB-DTPA-enhanced MRI as an imaging-based liver function test also correlates with the LiMAx test which in turn reflects cytochrome P450 function. The T1 reduction rate of the liver on Gd-EOB-DTPA-enhanced MRI allows prediction of liver function as determined by the LiMAx test both for 1.5 and 3.0 T.
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Affiliation(s)
- Dorothea Theilig
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
| | - Ana Tsereteli
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
| | - Aboelyazid Elkilany
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
| | - Philip Raabe
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
| | - Lutz Lüdemann
- Department of Medical Physics, Essen University Hospital, Essen, Germany
| | - Maciej Malinowski
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of General, Visceral and Transplantation Surgery, Berlin, Germany
| | - Martin Stockmann
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of General, Visceral and Transplantation Surgery, Berlin, Germany
| | - Johann Pratschke
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of General, Visceral and Transplantation Surgery, Berlin, Germany
| | - Bernd Hamm
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
| | - Timm Denecke
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
| | - Dominik Geisel
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
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Evaluating hepatotoxic effects of chemotherapeutic agents with gadoxetic-acid-enhanced magnetic resonance imaging. Eur J Radiol 2019; 124:108807. [PMID: 31926386 DOI: 10.1016/j.ejrad.2019.108807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/23/2019] [Accepted: 12/22/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE To evaluate the hepatotoxicity of different chemotherapeutic agents used to treat neuroendocrine tumours (NETs) with gadoxetic acid-enhanced magnetic resonance imaging (MRI). MATERIAL AND METHODS A total of 129 patients with NETs who underwent two or more serial gadoxetic-acid-enhanced MRI examinations between 2014 and 2018 and started chemotherapy in the beginning of that time period were retrospectively analysed. Linear mixed model analysis evaluating relative enhancement (RE) of the liver in the hepatobiliary phase with respect to time between MRI examinations, primary chemotherapy, hepatotoxicity score of preceding and subsequent chemotherapies as well as age and gender as fixed variables was performed. Binary logistic regression was used to verify whether the hepatotoxicity score predicts a significant impact of a chemotherapeutic regimen on RE and hence liver function. RESULTS Linear mixed model analysis of a total of 539 MRI examinations identified all chemotherapeutic agents with known hepatoxicity as a factor with a statistically significant negative impact on RE of the liver in gadoxetic-acid-enhanced MRI in addition to age. This result was confirmed by binary logistic regression analysis. CONCLUSION Our results confirm that gadoxetic acid-enhanced MRI can be used as an imaging-based liver function test for assessing hepatotoxicity of chemotherapeutic agents used for NETs. The findings underscore the known degrees of hepatotoxicity of the chemotherapeutic agents currently used in the treatment of NETs.
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40
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Donnelly SR, Hinkle SN, Rawal S, Grunnet LG, Chavarro JE, Vaag A, Wu J, Damm P, Mills JL, Li M, Bjerregaard AA, Thuesen ACB, Gore-Langton RE, Francis EC, Ley SH, Hu FB, Tsai MY, Olsen SF, Zhang C. Prospective study of gestational diabetes and fatty liver scores 9 to 16 years after pregnancy. J Diabetes 2019; 11:895-905. [PMID: 31001915 PMCID: PMC6791726 DOI: 10.1111/1753-0407.12934] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/01/2019] [Accepted: 04/12/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Women with gestational diabetes mellitus (GDM) may be at an increased risk of liver complications because chronic hyperglycemia is a risk factor for liver fat accumulation and potential liver dysfunction. Large prospective studies examining liver fat accumulation following a GDM pregnancy are lacking. METHODS The Diabetes & Women's Health Study (2012-2014) examined the association between GDM and subsequent fatty liver scores among 607 women with and 619 women without GDM in the Danish National Birth Cohort. Nine to 16 years postpartum, a clinical examination was performed, with measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase, from which fatty liver scoring indices were calculated to assess liver fat score, fatty liver index, hepatic steatosis index, and liver fat percentage. Relative risks (RR) with 95% confidence intervals (CI) for elevated liver scoring indices by GDM status were assessed adjusting for major risk factors, including prepregnancy body mass index. RESULTS Women with prior GDM had higher adjusted ALT and AST levels than women without GDM (by 6.7% [95% CI 1.7-12.0] and 4.8% [95% CI 0.6-9.1], respectively). Women with GDM also had adjusted increased risks for elevated liver fat score (RR 2.34; 95% CI 1.68-3.27), fatty liver index (RR 1.59; 95% CI 1.27-1.99), and hepatic steatosis index (RR 1.44; 95% CI 1.21-1.71). CONCLUSIONS Women with GDM during pregnancy were at an increased risk for fatty liver 9 to 16 years postpartum. Gestational diabetes mellitus may serve as another risk indicator for the early identification and prevention of liver fat accumulation.
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Affiliation(s)
- Sarah R Donnelly
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
- Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
| | - Stefanie N Hinkle
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Shristi Rawal
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
- Department of Nutritional Sciences, School of Health Professions, Rutgers University, Newark, New Jersey
| | - Louise G Grunnet
- Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark
- The Danish Diabetes Academy, Odense, Denmark
| | - Jorge E Chavarro
- Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Channing Division of Network Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Allan Vaag
- Cardiovascular and Metabolic Disease Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Jing Wu
- Glotech, Rockville, Maryland
| | - Peter Damm
- Center for Pregnant Women with Diabetes, Departments of Endocrinology and Obstetrics, Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, Faculty of Health and Medical Services, University of Copenhagen, Copenhagen, Denmark
| | - James L Mills
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Mengying Li
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Anne A Bjerregaard
- Centre for Fetal Programming, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | | | | | - Ellen C Francis
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
- Department of Public Health Sciences, Clemson University, Clemson, South Carolina
| | - Sylvia H Ley
- Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Channing Division of Network Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Frank B Hu
- Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Channing Division of Network Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael Y Tsai
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Sjurdur F Olsen
- Centre for Fetal Programming, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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Song X, Wang S, Zhao C, Zhang W, Wang G, Jia S. Visual method for evaluating liver function: targeted in vivo fluorescence imaging of the asialoglycoprotein receptor. BIOMEDICAL OPTICS EXPRESS 2019; 10:5015-5024. [PMID: 31646026 PMCID: PMC6788595 DOI: 10.1364/boe.10.005015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 08/28/2019] [Accepted: 09/01/2019] [Indexed: 06/10/2023]
Abstract
The visual evaluation of liver function (LF) has always been a hot topic in research on liver diseases. In vivo fluorescence imaging (IVFI) of the Cy5.5-galactosylated polylysine (Cy5.5-GP) probe targeting asialoglycoprotein receptor (ASGPR), for evaluating LF in chronic alcoholic liver injury (cALI) mice was investigated in this study. The decrease of fluorescence signals in the livers showed a biological relationship with the liver ASGPR expression, histology, and serum marker levels of LF in cALI mice. The targeted IVFI of ASGPR as a novel method can intuitively and noninvasively display the characteristics of liver's ASGPR level to provide a reference for evaluating LF.
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Affiliation(s)
- Xiaojing Song
- Department of Biomedical Engineering, Institute of Acupuncture & Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Shuyou Wang
- Department of Biomedical Engineering, Institute of Acupuncture & Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Chong Zhao
- Beijing Hapten and Protein Biomedical Institute, Beijing, 102206, China
| | - Weibo Zhang
- Department of Biomedical Engineering, Institute of Acupuncture & Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Guangjun Wang
- Department of Biomedical Engineering, Institute of Acupuncture & Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Shuyong Jia
- Department of Biomedical Engineering, Institute of Acupuncture & Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China
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Tang J, Li B, Howard CB, Mahler SM, Thurecht KJ, Wu Y, Huang L, Xu ZP. Multifunctional lipid-coated calcium phosphate nanoplatforms for complete inhibition of large triple negative breast cancer via targeted combined therapy. Biomaterials 2019; 216:119232. [DOI: 10.1016/j.biomaterials.2019.119232] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 05/24/2019] [Accepted: 05/28/2019] [Indexed: 11/25/2022]
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Plasma Disappearance Rate of Indocyanine Green for Determination of Liver Function in Three Different Models of Shock. Diagnostics (Basel) 2019; 9:diagnostics9030108. [PMID: 31480421 PMCID: PMC6787744 DOI: 10.3390/diagnostics9030108] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 08/27/2019] [Accepted: 08/29/2019] [Indexed: 01/21/2023] Open
Abstract
The measurement of the liver function via the plasma disappearance rate of indocyanine green (PDRICG) is a sensitive bed-side tool in critical care. Yet, recent evidence has questioned the value of this method for hyperdynamic conditions. To evaluate this technique in different hemodynamic settings, we analyzed the PDRICG and corresponding pharmacokinetic models after endotoxemia or hemorrhagic shock in rats. Male anesthetized Sprague-Dawley rats underwent hemorrhage (mean arterial pressure 35 ± 5 mmHg, 90 min) and 2 h of reperfusion, or lipopolysaccharide (LPS) induced moderate or severe (1.0 vs. 10 mg/kg) endotoxemia for 6 h (each n = 6). Afterwards, PDRICG was measured, and pharmacokinetic models were analyzed using nonlinear mixed effects modeling (NONMEM®). Hemorrhagic shock resulted in a significant decrease of PDRICG, compared with sham controls, and a corresponding attenuation of the calculated ICG clearance in 1- and 2-compartment models, with the same log-likelihood. The induction of severe, but not moderate endotoxemia, led to a significant reduction of PDRICG. The calculated ICG blood clearance was reduced in 1-compartment models for both septic conditions. 2-compartment models performed with a significantly better log likelihood, and the calculated clearance of ICG did not correspond well with PDRICG in both LPS groups. 3-compartment models did not improve the log likelihood in any experiment. These results demonstrate that PDRICG correlates well with ICG clearance in 1- and 2-compartment models after hemorrhage. In endotoxemia, best described by a 2-compartment model, PDRICG may not truly reflect the ICG clearance.
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Kunikowska AJ, Wildgruber M, Schulte-Frohlinde E, Lahmer T, Schmid RM, Huber W. Liver function assessment using indocyanine green plasma disappearance rate in a young male with icteric leptospirosis: a case report. BMC Infect Dis 2019; 19:473. [PMID: 31138261 PMCID: PMC6537418 DOI: 10.1186/s12879-019-4101-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 05/16/2019] [Indexed: 11/24/2022] Open
Abstract
Background Leptospirosis is one of the leading global zoonotic causes of morbidity and mortality. It is induced by a pathogenic spirochete of the genus Leptospira. The icteric form of leptospirosis is characterized by pronounced hyperbilirubinemia and associated with significantly increased mortality. Conventional static liver function tests insufficiently assess hepatic damage and have limited prognostic value. Dynamic tests, such as indocyanine green plasma (ICG) clearance, more adequately reflect hepatic functional status. In this case report we describe the ICG plasma disappearance rates (ICG-PDR) in a patient with leptospirosis and massive hyperbilirubinemia, expanding our knowledge of liver dysfunction in icteric leptospirosis. Case presentation A 21-year-old Caucasian man presented with acute-onset jaundice, myalgia, fever and headaches. Laboratory tests upon admission revealed, most notably, acute kidney failure and hyperbilirubinemia of 17 mg/dl with mild elevation of aminotransferases. In the course of the following 4 days, total serum bilirubin increased to 54 mg/dl. The clinical outcome was favorable with intravenous ceftriaxone and doxycycline. Presumptive diagnosis of leptospirosis was later confirmed by PCR-based amplification of leptospiral DNA in the blood. ICG-PDR values, bilirubin as well as aminotransferases were recorded throughout hospitalization and a 3-month follow-up period. Initially dramatically reduced ICG-PDR (2.0%/min, normal range: 18–25%/min) rapidly normalized within 10 days, while bilirubin remained elevated up to week 7. Mild elevation of serum alanine aminotransferase was at its peak of 124 U/l by day 12 and reached close to normal levels by week 7 upon admission. Conclusions Markedly diminished ICG-PDR values presented in this case report suggest severe liver function impairment in the acute phase of icteric leptospirosis. Prolonged elevation of serum bilirubin may not adequately reflect recovery of liver injury in this disease. ICG clearance appears to be a promising marker for the detection of hepatic dysfunction and recovery in icteric leptospirosis in addition to the static tests. Electronic supplementary material The online version of this article (10.1186/s12879-019-4101-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alicja J Kunikowska
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, D-81675, Munich, Germany.
| | - Monika Wildgruber
- Innere Medizin I, Klinikum Freising, Alois-Steinecker-Straße 18, D-85354, Freising, Germany
| | | | - Tobias Lahmer
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, D-81675, Munich, Germany
| | - Roland M Schmid
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, D-81675, Munich, Germany
| | - Wolfgang Huber
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, D-81675, Munich, Germany
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Huber W, Zanner R, Schneider G, Schmid R, Lahmer T. Assessment of Regional Perfusion and Organ Function: Less and Non-invasive Techniques. Front Med (Lausanne) 2019; 6:50. [PMID: 30968023 PMCID: PMC6438879 DOI: 10.3389/fmed.2019.00050] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 02/25/2019] [Indexed: 12/13/2022] Open
Abstract
Sufficient organ perfusion essentially depends on preserved macro- and micro-circulation. The last two decades brought substantial progress in the development of less and non-invasive monitoring of macro-hemodynamics. However, several recent studies suggest a frequent incoherence of macro- and micro-circulation. Therefore, this review reports on interactions of macro- and micro-circulation as well as on specific regional and micro-circulation. Regarding global micro-circulation the last two decades brought advances in a more systematic approach of clinical examination including capillary refill time, a graded assessment of mottling of the skin and accurate measurement of body surface temperatures. As a kind of link between macro- and microcirculation, a number of biochemical markers can easily be obtained. Among those are central-venous oxygen saturation (ScvO2), plasma lactate and the difference between central-venous and arterial CO2 (cv-a-pCO2-gap). These inexpensive markers have become part of clinical routine and guideline recommendations. While their potential to replace parameters of macro-circulation such as cardiac output (CO) is limited, they facilitate the interpretation of the adequacy of CO and other macro-circulatory markers. Furthermore, they give additional hints on micro-circulatory impairment. In addition, a number of more sophisticated technical approaches to quantify and visualize micro-circulation including video-microscopy, laser flowmetry, near-infrared spectroscopy (NIRS), and partial oxygen pressure measurement have been introduced within the last 20 years. These technologies have been extensively used for scientific purposes. Moreover, they have been successfully used for educational purposes and to visualize micro-circulatory disturbances during sepsis and other causes of shock. Despite several studies demonstrating the association of these techniques and parameters with outcome, their practical application still is limited. However, future improvements in automated and “online” diagnosis will help to make these technologies more applicable in clinical routine. This approach is promising with regard to several studies which demonstrated the potential to guide therapy in different types of shock. Finally several organs have specific patterns of circulation related to their special anatomy (liver) or their auto-regulatory capacities (brain, kidney). Therefore, this review also discusses specific issues of monitoring liver, brain, and kidney circulation and function.
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Affiliation(s)
- Wolfgang Huber
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Robert Zanner
- Klinik für Anästhesiologie, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Gerhard Schneider
- Klinik für Anästhesiologie, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Roland Schmid
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Tobias Lahmer
- Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technische Universität München, München, Germany
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Blüthner E, Bednarsch J, Pape UF, Karber M, Maasberg S, Gerlach UA, Pascher A, Wiedenmann B, Pratschke J, Stockmann M. Advanced liver function assessment in patients with intestinal failure on long-term parenteral nutrition. Clin Nutr 2019; 39:540-547. [PMID: 30885502 DOI: 10.1016/j.clnu.2019.02.039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 02/19/2019] [Accepted: 02/24/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Intestinal failure associated liver disease (IFALD) is one of the leading complications and causes of deaths in adult patients receiving home parenteral nutrition for chronic intestinal failure (CIF). Early diagnosis of IFALD is key to alleviate the progression of hepatic dysfunction. The aim of this study was to evaluate the capability of noninvasive liver function tests. METHODS 90 adult patients with CIF receiving long-term home parenteral nutrition were included in a prospective cross-sectional study at our department between 2014 and 2017. All participants underwent dynamic liver function assessment (maximum liver function capacity [LiMAx] test, indocyanine green [ICG] test), transient elastography (FibroScan), blood tests and comprehensive nutritional status assessment. Univariate and multivariable analysis were performed to identify predictors of liver function. RESULTS LiMAx, ICG test, and FibroScan highly correlated with standard liver function tests. Multivariable analysis identified intact ileum (B = 520.895; p = 0.010), digestive anatomy type 3 (B = 75.612; p = 0.025), citrulline level (B = 3.428; p = 0.040), parenteral olive oil intake (B = -0.570; p = 0.043), and oral intake (B = 182.227; p = 0.040) as independent risk factors affecting liver function determined by LiMAx test. ICG test and FibroScan showed no correlation with gastrointestinal and nutrition-related parameters. CONCLUSION The LiMAx test is significantly associated with widely accepted risk factors for IFALD by multivariable analysis, whereas ICG test and FibroScan failed to show significant correlations. Liver function assessment by LiMAx test may therefore have the potential to detect alterations in liver function and identify patients at risk for the development of IFALD. Longitudinal studies are needed to investigate the impact of liver function determined by LiMAx test on long-term outcome in patients with CIF.
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Affiliation(s)
- Elisabeth Blüthner
- Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
| | - Jan Bednarsch
- Department of General, Visceral and Transplantation Surgery, University Hospital Aachen, Rhine-Westphalia Institute of Technology, Pauwelsstraße 30, 52074 Aachen, Germany.
| | - Ulrich-Frank Pape
- Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, Asklepios Medical School, Lohmühlenstr. 5, 20099 Hamburg, Germany.
| | - Mirjam Karber
- Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Str. 2, 10178 Berlin, Germany.
| | - Sebastian Maasberg
- Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, Asklepios Medical School, Lohmühlenstr. 5, 20099 Hamburg, Germany.
| | - Undine A Gerlach
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
| | - Andreas Pascher
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of General, Visceral and Transplantation Surgery, Münster University Hospital, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
| | - Bertram Wiedenmann
- Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
| | - Johann Pratschke
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
| | - Martin Stockmann
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of General, Visceral and Vascular Surgery, Evangelisches Krankenhaus Paul Gerhardt Stift, Paul-Gerhardt-Str. 42-45, 06886 Lutherstadt Wittenberg, Germany.
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Blüthner E, Bednarsch J, Stockmann M, Karber M, Pevny S, Maasberg S, Gerlach UA, Pascher A, Wiedenmann B, Pratschke J, Pape U. Determinants of Quality of Life in Patients With Intestinal Failure Receiving Long‐Term Parenteral Nutrition Using the SF‐36 Questionnaire: A German Single‐Center Prospective Observational Study. JPEN J Parenter Enteral Nutr 2019; 44:291-300. [DOI: 10.1002/jpen.1531] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/19/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Elisabeth Blüthner
- Department of Surgery Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
- Department of Hepatology and Gastroenterology Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
| | - Jan Bednarsch
- Department of General Visceral, and Transplantation Surgery University Hospital Aachen Rhine‐Westphalia Institute of Technology Aachen Germany
| | - Martin Stockmann
- Department of Surgery Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
- Department of General, Visceral, and Vascular Surgery Evangelisches Krankenhaus Paul Gerhardt Stift Lutherstadt Wittenberg Germany
| | - Mirjam Karber
- Department of Hepatology and Gastroenterology Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
- Berlin Institute of Health Berlin Germany
| | - Sophie Pevny
- Department of Hepatology and Gastroenterology Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
| | - Sebastian Maasberg
- Department of Hepatology and Gastroenterology Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
- Department of Internal Medicine and Gastroenterology Asklepios Klinik St. Georg Asklepios Medical School Hamburg Germany
| | - Undine A. Gerlach
- Department of Surgery Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
| | - Andreas Pascher
- Department of Surgery Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
- Department of General, Visceral, and Transplantation Surgery Münster University Hospital Münster Germany
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
| | - Johann Pratschke
- Department of Surgery Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
| | - Ulrich‐Frank Pape
- Department of Hepatology and Gastroenterology Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany
- Department of Internal Medicine and Gastroenterology Asklepios Klinik St. Georg Asklepios Medical School Hamburg Germany
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Fuhrmann I, Brünn K, Probst U, Verloh N, Stroszczynski C, Jung EM, Wiggermann P, Haimerl M. Proof of principle: Estimation of liver function using color coded Doppler sonography of the portal vein. Clin Hemorheol Microcirc 2019; 70:585-594. [DOI: 10.3233/ch-189323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Irene Fuhrmann
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Karin Brünn
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Ute Probst
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Niklas Verloh
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | | | - Ernst Michael Jung
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Philipp Wiggermann
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Michael Haimerl
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
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Clearance of Indocyanine Green in Severe Pediatric Burns. J Trauma Acute Care Surg 2018; 86:817-822. [PMID: 30589752 DOI: 10.1097/ta.0000000000002180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Clearance of indocyanine green dye (ICGc) reflects sinusoidal perfusion and hepatocyte cell membrane function. Thus, ICGc is a reflection of the functional reserve of intact hepatocytes. The purpose of this study was to identify predictors of ICGc in severely burned children during the acute hospitalization and at the time of discharge from the intensive care unit (ICU). A secondary aim was to determine the relationship between liver size and patient ICGc. METHODS Twenty-six children (0.8-17 years old) with 35% or greater total body surface area burned (%TBSA-B) were included. Assessment of ICGc (in milliliters per minute per meter squared) was done during the acute hospitalization (median: 6 days after admission, median: 14 days postburn) and at the time of discharge from the ICU (median: 19 days after admission, median: 27 days postburn). Age, TBSA-B, % third-degree burns, inhalation injury, preexisting chronic malnutrition, hematocrit, liver dysfunction, and time from burn injury were incorporated in multiple linear regressions as predictive variables of ICGc. Only variables with p < 0.05 were retained in the final models. RESULTS Time from injury and age were the strongest predictors of ICGc during the acute admission but not at the time of discharge from the ICU. Time from injury was negatively associated with ICGc, whereas age was positively associated. At the time of discharge from the ICU, ICGc was increased in proportion to the %TBSA-B, whereas inhalation injury and preexisting chronic malnutrition were associated with lower ICGc. There was no correlation between change-to-predicted liver length and ICGc. CONCLUSIONS The intrinsic ability of the liver to extract ICG from plasma was lower in younger burned patients during the acute admission and in those with preexisting chronic malnutrition and inhalation injury at the time of discharge from the ICU. LEVEL OF EVIDENCE Prognostic/Epidemiologic, level III.
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Danin PE, Anty R, Patouraux S, Raucoules-Aimé M, Gugenheim J, Tran A, Gual P, Iannelli A. Non-invasive Evaluation of NAFLD with Indocyanine Green Clearance Test: a Preliminary Study in Morbidly Obese Patients Undergoing Bariatric Surgery. Obes Surg 2018; 28:735-742. [PMID: 28875438 DOI: 10.1007/s11695-017-2914-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Overweight and obesity dramatically increased in the last years. Hepatic complication of obesity, integrated in the term of non-alcoholic fatty liver disease (NAFLD), is a spectrum of abnormality ranging from steatosis to non-alcoholic steatohepatitis (NASH), potentially leading to cirrhosis. Liver biopsy remains the gold standard to evaluate the stage of NAFLD; however, the procedure is invasive. The indocyanine green (ICG) clearance test is performed since years to assess hepatic function before partial hepatectomy, or after liver transplantation. This study was designed to detect liver complications with the ICG clearance test in a population of obese patients scheduled for bariatric surgery. METHODS In a prospective cohort study, morbidly obese individuals receiving bariatric surgery with scheduled hepatic biopsies were investigated. Liver function was determined by the ICG test preoperatively, and blood samples were collected. Liver biopsy specimens were obtained for each patient and classified according to the NAFLD activity score (NAS) by a single pathologist that was blinded to the results of the ICG test. RESULTS Twenty-six patients were included (7 male and 19 female). The mean age of participants was 45.8 years; the mean body mass index was 41.4 kg/m2. According to the NAS, 6 (23.1%) patients revealed manifest NASH, and 5 patients were considered borderline (19.2%). A closed correlation was observed between the ICG clearance test and hepatic steatosis (r = 0.43, p = 0.03), NAS (r = 0.44, p = 0.025), and fibrosis (r = 0.49, p = 0.01). CONCLUSIONS In obese patients, non-invasive evaluation of liver function with the indocyanine green clearance test correlated with histological features of NAFLD. This may detect non-invasively hepatopathy in obese population and could motive biopsy.
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Affiliation(s)
- Pierre Eric Danin
- Anesthesia and Intensive care, L'Archet 2 Hospital, University Hospital of Nice, Archet 2 151 Route Saint Antoine de Ginestière, BP 3079, 062014, Nice, Cedex 3, France.,INSERM, U1065, C3M, Team 8 « Hepatic complications in obesity », 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France.,Université Côte d'Azur, Nice, France
| | - Rodolphe Anty
- INSERM, U1065, C3M, Team 8 « Hepatic complications in obesity », 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France.,Université Côte d'Azur, Nice, France.,CHU of Nice, Digestive Center, L'Archet 2 Hospital, University Hospital of Nice, Nice, France.,Digestive Unit, Archet 2 Hospital, 151 Route Saint Antoine de Ginestière, BP 3079, 06204, Nice, Cedex 3, France
| | - Stephanie Patouraux
- INSERM, U1065, C3M, Team 8 « Hepatic complications in obesity », 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France.,Université Côte d'Azur, Nice, France.,CHU of Nice, Biological Center, Pasteur Hospital, University Hospital of Nice, Nice, France.,Biological Center, Archet 2 Hospital, 151 Route Saint Antoine de Ginestière BP 3079, Nice, 06204, Cedex 3, France
| | - Marc Raucoules-Aimé
- Anesthesia and Intensive care, L'Archet 2 Hospital, University Hospital of Nice, Archet 2 151 Route Saint Antoine de Ginestière, BP 3079, 062014, Nice, Cedex 3, France.,Université Côte d'Azur, Nice, France
| | - Jean Gugenheim
- INSERM, U1065, C3M, Team 8 « Hepatic complications in obesity », 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France.,Université Côte d'Azur, Nice, France.,CHU of Nice, Digestive Center, L'Archet 2 Hospital, University Hospital of Nice, Nice, France.,Department of Digestive Surgery, Hôpital Archet 2, 151 Route Saint Antoine de Ginestière, BP3079, 06204, Nice, Cedex 3, France
| | - Albert Tran
- INSERM, U1065, C3M, Team 8 « Hepatic complications in obesity », 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France.,Université Côte d'Azur, Nice, France.,CHU of Nice, Digestive Center, L'Archet 2 Hospital, University Hospital of Nice, Nice, France.,Digestive Unit, Archet 2 Hospital, 151 Route Saint Antoine de Ginestière, BP 3079, 06204, Nice, Cedex 3, France
| | - Philippe Gual
- INSERM, U1065, C3M, Team 8 « Hepatic complications in obesity », 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France. .,Université Côte d'Azur, Nice, France. .,Inserm U1065, Bâtiment Universitaire ARCHIMED, Equipe 8 "Complications hépatiques de l'obésité", 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France.
| | - Antonio Iannelli
- INSERM, U1065, C3M, Team 8 « Hepatic complications in obesity », 151 route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice, Cedex 3, France. .,Université Côte d'Azur, Nice, France. .,CHU of Nice, Digestive Center, L'Archet 2 Hospital, University Hospital of Nice, Nice, France. .,Department of Digestive Surgery, Hôpital Archet 2, 151 Route Saint Antoine de Ginestière, BP3079, 06204, Nice, Cedex 3, France. .,Centre Hospitalier Universitaire de Nice, Service de Chirurgie Digestive et Transplantation Hépatique, Hôpital de l'Archet, Pôle Digestif, 151 route Saint Antoine de Ginestière, 06200, Nice, Cedex, France.
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