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Stilkerich A, Schicht G, Seidemann L, Hänsel R, Friebel A, Hoehme S, Seehofer D, Damm G. Cell Homeostasis or Cell Death-The Balancing Act Between Autophagy and Apoptosis Caused by Steatosis-Induced Endoplasmic Reticulum (ER) Stress. Cells 2025; 14:449. [PMID: 40136698 PMCID: PMC11941029 DOI: 10.3390/cells14060449] [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: 12/20/2024] [Revised: 03/04/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with potential progression to cirrhosis and impaired regeneration post-resection. A key mechanism underlying lipotoxicity is endoplasmic reticulum (ER) stress, particularly the activation of the unfolded protein response (UPR). This study investigates the interplay between lipid accumulation, endoplasmic reticulum (ER) stress, and cellular outcomes, focusing on the balance between autophagy and apoptosis. We cultured primary human hepatocytes (PHH) in a free fatty acid (FFA)-enriched medium for 120 h, assessing lipid accumulation, metabolism, and the expression of selected UPR markers. Additionally, we investigated the effects of lipid load on cell activity and growth in proliferating HepG2 cells. We observed that FFA uptake consistently induced ER stress, shifting cellular responses toward apoptosis under high lipid loads. Donor-specific differences were evident, particularly in lipid storage, excretion, and sensitivity to lipotoxicity. Some donors exhibited limited triglyceride (TAG) storage and excretion, leading to an excess of FFA whose metabolic fate remains unclear. Proliferation was more sensitive to lipid accumulation than overall cell activity, with even low FFA concentrations impairing growth, highlighting the vulnerability of regenerative processes to steatosis. The study elucidates how ER stress pathways, such as PERK-CHOP and IRE1α-JNK, are differentially activated in response to lipid overload, tipping the balance toward apoptosis in severe cases. The limited activation of repair mechanisms, such as autophagy, further emphasizes the critical role of ER stress in determining hepatocyte fate. The donor-dependent variability highlights the need for personalized strategies to mitigate lipotoxic effects and enhance liver regeneration in steatosis-related conditions.
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Affiliation(s)
- Anna Stilkerich
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Gerda Schicht
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Lena Seidemann
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - René Hänsel
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Adrian Friebel
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany
- Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), 04105 Leipzig, Germany
| | - Stefan Hoehme
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany
- Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), 04105 Leipzig, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
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Wu D, van de Graaf SFJ. Maladaptive regeneration and metabolic dysfunction associated steatotic liver disease: Common mechanisms and potential therapeutic targets. Biochem Pharmacol 2024; 227:116437. [PMID: 39025410 DOI: 10.1016/j.bcp.2024.116437] [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: 02/29/2024] [Revised: 07/12/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
The normal liver has an extraordinary capacity of regeneration. However, this capacity is significantly impaired in steatotic livers. Emerging evidence indicates that metabolic dysfunction associated steatotic liver disease (MASLD) and liver regeneration share several key mechanisms. Some classical liver regeneration pathways, such as HGF/c-Met, EGFR, Wnt/β-catenin and Hippo/YAP-TAZ are affected in MASLD. Some recently established therapeutic targets for MASH such as the Thyroid Hormone (TH) receptors, Glucagon-like protein 1 (GLP1), Farnesoid X receptor (FXR), Peroxisome Proliferator-Activated Receptors (PPARs) as well as Fibroblast Growth Factor 21 (FGF21) are also reported to affect hepatocyte proliferation. With this review we aim to provide insight into common molecular pathways, that may ultimately enable therapeutic strategies that synergistically ameliorate steatohepatitis and improve the regenerating capacity of steatotic livers. With the recent rise of prolonged ex-vivo normothermic liver perfusion prior to organ transplantation such treatment is no longer restricted to patients undergoing major liver resection or transplantation, but may eventually include perfused (steatotic) donor livers or even liver segments, opening hitherto unexplored therapeutic avenues.
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Affiliation(s)
- Dandan Wu
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, the Netherlands
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, the Netherlands.
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van Keulen AM, Olthof PB, Buettner S, Bednarsch J, Verheij J, Erdmann JI, Nooijen LE, Porte RJ, Minnee RC, Murad SD, Neumann UP, Heij L, Groot Koerkamp B, Doukas M. The Influence of Hepatic Steatosis and Fibrosis on Postoperative Outcomes After Major Liver Resection of Perihilar Cholangiocarcinoma. Ann Surg Oncol 2024; 31:133-141. [PMID: 37899413 PMCID: PMC10695871 DOI: 10.1245/s10434-023-14419-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/25/2023] [Indexed: 10/31/2023]
Abstract
BACKGROUND Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients. METHODS Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality. RESULTS Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69-2.68) or 90-day mortality (OR 1.22; 95% CI 0.62-2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41-1.41) or 90-day mortality (OR 0.60; 95% CI 0.33-1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36-4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31-4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36-4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30-3.87). CONCLUSION In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA.
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Affiliation(s)
| | - Pim B Olthof
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Stefan Buettner
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Joanne Verheij
- Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Joris I Erdmann
- Department of Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Lynn E Nooijen
- Department of Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Robert J Porte
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Robert C Minnee
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Sarwa Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Ulf P Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Lara Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
- Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Michail Doukas
- Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
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Maspero M, Yilmaz S, Cazzaniga B, Raj R, Ali K, Mazzaferro V, Schlegel A. The role of ischaemia-reperfusion injury and liver regeneration in hepatic tumour recurrence. JHEP Rep 2023; 5:100846. [PMID: 37771368 PMCID: PMC10523008 DOI: 10.1016/j.jhepr.2023.100846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/20/2023] [Accepted: 07/01/2023] [Indexed: 09/30/2023] Open
Abstract
The risk of cancer recurrence after liver surgery mainly depends on tumour biology, but preclinical and clinical evidence suggests that the degree of perioperative liver injury plays a role in creating a favourable microenvironment for tumour cell engraftment or proliferation of dormant micro-metastases. Understanding the contribution of perioperative liver injury to tumour recurrence is imperative, as these pathways are potentially actionable. In this review, we examine the key mechanisms of perioperative liver injury, which comprise mechanical handling and surgical stress, ischaemia-reperfusion injury, and parenchymal loss leading to liver regeneration. We explore how these processes can trigger downstream cascades leading to the activation of the immune system and the pro-inflammatory response, cellular proliferation, angiogenesis, anti-apoptotic signals, and release of circulating tumour cells. Finally, we discuss the novel therapies under investigation to decrease ischaemia-reperfusion injury and increase regeneration after liver surgery, including pharmaceutical agents, inflow modulation, and machine perfusion.
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Affiliation(s)
- Marianna Maspero
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Sumeyye Yilmaz
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Beatrice Cazzaniga
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Roma Raj
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Khaled Ali
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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Stern K, Aaltonen HL, Weykamp M, Gaskins D, Qui Q, O'Keefe G, Littman A, Linnau K, Rowhani-Rahbar A. Associations of Fatty Liver Disease With Recovery After Traumatic Injury. J Surg Res 2023; 291:270-281. [PMID: 37480755 PMCID: PMC11577254 DOI: 10.1016/j.jss.2023.06.014] [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: 11/28/2022] [Revised: 05/25/2023] [Accepted: 06/19/2023] [Indexed: 07/24/2023]
Abstract
INTRODUCTION Fatty liver disease (FLD) is associated with systemic inflammation, metabolic disease, and socioeconomic risk factors for poor health outcomes. Little is known on how adults with FLD recover from traumatic injury. METHODS We studied adults admitted to the intensive care unit of a level 1 trauma center (2016-2020), excluding severe head injury/cirrhosis (N = 510). We measured the liver-spleen attenuation difference in Hounsfield units (HUL-S) using virtual noncontrast computerized tomography scans: none (HUL-S>1), mild (-10≤HUL-S<1), moderate/severe (HUL-S < -10). We used Cox models to examine the "hazard" of recovery from systemic inflammatory response (SIRS score 2 or higher) organ dysfunction, defined as sequential organ failure assessment score 2 or higher, and lactate clearance (<2 mmol/L) in relation to FLD. RESULTS Fifty-one participants had mild and 29 had moderate/severe FLD. The association of FLD with recovery from SIRS differed according to whether an individual had shock on admission (hazard ratio [HR] = 0.76; 95% confidence interval [CI] 0.55-1.05 with shock; HR = 1.81; 95% CI 1.43-2.28 without shock). Compared to patients with no FLD, the hazard of lactate clearance was similar for mild FLD (HR = 1.04; 95% CI 0.63-1.70) and lower for moderate/severe FLD (HR = 0.40; 95% CI 0.18-0.89). CONCLUSIONS FLD is common among injured adults. Associations of FLD with outcomes after shock and critical illness warrant further study.
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Affiliation(s)
- Katherine Stern
- Division of Trauma, Burn & Critical Care, Department of Surgery, Harborview Medical Center, Seattle, Washington; Department of Surgery, University of Washington School of Medicine, Seattle, Washington; University of California San Francisco East Bay General Surgery Residency Program, Oakland, California; University of Washington School of Public Health, Seattle, Washington.
| | - H Laura Aaltonen
- Department of Surgery, University of Washington School of Medicine, Seattle, Washington; Department of Radiology, University of Washington School of Medicine, Seattle, Washington
| | - Mike Weykamp
- Division of Trauma, Burn & Critical Care, Department of Surgery, Harborview Medical Center, Seattle, Washington; Department of Surgery, University of Washington School of Medicine, Seattle, Washington; University of Washington School of Public Health, Seattle, Washington
| | - Devin Gaskins
- Department of Surgery, University of Washington School of Medicine, Seattle, Washington
| | - Qian Qui
- Harborview Injury Prevention & Research Center, Seattle, Washington
| | - Grant O'Keefe
- Division of Trauma, Burn & Critical Care, Department of Surgery, Harborview Medical Center, Seattle, Washington; Department of Surgery, University of Washington School of Medicine, Seattle, Washington; Harborview Injury Prevention & Research Center, Seattle, Washington
| | - Alyson Littman
- University of Washington School of Public Health, Seattle, Washington; VA Puget Sound Health Care System, Seattle, Washington
| | - Ken Linnau
- Division of Trauma, Burn & Critical Care, Department of Surgery, Harborview Medical Center, Seattle, Washington; Department of Surgery, University of Washington School of Medicine, Seattle, Washington; Department of Radiology, University of Washington School of Medicine, Seattle, Washington
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Kotsos D, Tziomalos K. Microsomal Prostaglandin E Synthase-1 and -2: Emerging Targets in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:3049. [PMID: 36769370 PMCID: PMC9918023 DOI: 10.3390/ijms24033049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population and is even more prevalent in obese and diabetic patients. NAFLD, and particularly the more advanced manifestation of the disease, nonalcoholic steatohepatitis (NASH), increases the risk for both liver-related and cardiovascular morbidity. The pathogenesis of NAFLD is complex and multifactorial, with many molecular pathways implicated. Emerging data suggest that microsomal prostaglandin E synthase-1 and -2 might participate in the development and progression of NAFLD. It also appears that targeting these enzymes might represent a novel therapeutic approach for NAFLD. In the present review, we discuss the association between microsomal prostaglandin E synthase-1 and -2 and NAFLD.
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Affiliation(s)
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
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7
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Patkar S, Kunte A, Sundaram S, Goel M. Post-hepatectomy biliary leaks: analysis of risk factors and development of a simplified predictive scoring system. Langenbecks Arch Surg 2023; 408:63. [PMID: 36692605 DOI: 10.1007/s00423-023-02776-w] [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: 04/01/2022] [Accepted: 12/14/2022] [Indexed: 01/25/2023]
Abstract
PURPOSE Most studies identifying risk factors for post-hepatectomy biliary leaks (PHBLs) have relatively small proportions of major hepatectomies. A simplified predictive score to identify high risk patients is necessary in order to investigate the efficacy of mitigation strategies. METHODS A retrospective analysis of a prospectively maintained database of liver resections from a high-volume cancer center was performed. Multivariate regression was utilized for identification of risk factors and development of the predictive score. RESULTS A total of 862 patients underwent a curative hepatic resection over 10 years, of whom 146 (16.9%) developed a biliary leak; 85 (9.86%), 52 (6.03%), and 9 (1.04%) patients had a grade A, B, and C leak respectively. A biliary-enteric anastomosis [OR 5.1 (95% CI 2.45-10.58); p < 0.001], a central [OR 4.33 (95% CI 1.25-14.95); p = 0.021] or an extended hepatectomy [OR 4.29 (95% CI 1.52-12.12); p = 0.006], liver steatosis [OR 2.28 (95% CI 1.09-4.77); p = 0.027], and blood loss of ≥ 2000 mL [OR 2.219 (95% CI 1.15-4.27); p = 0.017] were identified as independent predictors of a clinically significant biliary leak and were assigned 1 point each to develop the biliary leak score. Clinically significant biliary leaks were seen in 11 (2.79%), 20 (6.38%), 19 (15.4%), 9 (56.3%), and 1 (100%) patients with scores of 0, 1, 2, 3, and 4 respectively (p < 0.001). CONCLUSION A biliary-enteric anastomosis, a central or extended hepatectomy, liver steatosis, and blood loss ≥ 2L combined result in a simple predictive score for clinically significant biliary leaks.
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Affiliation(s)
- Shraddha Patkar
- GI & HPB Services, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Aditya Kunte
- GI & HPB Services, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Sridhar Sundaram
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Mahesh Goel
- GI & HPB Services, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
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Peloso A, Tihy M, Moeckli B, Rubbia-Brandt L, Toso C. Clearing Steatosis Prior to Liver Surgery for Colorectal Metastasis: A Narrative Review and Case Illustration. Nutrients 2022; 14:5340. [PMID: 36558499 PMCID: PMC9785595 DOI: 10.3390/nu14245340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/26/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Over recent years, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in the developed world, accounting for 20% to 46% of liver abnormalities. Steatosis is the hallmark of NAFLD and is recognized as an important risk factor for complication and death after general surgery, even more so after liver resection. Similarly, liver steatosis also impacts the safety of live liver donation and transplantation. We aim to review surgical outcomes after liver resection for colorectal metastases in patients with steatosis and discuss the most common pre-operative strategies to reduce steatosis. Finally, as illustration, we report the favorable effect of a low-caloric, hyper-protein diet during a two-stage liver resection for colorectal metastases in a patient with severe steatosis.
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Affiliation(s)
- Andrea Peloso
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, University of Geneva, 1205 Geneva, Switzerland
| | - Matthieu Tihy
- Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland
- Division of Clinical Pathology, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Beat Moeckli
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, University of Geneva, 1205 Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland
- Division of Clinical Pathology, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, University of Geneva, 1205 Geneva, Switzerland
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Miyazaki K, Saito Y, Ichimura-Shimizu M, Imura S, Ikemoto T, Yamada S, Tokuda K, Morine Y, Tsuneyama K, Shimada M. Defective endoplasmic reticulum stress response via X box-binding protein 1 is a major cause of poor liver regeneration after partial hepatectomy in mice with non-alcoholic steatohepatitis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2022; 29:1241-1252. [PMID: 35325502 DOI: 10.1002/jhbp.1142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 01/18/2022] [Accepted: 01/23/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Poor regeneration after hepatectomy in NAFLD is well recognized, but the mechanism is unclear. Endoplasmic reticulum (ER) stress plays an important role in the development of NAFLD. Here, we show that an impaired ER stress response contributes to poor liver regeneration in partially hepatectomized mice. METHODS Non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) was induced in mice using our patented feed and 70% partial hepatectomy (PH) was performed. Mice were sacrificed 0, 4, 8, 24, or 48 hours, or 7 days after PH, and liver regeneration and the mRNA expression of ER stress markers were assessed. RESULTS Non-alcoholic fatty liver disease activity score was calculated as 4-6 points for NAFL and 7 points for NASH. NASH was characterized by inflammation and high ER stress marker expression before PH. After PH, NASH mice showed poorer liver regeneration than controls. High expression of proinflammatory cytokine genes was present in NASH mice 4 hours after PH. Xbp1-s mRNA expression was high in control and NAFL mice after PH, but no higher in NASH mice. CONCLUSIONS Dysfunction of the ER stress response might be a cause of poor liver regeneration in NASH.
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Affiliation(s)
| | - Yu Saito
- Department of Surgery, Tokushima University, Tokushima, Japan
| | | | - Satoru Imura
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, Tokushima, Japan
| | | | - Kazunori Tokuda
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
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Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury. Cells 2022; 11:cells11233791. [PMID: 36497051 PMCID: PMC9739808 DOI: 10.3390/cells11233791] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice.
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Yamaguchi M, Tashiro H, Kuroda S, Okimoto S, Kobayashi T, Hinoi T, Ohdan H. Downregulation of thrombomodulin contributes to ischemia-reperfusion injury in mice with steatotic liver. Hepatol Res 2022; 52:762-772. [PMID: 35714128 DOI: 10.1111/hepr.13802] [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] [Received: 12/24/2021] [Revised: 06/03/2022] [Accepted: 06/13/2022] [Indexed: 02/08/2023]
Abstract
AIM Ischemia-reperfusion (IR) injury is one of the most critical complications commonly associated with liver surgery, including liver transplantation. Steatotic livers are particularly vulnerable to IR injury. However, the underlying mechanisms of this increased susceptibility have not fully been understood. In the present study, we used heterogeneous thrombomodulin (TM)-knockout (KO) (TM+/- ) mice, which express about 50% functional activity of TM as compared with wild type, to investigate whether dysregulation of TM enhances IR injury in steatotic livers. METHODS Steatotic livers were induced using choline-deficient diets (CDD) in mice. The biological activity of TM was assessed using the productivity of protein C. Susceptibility to IR injury was compared between steatotic livers and non-steatotic livers and also assessed in TM-KO mice. We investigated whether recombinant TM (rTM) and the lectin-like domain of TM (rTM-D1) ameliorated IR injury in steatotic livers. RESULTS Protein C activity was significantly decreased to less than 20% in CDD-fed mice compared with mice with non-steatotic livers. Steatotic livers showed exaggerated IR injury compared with non-steatotic livers. Recombinant TM (rTM) and the lectin-like domain of TM (rTM-D1), which has anti-inflammatory effects, ameliorated IR injury in steatotic livers. TM+/- mice showed increased susceptibility to IR injury, and rTM ameliorated the increased IR injury in TM+/- mice. CONCLUSION We conclude that downregulation of TM increases susceptibility to hepatic IR injury in steatotic livers and that rTM ameliorates hepatic IR injury through anti-inflammatory action.
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Affiliation(s)
- Megumi Yamaguchi
- Department of Surgery, Kure Medical Center, National Hospital Organization, Hiroshima, Japan.,Department of Gastroenterological and Transplant Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Hirotaka Tashiro
- Department of Surgery, Kure Medical Center, National Hospital Organization, Hiroshima, Japan
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Sho Okimoto
- Department of Gastroenterological and Transplant Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Takao Hinoi
- Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Hiroshima University Hospital, Hiroshima, Japan
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12
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Assessment of Factors Associated with Morbidity and Textbook Outcomes of Laparoscopic Liver Resection in Obese Patients: A French Nationwide Study. J Am Coll Surg 2022; 235:159-171. [PMID: 35675176 DOI: 10.1097/xcs.0000000000000221] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Liver surgeons need to know the expected outcomes of laparoscopic liver resection (LLR) in obese patients. OBJECTIVE The purpose of the present study is to assess morbidity, mortality and textbook outcomes (TO) after LLR in obese patients. METHODS This is a French multicenter study of patients undergoing LLR between 1996 and 2018. Obesity was defined by a BMI at or above 30 kg/m 2 . Short-term outcomes and TO were compared between obese (ob) and nonobese (non-ob) patients. Factors associated with severe morbidity and TO were investigated. RESULTS Of 3,154 patients included, 616 (19.5%) were obese. Ob-group patients had significantly higher American Society of Anesthesiologists (ASA) score and higher incidence of metabolic syndrome and chronic liver disease and were less likely to undergo major hepatectomy. Mortality rates were similar between ob and non-ob groups (0.8 vs 1.1%; p = 0.66). Overall morbidity and hospital stay were significantly increased in the ob group compared with the non-ob group (39.4 vs 34.7%, p = 0.03; and 9.5 vs 8.6 days, p = 0.02), whereas severe 90-day morbidity (at or above Clavien-Dindo grade III) was similar between groups (8% in both groups; p = 0.90). TO rate was significantly lower for the ob group than the non-ob group (58.3 vs 63.7%; p = 0.01). In multivariate analysis, obesity did not emerge as a risk factor for severe 90-day morbidity but was associated with a lower TO rate after LLR (odds ratio = 0.8, 95% CI 0.7-1.0; p = 0.03). CONCLUSIONS LLR in obese patients is safe and effective with acceptable mortality and morbidity. Obesity had no impact on severe morbidity but was a factor for failing to achieve TO after LLR.
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13
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Hitchins CR, Jones RM, Kanwar A, Aroori S. Is there a role for preoperative liver reducing diet in hepatectomy? A systematic review. Langenbecks Arch Surg 2022; 407:1357-1367. [PMID: 35230526 DOI: 10.1007/s00423-022-02484-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 02/24/2022] [Indexed: 11/26/2022]
Abstract
PURPOSE Preoperative very low-calorie diets (VLCDs) have been shown to reduce liver volume, reduce the risk of liver injury and improve safety during bariatric surgery. Hepatic steatosis (HS) has been associated with poorer outcomes in liver resection. VLCD can be used to improve HS. We aim to explore if preoperative VLCD could improve outcomes for patients with HS undergoing liver resection. METHODS We performed a systematic review of MEDLINE, EMBASE, PubMed and Cochrane databases. Studies were included if they were full-text articles investigating the effect of a preoperative dietary intervention in patients undergoing liver resection on intra-operative and post-operative outcomes. The last search was performed on 11 Jun 2020. Evidence quality was assessed by "GRADE". A narrative review was undertaken. RESULTS Five studies were found: one RCT and four cohort studies including 133 patients in intervention groups and 181 controls. Three used diet-only strategies and two diet and exercise strategies with varying time courses and monitoring. The quality of evidence assessed by GRADE was "high" for the RCT and "low" for the four cohort studies. Steatosis objectively improved in three studies, with evidence of reduced liver volume and increased attenuation on imaging in one. All studies showed a reduction in body weight and body mass index (BMI). Intra-operative blood loss was decreased following a diet-only intervention in two studies, and liver mobility improved in one. No difference was found in morbidity, mortality or hospital length of stay between intervention and control groups. CONCLUSIONS There is evidence of poorer outcomes in liver resection patients with existing HS. There is an expected role for a preoperative VLCD to optimise these patients for surgery. Existing publications support this, but diet interventions and outcome measures are inconsistent, and patient numbers are small. There is scope for a well-designed, multi-centre randomised trial to investigate this further.
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Affiliation(s)
- Charlotte R Hitchins
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, PL6 8DH, UK.
| | - Rebecca M Jones
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, PL6 8DH, UK
| | - Aditya Kanwar
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, PL6 8DH, UK
| | - Somaiah Aroori
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, PL6 8DH, UK
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14
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Jindal A, Jagdish RK, Kumar A. Hepatic Regeneration in Cirrhosis. J Clin Exp Hepatol 2022; 12:603-616. [PMID: 35535091 PMCID: PMC9077225 DOI: 10.1016/j.jceh.2021.08.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/31/2021] [Indexed: 01/03/2023] Open
Abstract
End-stage liver disease is characterized by massive hepatocyte death resulting in clinical decompensation and organ failures. Clinical consequences in cirrhosis are the results of the loss of functional hepatocytes and excessive scarring. The only curative therapy in advanced cirrhosis is orthotropic liver transplantation, but the clinical demand outweighs the availability of acceptable donor organs. Moreover, this also necessitates lifelong immunosuppression and carries associated risks. The liver has a huge capability for regeneration. Self-replication of quiescent differentiated hepatocytes and cholangiocytes occurs in patients with acute liver injury. Due to limited hepatocyte self-renewal capacity in advanced cirrhosis, great interest has therefore been shown in characterizing the possible role of hepatic progenitor cells and bone marrow-derived stem cells to therapeutically aid this process. Transplantation of cells from various sources that can be properly differentiated into functional liver cells or use of growth factors for ex-vivo expansion of progenitor cells is needed at utmost priority. Multiple researches over the last two decades have aided researchers in refining proliferation, differentiation, and storage techniques and understand the functionality of these cells for use in clinical practice. However, these cell-based therapies are still experimental and have to be used in trial settings.
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Key Words
- Ang2, angiopoietin 2
- BM, Bone marrow
- BM-MNCs, bone marrow mononuclear cells
- BMSC, bone marrow stem cells
- DAMPs, Damage associated molecular patterns
- EPCs, endothelial progenitor cells
- ESRP2, epithelial splicing regulatory protein 2
- GCSF
- HGF, hepatocyte growth factor
- HPC, Hepatocyte progenitor cells
- HSCs, hematopoietic stem cells
- Hh, Hedgehog
- HybHP, hybrid periportal hepatocytes
- MMP, matrix metalloprotease
- MSCs, mesenchymal stromal cells
- OLT, Orthotropic liver transplantation
- PAMPs, Pathogen associated molecular patterns
- SAH, severe alcoholic hepatitis
- SDF1, stromal-derived factor 1
- TNFSF12, tumor necrosis factor ligand superfamily member 12
- Terthigh, high Telomerase reverse transcriptase
- [Hnf4a], Hepatocyte Nuclear Factor 4 Alpha
- [Mfsd2a], Major Facilitator Superfamily Domain containing 2A
- acute liver failure
- chronic liver diseases
- hepatocyte transplant
- liver regeneration
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | | | - Anupam Kumar
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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15
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Sim KH, Shu MS, Kim S, Kim JY, Choi BH, Lee YJ. Cilostazol Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma Cells by Activating AMPK. BIOTECHNOL BIOPROC E 2021. [DOI: 10.1007/s12257-021-0002-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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16
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Acute Myocardial Infarction of the Left Main Coronary Artery Presenting with Cardiogenic Shock and Pulmonary Edema during Noncardiac Surgery. Case Rep Cardiol 2021; 2021:5460816. [PMID: 34430055 PMCID: PMC8380411 DOI: 10.1155/2021/5460816] [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: 02/15/2020] [Revised: 11/10/2020] [Accepted: 07/27/2021] [Indexed: 11/29/2022] Open
Abstract
Acute myocardial infarction (AMI) caused by severe stenosis of left main coronary artery (LMCA) presenting with cardiogenic shock and pulmonary edema during noncardiac surgery is uncommon, but a catastrophic event. A 77-year-old male with cholangiocarcinoma underwent hepatectomy. During the surgery, he presented with cardiogenic shock, which did not respond to infusion administration or vasopressor. A transesophageal echocardiogram revealed anterior, septal, and lateral severe hypokinesia and impaired left ventricular function. Emergent coronary angiogram showed severe stenosis of LMCA. The patient underwent primary percutaneous coronary intervention (PCI) under the support of intra-aortic balloon pump, followed by extracorporeal membrane oxygenation. The chest roentgenogram showed pulmonary edema. Two days after PCI, he successfully underwent hepatectomy and bile duct resection. Early identification of the cause of hemodynamic instability during noncardiac surgery and invasive strategy are important for minimizing the myocardial injury and improving clinical outcomes in AMI of LMCA.
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17
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Outcomes after curative therapy for hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: a meta-analysis and review of current literature. HPB (Oxford) 2021; 23:1164-1174. [PMID: 33608215 DOI: 10.1016/j.hpb.2021.01.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/02/2020] [Accepted: 01/13/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND This systematic review and meta-analysis aimed to compare the outcomes of curative therapy (resection, transplantation, ablation) for hepatocellular carcinoma (HCC) arising from non-alcoholic fatty liver disease (NAFLD) and non-NAFLD etiologies. METHODS A systematic search of PubMed, EMBASE and Cochrane Library was conducted for studies comparing survival, peri- and post-operative outcomes. Quality assessment was performed using the Newcastle-Ottawa scale. RESULTS Findings for 5579 patients were pooled across 9 studies and examined. Analysis demonstrated improved disease-free survival (DFS; HR 0.85, 95% CI 0.74-0.98, p = 0.03) and overall survival (OS; HR 0.87; 95% CI 0.81-0.93; p < 0.0001) in NAFLD-HCC patients undergoing liver resection as compared to non-NAFLD HCC patients. NAFLD-HCC patients undergoing all forms of curative therapy were similarly associated with improved OS (HR 0.96; 95% CI 0.86-1.06; p = 0.40) and DFS (HR 0.85; 95% CI 0.74-0.98; p = 0.03), albeit results being significant only for DFS. Only 2 studies reported higher rates of peri- and post-operative complications in patients with NAFLD-HCC. Significant inter-study heterogeneity precluded further analysis. CONCLUSION NAFLD-HCC patients can enjoy long-term survival benefit with aggressive curative therapy. Peri- and post-operative morbidity should be mitigated with pre-operative optimization of comorbidities, and deliberately close post-operative monitoring.
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18
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Sanyal S, Alabraba E, Ibrahim H, Olaru A, Cameron I, Gomez D. ACE Inhibitor Therapy Does Not Influence the Survival Outcomes of Patients with Colorectal Liver Metastases Following Liver Resection. J Gastrointest Cancer 2021; 52:106-112. [PMID: 31853827 DOI: 10.1007/s12029-019-00350-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors have been shown to possibly influence the survival outcomes in certain cancers. The aim of this study was to evaluate the impact of ACE inhibitors on the outcomes of patients undergoing liver resection for colorectal liver metastases (CRLM). The secondary aim was to determine whether ACE inhibitors influenced histopathological changes in CRLM. METHODS Patients treated with liver resection for CRLM over a 13-year period were identified from a prospectively maintained database. Data including demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome were collated and analysed. RESULTS A total of 586 patients underwent primary hepatic resections for CRLM during this period including 100 patients on ACE inhibitors. The median follow-up period was 23 (range: 12-96) months, in which 267 patients developed recurrent disease and 131 patients died. Independent predictors of disease-free survival on multivariate analysis included synchronous presentation, neoadjuvant chemotherapy, major liver resection, tumour size and number, extent of hepatic steatosis, R0 resection and presence of perineural invasion. Poorer overall survival was associated with neoadjuvant treatment, major liver resection, presence of multiple metastases, perineural invasion and positive resection margins on multivariate analysis. ACE inhibitors did not influence the survival outcome or histological presentation in CRLM. CONCLUSION The use of ACE inhibitors did not affect the survival outcome or tumour biology in patients with CRLM following liver resection.
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Affiliation(s)
- Sudip Sanyal
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Rd, Nottingham, NG7 2UH, UK
| | - Edward Alabraba
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Rd, Nottingham, NG7 2UH, UK
| | - Hussain Ibrahim
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Rd, Nottingham, NG7 2UH, UK
| | - Adina Olaru
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Rd, Nottingham, NG7 2UH, UK
| | - Iain Cameron
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Rd, Nottingham, NG7 2UH, UK
| | - Dhanny Gomez
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Rd, Nottingham, NG7 2UH, UK. .,NIHR Nottingham Digestive Disease Biomedical Research Uni, University of Nottingham, Nottingham, UK.
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19
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Paternostro R, Sieghart W, Trauner M, Pinter M. Cancer and hepatic steatosis. ESMO Open 2021; 6:100185. [PMID: 34139486 PMCID: PMC8219773 DOI: 10.1016/j.esmoop.2021.100185] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and increasing liver disease, which encompasses a variety of liver diseases of different severity. NAFLD can lead to liver cirrhosis with all its complications as well as hepatocellular carcinoma (HCC). Steatosis of the liver is not only related to obesity and other metabolic risk factors, but can also be caused by several drugs, including certain cytotoxic chemotherapeutic agents. In patients undergoing liver surgery, hepatic steatosis is associated with an increased risk of post-operative morbidity and mortality. This review paper summarizes implications of hepatic steatosis on the management of patients with cancer. Specifically, we discuss the epidemiological trends, pathophysiological mechanisms, and management of NAFLD, and its role as a leading cause of liver cancer. We elaborate on factors promoting immunosuppression in patients with NAFLD-related HCC and how this may affect the efficacy of immunotherapy. We also summarize the mechanisms and clinical course of chemotherapy-induced acute steatohepatitis (CASH) and its implications on cancer treatment, especially in patients undergoing liver resection.
Non-alcoholic fatty liver disease can lead to cirrhosis with all its complications, including hepatocellular carcinoma. Chemotherapy-associated acute steatohepatitis is a side-effect of chemotherapeutic agents and may limit treatment options. In this review we summarize current clinical concepts of NAFLD and CASH that help clinicians in their clinical practice.
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Affiliation(s)
- R Paternostro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - W Sieghart
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - M Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - M Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.
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20
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Predictors of complications after liver surgery: a systematic review of the literature. HPB (Oxford) 2021; 23:645-655. [PMID: 33485797 DOI: 10.1016/j.hpb.2020.12.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/21/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Numerous potential predictors of adverse outcomes have been reported but their performance and utilization in practice seem heterogenous. This study aimed to systematically review the literature on the role and value of predictors of complications after hepatectomy. METHODS A systematic review following the PRISMA guidelines was performed. Studies on liver transplant were excluded. Only studies assessing overall or major complications were included. RESULTS A total of 10'965 abstracts were screened. After application of exclusion criteria, 72 articles including 68'480 patients were included. A total of 72 markers with 48 pre-, 9 intra- and 15 postoperative factors were identified as predictors of complications. Preoperative and intraoperative predictive markers retrieved several times with the highest odds ratios (OR) were ASA score (OR range: 1.3-7.5, significant in 8 studies) and intraoperative need for red blood cell transfusion (OR range: 1.2-17.1, significant in 24 studies), respectively. CONCLUSION Numerous markers have been described to predict the complication risk after hepatectomy. Because of their intrinsic characteristics, most markers such as ASA score and need for red blood cell transfusion are of limited clinical interest. There is a clear need to identify new biomarkers and to develop scores that could easily be implemented in clinical practice.
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21
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Yoon YI, Song GW, Lee SG, Park GC, Hwang S, Kim KH, Ahn CS, Moon DB, Ha TY, Jung DH, Kim KW, Shim JH, Tak EY, Kirchner VA, Pruett TL. Safe use of right lobe living donor livers with moderate steatosis in adult-to-adult living donor liver transplantation: a retrospective study. Transpl Int 2021; 34:872-881. [PMID: 33660330 DOI: 10.1111/tri.13859] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/09/2021] [Accepted: 02/28/2021] [Indexed: 01/22/2023]
Abstract
Hepatic steatosis (HS) beyond a certain degree can jeopardize living donor (LD) safety, particularly in right lobe (RL) donors, making it a major obstacle for donor pool expansion in adult-to-adult living donor liver transplantation (ALDLT). From July 2004 to June 2016, 58 LDs donated their RLs despite having moderate HS (30%-50% steatosis) determined by intraoperative biopsy at a single center. We performed greedy matching to compare the outcomes of the donors and recipients of this group with those of LDs with no HS. The mean left lobe (LL) HS value in the 58 cases was 20.9 ± 12.4%, which was significantly lower than the mean RL HS value (38.8 ± 6.7%, P < 0.001). The mean ratio of the remnant LL to the total liver volume was 37.8 ± 2.2. No differences were observed in the postoperative liver function and donor and recipient morbidity and mortality rates. The liver regeneration rates in recipients and donors at 1 month, 6 months, and 1 year postoperatively did not differ significantly. The patient and graft survival rates of the recipients showed no differences. The use of well-selected RL grafts with moderate steatosis does not impair graft function, recipient outcomes, or donor safety.
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Affiliation(s)
- Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gil-Chun Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chul-Soo Ahn
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Yong Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung-Won Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ju-Hyun Shim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun-Young Tak
- Asan Institute for Life Sciences and Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Varvara A Kirchner
- Division of Transplantation, Department of Surgery, and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Timothy L Pruett
- Division of Transplantation, Department of Surgery, and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN, USA
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22
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Kwan B, Waters PS, Keogh C, Cavallucci DJ, O'Rourke N, Bryant RD. Body mass index and surgical outcomes in laparoscopic liver resections: a systematic review. ANZ J Surg 2021; 91:2296-2307. [PMID: 33682289 DOI: 10.1111/ans.16674] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/28/2021] [Accepted: 02/06/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Laparoscopic liver resection is gaining momentum; however, there is limited evidence on its efficacy and safety in obese patients. The aim of this study was to examine the relationship between BMI and outcomes after laparoscopic liver resection (LLR) using a systematic review of the existing literature. METHODS A systematic search of Medline (Ovid 1946-present), PubMed (NCBI), Embase (Ovid 1966-present) and Cochrane Library was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for parameters of LLR and BMI. Operative, post-operative and oncological outcomes were recorded. RESULTS Of 1460 abstracts, seven retrospective studies were analysed, published between 2015 and 2017 (study periods 1998-2017). Total patient cohort were classified as 481 obese and 1180 non-obese with a median age range of 42.5-69.4 years. Variations existed in definitions of obesity (Asia BMI >25 kg/m2 , Western BMI >30 kg/m2 ). Rates of conversion were examined in four studies (0-31%) with one reporting BMI >28 kg/m2 as an independent risk factor. Estimated blood loss and transfusion rates were similar. Operative time was increased in obese patients in one study (P = 0.02). Mortality rates ranged from 0% to 4.3% with no difference between BMI classes. No difference in major morbidity was demonstrated. Bile leak rates were increased in obese groups in one study (0-3.44%, P < 0.05). Wound infections were reported in five studies, with higher rates in obese patients (0-5.8% versus 0-1.9%). Tumour size was comparable in both groups. Completeness of resection was analysed in four studies with one study reporting increased R0 rates in obese patients (P = 0.012). CONCLUSION This systematic review highlights that current evidence shows LLR in obese patients is safe, however, further studies are required.
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Affiliation(s)
- Bianca Kwan
- Department of HPB Surgery, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Peadar S Waters
- Department of HPB Surgery, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Cian Keogh
- Department of HPB Surgery, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - David J Cavallucci
- Department of HPB Surgery, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,Department of Surgery, Wesley Hospital, Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Nicholas O'Rourke
- Department of HPB Surgery, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,Department of Surgery, Wesley Hospital, Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Richard D Bryant
- Department of HPB Surgery, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Department of Surgery, St Vincent's Northside Medical Centre, St Vincent's Private Hospital Northside, Brisbane, Queensland, Australia
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23
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Fagenson AM, Pitt HA, Moten AS, Karhadkar SS, Di Carlo A, Lau KN. Fatty liver: The metabolic syndrome increases major hepatectomy mortality. Surgery 2020; 169:1054-1060. [PMID: 33358472 DOI: 10.1016/j.surg.2020.11.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/01/2020] [Accepted: 11/17/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND As the obesity epidemic worsens, the prevalence of fatty liver disease has increased. However, minimal data exist on the impact of combined fatty liver and metabolic syndrome on hepatectomy outcomes. Therefore, the aim of this analysis is to measure the outcomes of patients who do and do not have a fatty liver undergoing hepatectomy in the presence and absence of the metabolic syndrome. METHODS Patients with fatty and normal livers undergoing major hepatectomy (≥3 segments) were identified in the 2014 to 2018 American College of Surgeon National Surgical Quality Improvement Program database. Patients undergoing partial hepatectomy and those with missing liver texture data were excluded. Propensity matching was used and adjusted for multiple variables. A subgroup analysis stratified by the metabolic syndrome (body mass index ≥30 kg/m2, hypertension and diabetes) was performed. Demographics and outcomes were compared by χ2 and Mann-Whitney tests. RESULTS Of 2,927 hepatectomies, 30% of patients (N = 863) had a fatty liver. The median body mass index was 28.6, and the metabolic syndrome was present in 6.3% of patients (N = 184). After propensity matching, 863 patients with fatty and 863 with normal livers were compared. Multiple outcomes were significantly worse in patients with fatty livers (P <.05), including serious morbidity (32% vs 24%), postoperative invasive biliary procedures (15% vs 10%), organ space infections (11% vs 7.8%), and pulmonary complications. Patients with fatty livers and the metabolic syndrome had significantly increased postoperative cardiac arrests, pulmonary embolisms, and mortality (P < .05). CONCLUSION Fatty liver disease is associated with significantly worse outcomes after major hepatectomy. The metabolic syndrome confers an increased risk of postoperative mortality.
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Affiliation(s)
| | - Henry A Pitt
- Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ
| | - Ambria S Moten
- Department of Surgery, Temple University Hospital, Philadelphia, PA
| | | | - Antonio Di Carlo
- Department of Surgery, Temple University Hospital, Philadelphia, PA
| | - Kwan N Lau
- Department of Surgery, Temple University Hospital, Philadelphia, PA.
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Yang X, Li C, Ng KTP, Liu J, Liu H, Zhang W, Xiao F, Li X, Lo CM, Lu L, Man K. IL-17a exacerbates hepatic ischemia-reperfusion injury in fatty liver by promoting neutrophil infiltration and mitochondria-driven apoptosis. J Leukoc Biol 2020; 108:1603-1613. [PMID: 32531822 DOI: 10.1002/jlb.3ma0520-716r] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/08/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatic ischemia-reperfusion (IR) injury is a critical issue during liver transplantation (LT). Recent studies have demonstrated that IL-17a contributes to IR injury and steatohepatitis. However, the underlying mechanism is not understood. This study aimed to examine the role of IL-17a on hepatic IR injury in fatty liver and to investigate the underlying mechanisms. The correlation between serum IL-17a levels and liver function was analyzed in LT patients receiving fatty (n = 42) and normal grafts (n = 44). Rat LT model was applied to validate the clinical findings. IL-17a knockout (KO) and wild-type mice were fed with high-fat diets to induce fatty liver and subjected to hepatic IR injury with major hepatectomy. Frequency of circulating neutrophils and IL-17a expression on PBMCs were analyzed by flow cytometry. Mitochondrial outer membrane permeabilization (MOMP) was examined by a living intravital image system. Serum IL-17a was elevated after human LT, especially with fatty grafts. The aspartate aminotransferase and alanine transaminase levels were increased in recipients with fatty grafts compared with normal grafts. In rat LT model, the intragraft IL-17a expression was significantly higher in fatty grafts than normal ones post-LT. KO of IL-17a in mice notably attenuated liver damage after IR injury in fatty liver, characterized by better-preserved liver architecture, improved liver function, and reduced neutrophil infiltration. MOMP triggered cell death after hepatic IR injury in a caspase-independent way via IL-17a/NF-κB signaling pathway. KO of IL-17a protected the fatty liver against IR injury through the suppression of neutrophil infiltration and mitochondria-driven apoptosis.
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Affiliation(s)
- Xinxiang Yang
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Changxian Li
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kevin Tak-Pan Ng
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jiang Liu
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Hui Liu
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Weiyi Zhang
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Fan Xiao
- Department of Pathology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xiangcheng Li
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chung Mau Lo
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Liwei Lu
- Department of Pathology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kwan Man
- Department of Surgery, HKU-SZH & Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Ammar MA, Abdou AMH. Benefits of N-acetylcysteine on liver functions in living donor hepatectomy. Indian J Anaesth 2020; 64:204-209. [PMID: 32346167 PMCID: PMC7179774 DOI: 10.4103/ija.ija_876_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 12/31/2019] [Accepted: 01/25/2020] [Indexed: 01/17/2023] Open
Abstract
Background and Aims: The proportion of patients undergoing living donor liver transplantation is high especially in countries without or with limited cadaver organ sharing programs. The aim of this study was to evaluate the post-hepatectomy effect of using N-Acetylcysteine (NAC) infusion in living donors undergoing donor hepatectomy. Methods: In a prospective randomised non-blinded study, 50 healthy donors were enrolled; following hepatectomy patients were randomised into 2 groups: Group NC receiving NAC 150 mg/kg diluted in 100 ml glucose 5% over 40 minutes, followed by NAC 12.5 mg/kg in 500 ml glucose 5% over 4 hours. This was followed by NAC 6.25 mg/kg for 2 post-operative days, Group C (Control group) received ringer acetate infusion at same rate for 2 days. The primary outcome was serum lactate levels. Secondary outcomes were liver function tests, serum creatinine and urine output on intensive care unit (ICU) admission (0 hr.), after 24 hours and 48 hours, length of ICU stay. Results: Our study revealed significant reduction in serum lactate in Group NC at 0, 24 and 48 hours compared to C group (P = 0.017, 0.002, 0.014). INR values showed significant reduction after 48 hours in Group NC compared to Group C (P = 0.049). Total Bilirubin, ALT, and Creatinine, urine output and ICU stay showed no statistical difference between the 2 groups. Conclusion: The NAC protocol is a safe, cost-effective tool for improvement of post hepatectomy liver function and early stabilisation of the metabolic profile.
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Affiliation(s)
- Mona A Ammar
- Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Amr M Hilal Abdou
- Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Fujii Y, Kawamura N, Zaitsu M, Watanabe M, Goto R, Kamiyama T, Taketomi A, Shimamura T. Outcome of Living-Donor Liver Transplantation Using Grafts from Donors Treated for Fatty Liver. Ann Transplant 2020; 25:e920677. [PMID: 31919339 PMCID: PMC6977639 DOI: 10.12659/aot.920677] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background The aim of this study was to determine the efficacy of treating donors’ fatty liver (FL) and to assess early graft function in recipients who received treated FL grafts in living-donor liver transplantation (LDLT). Material/Methods Data were collected for adult-to-adult LDLTs. Donors diagnosed with FL (FL group) received diet–exercise and pharmacological treatment. The perioperative findings and early transplanted graft function were compared with those of donors without FL (non-FL group) during the same period. Results Of 30 donors, 8 were determined to have FL. The median duration of treatment for FL was 58 days. The liver-to-spleen attenuation ratios on CT scan in the FL group were significantly improved after treatment: 0.95 (0.62–1.06) to 1.2 (1.12–1.46) (P=0.003). Liver biopsy prior to donor surgery showed ≤10% fatty infiltration. Postoperative laboratory findings of the donors in the FL group were comparable to those in the non-FL group: maximum alanine transaminase (189.6±94.7 IU/L vs. 196.8±57.4) and maximum total bilirubin (2.2±1.1 mg/dL vs. 1.7±0.5 mg/dL). No major complications were observed after donor hepatectomy in either group. There were no significant differences between the 2 groups in early graft function, as evaluated by laboratory data, ascites volume, and bile production 2 weeks postoperatively. Graft and patient survival were 100% in both groups at 3 months. Conclusions Preoperative intentional treatment for FL was effective. Early graft function and donor postoperative course were comparable in the 2 groups. These results suggest that well-treated steatotic grafts can be used without jeopardizing donor safety.
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Affiliation(s)
- Yuki Fujii
- Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Norio Kawamura
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine and Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Masaaki Zaitsu
- Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Masaaki Watanabe
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine and Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
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Hepatic steatosis in patients undergoing resection of colorectal liver metastases: A target for prehabilitation? A narrative review. Surg Oncol 2019; 30:147-158. [PMID: 31471139 DOI: 10.1016/j.suronc.2019.07.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 06/20/2019] [Accepted: 07/22/2019] [Indexed: 12/16/2022]
Abstract
The prevalence of elevated intra-hepatic fat (IHF) is increasing in the Western world, either alone as hepatic steatosis (HS) or in conjunction with inflammation (steatohepatitis). These changes to the hepatic parenchyma are an independent risk factor for post-operative morbidity following liver resection for colorectal liver metastases (CRLM). As elevated IHF and colorectal malignancy share similar risk factors for development it is unsurprisingly frequent in this cohort. In patients undergoing resection IHF may be elevated due to excess adiposity or its elevation may be induced by neoadjuvant chemotherapy, termed chemotherapy associated steatosis (CAS). Additionally, chemotherapy is implicated in the development of inflammation termed chemotherapy associated steatohepatitis (CASH). Following cessation of chemotherapy, patients awaiting resection have a 4-6 week washout period prior to resection that is a window for prehabilitation prior to surgery. In patients with NAFLD dietary and pharmacological interventions can reduce IHF within this timeframe but this approach to modifying IHF is untested in this population. In this review, the aetiology of CAS and CASH is reviewed with recommendations to identify those at risk. We also focus on the post-chemotherapy washout period, reviewing dietary interventions applied to the metabolic population and suggest this window may be used as an opportunity to optimise IHF with such a regime as part of a pre-operative prehabilitation programme to produce improved patient outcomes.
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Tan HL, Goh BKP. The effect of preoperative low-calorie diets on liver resection outcomes. Transl Gastroenterol Hepatol 2019; 4:29. [PMID: 31231696 PMCID: PMC6556692 DOI: 10.21037/tgh.2019.04.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 04/23/2019] [Indexed: 12/30/2022] Open
Affiliation(s)
- Hwee Leong Tan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Brian K. P. Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
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Kinoshita K, Beppu T, Sato N, Akahoshi S, Yuki H, Yoshida Y. Preoperative 1-week diet can markedly decrease blood loss during hepatectomy. Transl Gastroenterol Hepatol 2019; 4:20. [PMID: 30976723 DOI: 10.21037/tgh.2019.03.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 03/22/2019] [Indexed: 11/06/2022] Open
Affiliation(s)
- Koichi Kinoshita
- Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan
| | - Toru Beppu
- Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan
| | - Nobutaka Sato
- Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan
| | | | - Hideaki Yuki
- Department of Radiology, Yamaga City Medical Center, Kumamoto, Japan
| | - Yasushi Yoshida
- Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan
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Reistad N, Nilsson JH, Bergenfeldt M, Rissler P, Sturesson C. Intraoperative liver steatosis characterization using diffuse reflectance spectroscopy. HPB (Oxford) 2019; 21:175-180. [PMID: 30049643 DOI: 10.1016/j.hpb.2018.06.1809] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 06/03/2018] [Accepted: 06/24/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver steatosis is associated with poor outcome after liver transplantation and liver resection. There is a need for an accurate and reliable intraoperative tool to identify and quantify steatosis. This study aimed to investigate whether surface diffuse reflectance spectroscopy (DRS) measurements could detect liver steatosis on humans during liver surgery. METHODS The DRS instrumentation setup consists of a computer, a high-power tungsten halogen light source and two spectrometers, connected through a trifurcated optical fiber to a hand-held probe. Patients scheduled for open resection for liver tumors were considered for inclusion. Multiple DRS measurements were performed on the liver surface after mobilization. RESULTS In total, 1210 DRS spectra originated from 38 patients, were analyzed. When applying the data to an analytical model the volumetric absorption ratio factor of fat and water specified an explicit distinction between mild to moderate, and moderate to severe steatosis (p < 0.001). There were significant differences between none-to-mild and moderate-to-severe steatosis grade for the following parameters: reduced scattering coefficient (p < 0.001), Mie to total scattering fraction (p < 0.001), Mie slope (p = 0.003), lipid/(lipid + water) (p < 0.001), blood volume (p = 0.044) and bile volume (p < 0.001). CONCLUSION This study shows that it is possible to evaluate steatosis grades with hepatic surface diffuse reflectance spectroscopy measurements.
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Affiliation(s)
- Nina Reistad
- Department of Physics, Lund University, Lund, Sweden
| | - Jan H Nilsson
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Magnus Bergenfeldt
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Pehr Rissler
- Department of Pathology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Christian Sturesson
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.
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31
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Desjardin M, Bonhomme B, Le Bail B, Evrard S, Brouste V, Desolneux G, Fonck M, Bécouarn Y, Béchade D. Hepatotoxicities Induced by Neoadjuvant Chemotherapy in Colorectal Cancer Liver Metastases: Distinguishing the True From the False. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2019; 13:1179554918825450. [PMID: 30718969 PMCID: PMC6348554 DOI: 10.1177/1179554918825450] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 12/25/2018] [Indexed: 02/06/2023]
Abstract
Background: Pre-operative chemotherapy for colorectal liver metastasis (CRLM) is thought to be the cause of hepatotoxicity of non-tumoural parenchyma. Studies on hepatotoxicity are contradictory. We investigated the impact of a single-line pre-operative chemotherapy on non-tumoural liver analysed by an expert hepatico-pancreatico-biliary pathologist, and the consequences on surgical outcomes. Patients and methods: Patients operated for CRLM, after a pure first-line pre-operative chemotherapy, were retrospectively included. Two comparative histopathological analyses were performed for vascular toxicity and steatohepatitis. Results: Between 2003 and 2015, 147 patients were included. Chemotherapy was based on oxaliplatin (40.1%), irinotecan (55.8%), or both (4.1%). The expert pathologist described 38.8% of vascular lesions including dilation, nodular regeneration, and peliosis. In multivariate analysis, vascular lesions correlated to male sex (P = .01), pre-operative platelets <150 g/L (P = .04), and aspartate aminotransferase to platelet ratio index (APRI) score >0.36 (P = .02). Steatohepatitis was observed in 15 patients (10.2%), more frequently after irinotecan (14.8% vs 3.4%, P = .01; odds ratio [OR] = 7.3; 95% confidence interval [CI] = [1.5-34.7]), and for patients with body mass index (BMI) >25 kg/m2 (P = .004; OR = 10.0; 95% CI = [2.1-47.5]). A total of 29 patients (19.7%) developed major complications with 2 risk factors: portal vein obstruction (PVO) and septic surgery. Reproducibility assessment of steatohepatitis and dilated lesions by 2 pathologists showed moderate agreement (Kappa score 0.53 and 0.54, respectively). Conclusions: There is a probable association between non-alcoholic steatohepatitis (NASH) and irinotecan. Oxaliplatin seems to lead to higher vascular lesions. Except in the presence of pre-existent comorbidities, liver toxicities should not restrain the use of pre-operative chemotherapy prior to parenchymal-sparing surgery.
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Affiliation(s)
| | | | - Brigitte Le Bail
- Department of Anatomopathology, University Hospital, Bordeaux, France
| | - Serge Evrard
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
| | - Véronique Brouste
- Clinical and Epidemiological Research Unit, Institut Bergonié, Bordeaux, France
| | | | - Marianne Fonck
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
| | - Yves Bécouarn
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
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Barth RJ, Mills JB, Suriawinata AA, Putra J, Tosteson TD, Axelrod D, Freeman R, Whalen GF, LaFemina J, Tarczewski SM, Kinlaw WB. Short-term Preoperative Diet Decreases Bleeding After Partial Hepatectomy: Results From a Multi-institutional Randomized Controlled Trial. Ann Surg 2019; 269:48-52. [PMID: 29489484 DOI: 10.1097/sla.0000000000002709] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Our previous case series suggested that a 1-week, low-calorie and low-fat diet was associated with decreased intraoperative blood loss in patients undergoing liver surgery. OBJECTIVE The current study evaluates the effect of this diet in a randomized controlled trial. METHODS We randomly assigned 60 patients with a body mass index ≥25 kg/m(2) to no special diet or an 800-kcal, 20 g fat, and 70 g protein diet for 1 week before liver resection. Surgeons were blinded to diet assignment. Hepatic glycogen stores were evaluated using periodic acid Schiff (PAS) stains. RESULTS Ninety four percent of the patients complied with the diet. The diet group consumed fewer daily total calories (807 vs 1968 kcal, P < 0.001) and fat (21 vs 86 g, P < 0.001) than the no diet group. Intraoperative blood loss was less in the diet group: mean blood loss 452 vs 863 mL (P = 0.021). There was a trend towards decreased transfusion in the diet group (138 vs 322 mL, P = 0.06). The surgeon judged the liver to be easier to manipulate in the diet group: 1.86 versus 2.90, P = 0.004. Complication rate (20% vs 17%), length of stay (median 5 vs 4 days) and mortality did not differ between groups. There was no difference in hepatic steatosis between groups. There was less glycogen in hepatocytes in the diet group (PAS stain score 1.61 vs 2.46, P < 0.0001). CONCLUSIONS A short-course, low-fat, and low-calorie diet significantly decreases bleeding and makes the liver easier to manipulate in hepatic surgery.
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Affiliation(s)
- Richard J Barth
- Departments of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Jeannine B Mills
- Departments of Radiation Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | | | - Juan Putra
- Departments of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Tor D Tosteson
- Departments of Biomedical Data Science, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - David Axelrod
- Departments of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Richard Freeman
- Departments of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Giles F Whalen
- Department of Surgery, University of Massachusetts Medical Center, Worcester, MA
| | - Jennifer LaFemina
- Department of Surgery, University of Massachusetts Medical Center, Worcester, MA
| | - Susan M Tarczewski
- Departments of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - William B Kinlaw
- Departments of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH
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Gilgenkrantz H, Collin de l'Hortet A. Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1316-1327. [PMID: 29673755 DOI: 10.1016/j.ajpath.2018.03.008] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 03/15/2018] [Accepted: 03/23/2018] [Indexed: 02/06/2023]
Abstract
Liver regeneration is a complex and unique process. When two-thirds of a mouse liver is removed, the remaining liver recovers its initial weight in approximately 10 days. The understanding of the mechanisms responsible for liver regeneration may help patients needing large liver resections or transplantation and may be applied to the field of regenerative medicine. All differentiated hepatocytes are capable of self-renewal, but different subpopulations of hepatocytes seem to have distinct proliferative abilities. In the setting of chronic liver diseases, a ductular reaction ensues in which liver progenitor cells (LPCs) proliferate in the periportal region. Although these LPCs have the capacity to differentiate into hepatocytes and biliary cells in vitro, their ability to participate in liver regeneration is far from clear. Their expansion has even been associated with increased fibrosis and poorer prognosis in chronic liver diseases. Controversies also remain on their origin: lineage studies in experimental mouse models of chronic injury have recently suggested that these LPCs originate from hepatocyte dedifferentiation, whereas in other situations, they seem to come from cholangiocytes. This review summarizes data published in the past 5 years in the liver regeneration field, discusses the mechanisms leading to regeneration disruption in chronic liver disorders, and addresses the potential use of novel approaches for regenerative medicine.
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Affiliation(s)
- Hélène Gilgenkrantz
- INSERM U1149, Center for Research on Inflammation, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
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Eriksson S, Borsiin H, Öberg CF, Brange H, Mijovic Z, Sturesson C. Perioperative liver and spleen elastography in patients without chronic liver disease. World J Gastrointest Surg 2018; 10:21-27. [PMID: 29492187 PMCID: PMC5827034 DOI: 10.4240/wjgs.v10.i2.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/14/2018] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate changes in hepatic and splenic stiffness in patients without chronic liver disease during liver resection for hepatic tumors.
METHODS Patients scheduled for liver resection for hepatic tumors were considered for enrollment. Tissue stiffness measurements on liver and spleen were conducted before and two days after liver resection using point shear-wave elastography. Histological analysis of the resected liver specimen was conducted in all patients and patients with marked liver fibrosis were excluded from further study analysis. Patients were divided into groups depending on size of resection and whether they had received preoperative chemotherapy or not. The relation between tissue stiffness and postoperative biochemistry was investigated.
RESULTS Results are presented as median (interquartile range). 35 patients were included. The liver stiffness increased in patients undergoing a major resection from 1.41 (1.24-1.63) m/s to 2.20 (1.72-2.44) m/s (P = 0.001). No change in liver stiffness in patients undergoing a minor resection was found [1.31 (1.15-1.52) m/s vs 1.37 (1.12-1.77) m/s, P = 0.438]. A major resection resulted in a 16% (7%-33%) increase in spleen stiffness, more (P = 0.047) than after a minor resection [2 (-1-13) %]. Patients who underwent preoperative chemotherapy (n = 20) did not differ from others in preoperative right liver lobe [1.31 (1.16-1.50) vs 1.38 (1.12-1.56) m/s, P = 0.569] or spleen [2.79 (2.33-3.11) vs 2.71 (2.37-2.86) m/s, P = 0.515] stiffness. Remnant liver stiffness on the second postoperative day did not show strong correlations with maximum postoperative increase in bilirubin (R2 = 0.154, Pearson’s r = 0.392, P = 0.032) and international normalized ratio (R2 = 0.285, Pearson’s r = 0.534, P = 0.003).
CONCLUSION Liver and spleen stiffness increase after a major liver resection for hepatic tumors in patients without chronic liver disease.
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Walcott-Sapp S, Billingsley KG. Preoperative optimization for major hepatic resection. Langenbecks Arch Surg 2017; 403:23-35. [PMID: 29150719 DOI: 10.1007/s00423-017-1638-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 11/06/2017] [Indexed: 12/16/2022]
Abstract
PURPOSE Major hepatic resections are performed for primary hepatobiliary malignancies, metastatic disease, and benign lesions. Patients with chronic liver disease, including cirrhosis and steatosis, are at an elevated risk of malnutrition and impaired strength and exercise capacity, deficits which cause increased risk of postoperative complications and mortality. The aims of this report are to discuss the pathophysiology of changes in nutrition, exercise capacity, and muscle strength in patient populations likely to require major hepatectomy, and review recommendations for preoperative evaluation and optimization. METHODS Nutritional and functional impairment in preoperative hepatectomy patients, especially those with underlying liver disease, have a complex and multifactorial physiologic basis that is not completely understood. RESULTS Recognition of malnutrition and compromised strength and exercise tolerance preoperatively can be difficult, but is critical in providing the opportunity to intervene prior to major hepatic resection and potentially improve postoperative outcomes. There is promising data on a variety of nutritional strategies to ensure adequate intake of calories, proteins, vitamins, and minerals in patients with cirrhosis and reduce liver size and degree of fatty infiltration in patients with hepatic steatosis. Emerging evidence supports structured exercise programs to improve exercise tolerance and counteract muscle wasting. CONCLUSIONS The importance of nutrition and functional status in patients indicated for major liver resection is apparent, and emerging evidence supports structured preoperative preparation programs involving nutritional intervention and exercise training. Further research is needed in this field to develop optimal protocols to evaluate and treat this heterogeneous cohort of patients.
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Affiliation(s)
- Sarah Walcott-Sapp
- Division of Surgical Oncology, Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Mail Code: L223, Portland, OR, 97239, USA.
| | - Kevin G Billingsley
- Division of Surgical Oncology, Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Mail Code: L223, Portland, OR, 97239, USA
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Ludwig DR, Mintz AJ, Sanders VR, Fowler KJ. Liver Imaging for Colorectal Cancer Metastases. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0391-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Kolachala VL, Palle S, Shen M, Feng A, Shayakhmetov D, Gupta NA. Loss of L-selectin-guided CD8 + , but not CD4 + , cells protects against ischemia reperfusion injury in a steatotic liver. Hepatology 2017; 66:1258-1274. [PMID: 28543181 PMCID: PMC5605411 DOI: 10.1002/hep.29276] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 04/30/2017] [Accepted: 05/08/2017] [Indexed: 12/15/2022]
Abstract
UNLABELLED Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic-reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically nonexistent. The objective of the current study was to delineate the contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. RNA sequencing was performed on isolated steatotic primary hepatocytes, and T-cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high-fat diet (HFD)-fed mice. Cluster of differentiation 8 knockout (CD8-/- ) and CD4-/- mice along with CD8 and L-selectin antibody-treated mice were fed an HFD, and hepatocellular injury was assessed by histology, propidium iodide injection, and alanine aminotransferase after IRI. RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes versus lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8+ cells, alanine aminotransferase, and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8+ /CD62L+ (L-selectin) cells in HFD-fed mice after IRI. CD8-/- mice and CD8-depleted C57BL/6 mice demonstrated significant protection from injury, which was not seen in CD4-/- mice. L-selectin blockade also demonstrated significant hepatoprotection from IRI. L-selectin ligand MECA-79 was increased in HFD-fed mice undergoing IRI. CONCLUSION Blockade of CD8 and L-selectin, but not CD4, ameliorated hepatocellular injury, confirming that CD8+ cells are critical drivers of injury in a steatotic liver; this represents a therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. (Hepatology 2017;66:1258-1274).
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Affiliation(s)
| | - Sirish Palle
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Ming Shen
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Alayna Feng
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | | | - Nitika A. Gupta
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA,Transplant services, Children’s Healthcare of Atlanta. Atlanta, GA
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Kanoria S, Robertson FP, Mehta NN, Fusai G, Sharma D, Davidson BR. Effect of Remote Ischaemic Preconditioning on Liver Injury in Patients Undergoing Major Hepatectomy for Colorectal Liver Metastasis: A Pilot Randomised Controlled Feasibility Trial. World J Surg 2017; 41:1322-1330. [PMID: 27933431 PMCID: PMC5394145 DOI: 10.1007/s00268-016-3823-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Liver resection produces excellent long-term survival for patients with colorectal liver metastases but is associated with significant morbidity and mortality from ischaemia reperfusion injury (IRI). Remote ischaemic preconditioning (RIPC) can reduce the effect of IRI. This pilot randomised controlled trial evaluated RIPC in patients undergoing major hepatectomy at the Royal Free Hospital, London. Methods Sixteen patients were randomised to RIPC or sham control. RIPC was induced through three 10-min cycles of alternate ischaemia and reperfusion to the leg. At baseline and immediately post-resection, transaminases and indocyanine green (ICG) clearance were measured. Findings The RIPC group had lower ALT and AST levels immediately post-resection (ALT: 43% lower 497 ± 165 vs 889 ± 170 IU/L; p = 0.019 AST: 54% lower 408 ± 166 vs 836 ± 167 IU/L; p = 0.001) and at 24 h (ALT: 41% lower 412 ± 144 vs 698 ± 137 IU/L; p = 0.026 AST: 50% lower 316 ± 116 vs 668 ± 115 IU/L; p = 0.02). ICG clearance was reduced in controls versus RIPC immediately after resection (ICG-PDR: 11.1 ± 1.1 vs 16.5 ± 1.4%/min; p = 0.035). Conclusions This pilot study shows that RIPC has potential to reduce liver injury following hepatectomy justifying a prospective RCT powered to demonstrate clinical benefits.
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Affiliation(s)
- Sanjeev Kanoria
- Hepato-Pancreatico-Biliary and Liver Transplant Unit, University Department of Surgery, Royal Free Hospital, London, NW3 2QG, UK.,Department of Surgical and Interventional Science, Royal Free Campus, University College London, 9th Floor Royal Free Hospital, Pond Street, London, NW3 2QG, UK
| | - Francis P Robertson
- Hepato-Pancreatico-Biliary and Liver Transplant Unit, University Department of Surgery, Royal Free Hospital, London, NW3 2QG, UK. .,Department of Surgical and Interventional Science, Royal Free Campus, University College London, 9th Floor Royal Free Hospital, Pond Street, London, NW3 2QG, UK.
| | - Naimish N Mehta
- Hepato-Pancreatico-Biliary and Liver Transplant Unit, University Department of Surgery, Royal Free Hospital, London, NW3 2QG, UK.,Department of Surgical and Interventional Science, Royal Free Campus, University College London, 9th Floor Royal Free Hospital, Pond Street, London, NW3 2QG, UK
| | - Giuseppe Fusai
- Hepato-Pancreatico-Biliary and Liver Transplant Unit, University Department of Surgery, Royal Free Hospital, London, NW3 2QG, UK.,Department of Surgical and Interventional Science, Royal Free Campus, University College London, 9th Floor Royal Free Hospital, Pond Street, London, NW3 2QG, UK
| | - Dinesh Sharma
- Hepato-Pancreatico-Biliary and Liver Transplant Unit, University Department of Surgery, Royal Free Hospital, London, NW3 2QG, UK
| | - Brian R Davidson
- Hepato-Pancreatico-Biliary and Liver Transplant Unit, University Department of Surgery, Royal Free Hospital, London, NW3 2QG, UK.,Department of Surgical and Interventional Science, Royal Free Campus, University College London, 9th Floor Royal Free Hospital, Pond Street, London, NW3 2QG, UK
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Ünal E, Akata D, Karcaaltincaba M. Liver Function Assessment by Magnetic Resonance Imaging. Semin Ultrasound CT MR 2016; 37:549-560. [DOI: 10.1053/j.sult.2016.08.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Kageyama Y, Kokudo T, Amikura K, Miyazaki Y, Takahashi A, Sakamoto H. Impaired liver function attenuates liver regeneration and hypertrophy after portal vein embolization. World J Hepatol 2016; 8:1200-1204. [PMID: 27729956 PMCID: PMC5055589 DOI: 10.4254/wjh.v8.i28.1200] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 06/26/2016] [Accepted: 08/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To clarify the clinical factors associated with liver regeneration after major hepatectomy and the hypertrophic rate after portal vein embolization (PVE).
METHODS A total of 63 patients who underwent major hepatectomy and 13 patients who underwent PVE in a tertiary care hospital between January 2012 and August 2015 were included in the analysis. We calculated the remnant liver volume following hepatectomy using contrast-enhanced computed tomography (CT) performed before and approximately 3-6 mo after hepatectomy. Furthermore, we calculated the liver volume using CT performed 2-4 wk after PVE. Preoperative patient characteristics and laboratory data were analyzed to identify factors affecting postoperative liver regeneration or hypertrophy rate following PVE.
RESULTS The remnant liver volume/total liver volume ratio negatively correlated with the liver regeneration rate after hepatectomy (ρ = -0.850, P < 0.001). The regeneration rate was significantly lower in patients with an indocyanine green retention rate at 15 min (ICG-R15) of ≥ 20% in the right hepatectomy group but not in the left hepatectomy group. The hypertrophic rate after PVE positively correlated with the regeneration rate after hepatectomy (ρ = 0.648, P = 0.017). In addition, the hypertrophic rate after PVE was significantly lower in patients with an ICG-R15 ≥ 20% and a serum total bilirubin ≥ 1.5 mg/dL.
CONCLUSION The regeneration rate after major hepatectomy correlated with hypertrophic rate after PVE. Both of them were attenuated in the presence of impaired liver function.
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Nilsson JH, Reistad N, Brange H, Öberg CF, Sturesson C. Diffuse Reflectance Spectroscopy for Surface Measurement of Liver Pathology. Eur Surg Res 2016; 58:40-50. [PMID: 27658312 DOI: 10.1159/000449378] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 08/23/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Liver parenchymal injuries such as steatosis, steatohepatitis, fibrosis, and sinusoidal obstruction syndrome can lead to increased morbidity and liver failure after liver resection. Diffuse reflectance spectroscopy (DRS) is an optical measuring method that is fast, convenient, and established. DRS has previously been used on the liver with an invasive technique consisting of a needle that is inserted into the parenchyma. We developed a DRS system with a hand-held probe that is applied to the liver surface. In this study, we investigated the impact of the liver capsule on DRS measurements and whether liver surface measurements are representative of the whole liver. We also wanted to confirm that we could discriminate between tumor and liver parenchyma by DRS. MATERIALS AND METHODS The instrumentation setup consisted of a light source, a fiber-optic contact probe, and two spectrometers connected to a computer. Patients scheduled for liver resection due to hepatic malignancy were included, and DRS measurements were performed on the excised liver part with and without the liver capsule and alongside a newly cut surface. To estimate the scattering parameters and tissue chromophore volume fractions, including blood, bile, and fat, the measured diffuse reflectance spectra were applied to an analytical model. RESULTS In total, 960 DRS spectra from the excised liver tissue of 18 patients were analyzed. All factors analyzed regarding tumor versus liver tissue were significantly different. When measuring through the capsule, the blood volume fraction was found to be 8.4 ± 3.5%, the lipid volume fraction was 9.9 ± 4.7%, and the bile volume fraction was 8.2 ± 4.6%. No differences could be found between surface measurements and cross-sectional measurements. In measurements with/without the liver capsule, the differences in volume fraction were 1.63% (0.75-2.77), -0.54% (-2.97 to 0.32), and -0.15% (-1.06 to 1.24) for blood, lipid, and bile, respectively. CONCLUSION This study shows that it is possible to manage DRS measurements through the liver capsule and that surface DRS measurements are representative of the whole liver. The results are consistent with data published earlier on the combination of liver chromophores. The results encourage us to proceed with in vivo measurements for further quantification of the liver's composition and assessment of parenchymal damage such as steatosis and fibrosis grade.
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Affiliation(s)
- Jan H Nilsson
- Department of Clinical Sciences Lund, Surgery, Skåne University Hospital, Lund University, Lund, Sweden
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A New Look at Toxicity in the Era of Precision Oncology: Imaging Findings, Their Relationship With Tumor Response, and Effect on Metastasectomy. AJR Am J Roentgenol 2016; 207:4-14. [DOI: 10.2214/ajr.15.15480] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Grendar J, Ouellet JF, McKay A, Sutherland FR, Bathe OF, Ball CG, Dixon E. Effect of N-acetylcysteine on liver recovery after resection: A randomized clinical trial. J Surg Oncol 2016; 114:446-50. [PMID: 27302646 DOI: 10.1002/jso.24312] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/16/2016] [Indexed: 11/09/2022]
Abstract
BACKGROUND AND OBJECTIVES Liver failure following hepatic resection is a multifactorial complication. In experimental studies, infusion of N-acetylcysteine (NAC) can minimize hepatic parenchymal injury. METHODS Patients undergoing liver resection were randomized to postoperative care with or without NAC. No blinding was performed. Overall complication rate was the primary outcome; liver failure, length of stay, and mortality were secondary outcomes. Due to safety concerns, a premature multivariate analysis was performed and included within the model randomization to NAC, preoperative ASA, extent of resection, and intraoperative vascular occlusion as factors. RESULTS Two hundred and six patients were randomized (110 to conventional therapy; 96 to NAC). No significant differences were noted in overall complications (32.7% and 45.7%, P = 0.06) or hepatic failure (3.6% and 5.4%, P = 0.537) between treatment groups. There was significantly more delirium within the NAC group (2.7% and 9.8%, P < 0.05) that caused early trial termination. In multivariate analysis, only randomization to NAC (OR = 2.21, 95%CI = 1.16-4.19) and extensive resections (OR = 2.28, 95%CI = 1.22-4.29) were predictive of postoperative complications. CONCLUSIONS Patients randomized to postoperative NAC received no benefit. There was a trend toward a higher rate of overall complications and a significantly higher rate of delirium in the NAC group. J. Surg. Oncol. 2016;114:446-450. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Jan Grendar
- Providence Portland Medical Center, Portland, Oregon
| | - Jean F Ouellet
- CHU-Pavillon Hopital de l'Enfant-Jesus, Quebec City, Quebec, Canada
| | - Andrew McKay
- Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Oliver F Bathe
- Division of General Surgery, University of Calgary, Calgary, Alberta, Canada
| | - Chad G Ball
- Division of General Surgery, University of Calgary, Calgary, Alberta, Canada
| | - Elijah Dixon
- Division of General Surgery, University of Calgary, Calgary, Alberta, Canada
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Amini N, Margonis GA, Buttner S, Besharati S, Kim Y, Gani F, Sobhani F, Kamel IR, Pawlik TM. Liver regeneration after major liver hepatectomy: Impact of body mass index. Surgery 2016; 160:81-91. [PMID: 27059638 DOI: 10.1016/j.surg.2016.02.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 01/11/2016] [Accepted: 02/05/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Obese patients may present with metabolic abnormalities that impact liver regeneration. We sought to assess the impact of body mass index (BMI) on liver volume regeneration index (RI) and kinetic growth rate (KGR) among patients undergoing liver resection. METHODS The study included 102 patients undergoing major hepatectomy (≥3 segments) between July 2004 and April 2015 and stratified the patients by preoperative BMI, number of segments resected, and postoperative remnant liver volume (RLVp) to total liver volume ratio. Resected volume at operation was subtracted from total liver volume to calculate postoperative RLVp. RI was defined as the relative increase in RLV within 2 months [(RLV2m-RLVp)/RLVp] and 7 months [(RLV7m-RLVp)/RLVp] postoperatively; KGR was calculated as RI divided by time postoperatively (weeks). RESULTS Median patient age was 59.6 years (interquartile range 48.1-68.7 years), and most patients were men (52.0%). Liver failure was associated with the KGR at 2 months (KGR2m) and was greater among patients with KGR2m <2.5% per week (KGR <2.5%, 18.5% vs KGR ≥ 2.5%, 4.6%; P = .04). Although RI and KGR within 2 and 7 months postoperatively were similar among all patients, after excluding patients with fibrosis, obese (0.42% per week) and overweight patients (0.29% per week) had lesser KGR2-7m compared with patients of normal BMI (0.82% per week; P < .05). Additionally, risk of a major complication was greatest among obese patients (normal weight, 8.1% vs overweight, 12.9% vs obese, 29.4%; P = .04). CONCLUSION BMI did not impact liver regeneration during the first 2 months. In contrast, KGR per week between 2 and 7 months postoperatively was less among overweight and obese patients.
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Affiliation(s)
- Neda Amini
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Georgios A Margonis
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Stefan Buttner
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sepideh Besharati
- Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yuhree Kim
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Faiz Gani
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Fatemeh Sobhani
- Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ihab R Kamel
- Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Timothy M Pawlik
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD.
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The influence of steatosis on the short- and long-term results of resection of liver metastases from colorectal carcinoma. HPB (Oxford) 2016; 18:389-96. [PMID: 27037210 PMCID: PMC4814618 DOI: 10.1016/j.hpb.2015.12.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/16/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED We aimed to establish whether the presence of hepatic steatosis influences outcome after resection of colorectal liver metastases (CLM). PATIENTS AND METHODS Patients operated between 1990 and 2014 were divided into four groups based on the degree of hepatic steatosis. The association between hepatic steatosis and outcome was analyzed, using a multivariate and a propensity score case-match analysis. RESULTS No significant differences were observed between patients with and without steatosis in either mortality or morbidity in the complete series or after matching (3.2% vs. 3.5%/p = 0.845) (32.3% vs 31.4%/p = 0.802). Five-year survival in patients with and without steatosis were 56.5% and 46.5% respectively (p = 0.046). The steatosis had a significant protective effect in the univariate analysis (HR (95% CI) = 0.78 (0.62-0.99) p = 0.048), and was close to significance in the multivariate analysis (HR (95%) = 0.81 (0.63-1.03) p = 0.089). No significant differences were seen with regard to liver recurrence. CONCLUSIONS The presence of steatosis does not predict short-outcome after resection of CLM, but appears to be a favorable prognostic factor for survival. This protective effect does not depend on a decrease in liver recurrence.
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Liver steatosis assessed by preoperative MRI: An independent risk factor for severe complications after major hepatic resection. Surgery 2016; 159:1050-7. [DOI: 10.1016/j.surg.2015.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 09/20/2015] [Accepted: 10/06/2015] [Indexed: 02/06/2023]
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Defining Post Hepatectomy Liver Insufficiency: Where do We stand? J Gastrointest Surg 2015; 19:2079-92. [PMID: 26063080 DOI: 10.1007/s11605-015-2872-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 06/02/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND Post-hepatectomy liver failure (PHLF) is a major source of morbidity and mortality in patients undergoing liver resection. The aim of this review is to summarize the recent literature available on PHLF including its definition, predictive factors, preoperative risk assessment, severity grading, preventative measures, and management strategies. METHODS A systematic literature search was carried out with the search engines PubMed, Medline, and Cochrane Database using the keywords related to "liver failure", "posthepatectomy", and "hepatic resection". RESULTS Liver resection is a curative treatment of liver tumors. However, it leads to concurrent death and regeneration of the remaining hepatocytes. Factors related to the patient, liver parenchyma and the extent of surgery can inhibit regeneration leading to PHLF. CONCLUSION Given its resistance to treatment and the high postoperative mortality associated with PHLF, great effort has been put in to both accurately identify patients at high risk and to develop strategies that can help prevent its occurrence.
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Tashiro H, Kuroda S, Mikuriya Y, Ohdan H. Ischemia–reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery. Surg Today 2015; 44:1611-25. [PMID: 24078000 DOI: 10.1007/s00595-013-0736-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 08/22/2013] [Indexed: 12/15/2022]
Abstract
Hepatic steatosis is one of the most common hepatic disorders in developed countries. The epidemic of obesity in developed countries has increased with its attendant complications, including metabolic syndrome and non-alcoholic fatty liver disease. Steatotic livers are particularly vulnerable to ischemia/reperfusion injury, resulting in an increased risk of postoperative morbidity and mortality after liver surgery, including liver transplantation. There is growing understanding of the molecular and cellular mechanisms and therapeutic approaches for treating ischemia/reperfusion injury in patients with steatotic livers. This review discusses the mechanisms underlying the susceptibility of steatotic livers to ischemia/reperfusion injuries, such as mitochondrial dysfunction and signal transduction alterations, and summarizes the clinical impact of steatotic livers in the setting of hepatic resection and liver transplantation. This review also describes potential therapeutic approaches, such as ischemic and pharmacological preconditioning, to prevent ischemia/reperfusion injury in patients with steatotic livers. Other approaches, including machine perfusion, are also under clinical investigation; however, many pharmacological approaches developed through basic research are not yet suitable for clinical application.
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Amptoulach S, Gross G, Kalaitzakis E. Differential impact of obesity and diabetes mellitus on survival after liver resection for colorectal cancer metastases. J Surg Res 2015; 199:378-85. [PMID: 26115811 DOI: 10.1016/j.jss.2015.05.059] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 05/27/2015] [Accepted: 05/29/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND Data on the potential effect of obesity and diabetes mellitus on survival after liver resection due to colorectal cancer (CRC) metastases are very limited. METHODS Patients undergoing liver resection for CRC metastases in a European institution in 2004-2011 were retrospectively enrolled. Relevant data, such as body mass index, extent of resection, chemotherapy, and perioperative outcome, were collected from medical records. The relation of obesity and diabetes mellitus with overall and disease-free survival was assessed using adjusted Cox models. RESULTS Thirty of 207 patients (14.4%) included in the study were obese (BMI ≥30 kg/m(2)) and 25 (12%) had diabetes mellitus. Major hepatectomy was performed in 46%. Although both obese patients and those with diabetes had higher American Society of Anesthesiologist scores (P < 0.05 for both), neither obesity nor diabetes was significantly related to primary tumor characteristics, liver metastasis features, extent or radicality of resection, extrahepatic disease at hepatectomy, preoperative or postoperative oncologic therapy, or perioperative outcome (P > 0.05 for all). Patients were followed up for a median of 39 mo posthepatectomy (interquartile range, 13-56 mo). After adjustment for confounders, obesity was an independent predictor of improved (hazard ratio, 0.305, 95% confidence interval, 0.103-0.902) and diabetes of worse overall survival (hazard ratio, 3.298, 95% confidence interval, 1.306-8.330). Obese patients with diabetes had also worse disease-free survival compared with the rest of the cohort (P < 0.05). CONCLUSIONS After hepatectomy for CRC metastases, obesity does not seem to be associated to poor outcome while diabetes mellitus has a negative impact on prognosis.
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Affiliation(s)
- Sousana Amptoulach
- Department of Oncology, Skåne University Hospital, University of Lund, Malmö, Sweden
| | - Gillis Gross
- Institution of Clinical Sciences, Faculty of Medicine, University of Lund, Lund, Sweden
| | - Evangelos Kalaitzakis
- Institution of Clinical Sciences, Faculty of Medicine, University of Lund, Lund, Sweden.
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