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1
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Odenwald MA, Roth HF, Reticker A, Segovia M, Pillai A. Evolving challenges with long-term care of liver transplant recipients. Clin Transplant 2023; 37:e15085. [PMID: 37545440 DOI: 10.1111/ctr.15085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 08/08/2023]
Abstract
The number of liver transplants (LT) performed worldwide continues to rise, and LT recipients are living longer post-transplant. This has led to an increasing number of LT recipients requiring lifelong care. Optimal care post-LT requires careful attention to both the allograft and systemic issues that are more common after organ transplantation. Common causes of allograft dysfunction include rejection, biliary complications, and primary disease recurrence. While immunosuppression prevents rejection and reduces incidences of some primary disease recurrence, it has detrimental systemic effects. Most commonly, these include increased incidences of metabolic syndrome, various malignancies, and infections. Therefore, it is of utmost importance to optimize immunosuppression regimens to prevent allograft dysfunction while also decreasing the risk of systemic complications. Institutional protocols to screen for systemic disease and heightened clinical suspicion also play an important role in providing optimal long-term post-LT care. In this review, we discuss these common complications of LT as well as unique considerations when caring for LT recipients in the years after transplant.
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Affiliation(s)
- Matthew A Odenwald
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Hannah F Roth
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Anesia Reticker
- Department of Pharmacy, University of Chicago Medicine, Chicago, USA
| | - Maria Segovia
- Department of Medicine, Section of Gastroenterology, Duke University School of Medicine, Durham, USA
| | - Anjana Pillai
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
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2
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Zhang Z, Sun J, Guo M, Yuan X. Progress of new-onset diabetes after liver and kidney transplantation. Front Endocrinol (Lausanne) 2023; 14:1091843. [PMID: 36843576 PMCID: PMC9944581 DOI: 10.3389/fendo.2023.1091843] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/27/2023] [Indexed: 02/11/2023] Open
Abstract
Organ transplantation is currently the most effective treatment for end-stage organ failure. Post transplantation diabetes mellitus (PTDM) is a severe complication after organ transplantation that seriously affects the short-term and long-term survival of recipients. However, PTDM is often overlooked or poorly managed in its early stage. This article provides an overview of the incidence, and pathogenesis of and risk factors for PTDM, aiming to gain a deeper understanding of PTDM and improve the quality of life of recipients.
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Affiliation(s)
- Zhen Zhang
- Department of Urology, The People's Hospital of Linyi, Linyi, Shandong, China
| | - Jianyun Sun
- Department of Gastroenterology, The People's Hospital of Linyi, Linyi, Shandong, China
| | - Meng Guo
- National Key Laboratory of Medical Immunology &Institute of Immunology, Navy Medical University, Shanghai, China
| | - Xuemin Yuan
- Department of Gastroenterology, The People's Hospital of Linyi, Linyi, Shandong, China
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3
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Cheng CH, Chu CY, Chen HL, Lin IT, Wu CH, Lee YK, Bair MJ. Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients. Front Endocrinol (Lausanne) 2021; 12:799382. [PMID: 35095765 PMCID: PMC8792856 DOI: 10.3389/fendo.2021.799382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/20/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Chronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies. METHODS We screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients' baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and β-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment. RESULTS High IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in β-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039). CONCLUSIONS There were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.
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Affiliation(s)
- Chun-Han Cheng
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Chia-Ying Chu
- Department of Pathology, Taitung Mackay Memorial Hospital, Taitung, Taiwan
| | - Huan-Lin Chen
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - I-Tsung Lin
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Chia-Hsien Wu
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Yuan-Kai Lee
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
- *Correspondence: Ming-Jong Bair,
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4
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Management of metabolic syndrome and cardiovascular risk after liver transplantation. Lancet Gastroenterol Hepatol 2020; 4:731-741. [PMID: 31387736 DOI: 10.1016/s2468-1253(19)30181-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/22/2019] [Accepted: 04/23/2019] [Indexed: 12/11/2022]
Abstract
Cardiovascular events are the second most prevalent cause of non-hepatic mortality in liver transplant recipients. The incidence of these events is projected to rise because of the growing prevalence of non-alcoholic steatohepatitis as a transplant indication and the ageing population of liver transplant recipients. Recipients with metabolic syndrome are up to four times more likely to have a cardiovascular event than recipients without, therefore prevention and optimal treatment of the components of metabolic syndrome are key in reducing the risk of these events. Although data on the treatment of metabolic comorbidities specifically in liver transplant recipients are scarce, there is detailed guidance from learned societies that mostly mirrors the guidance for patients at increased cardiovascular risk in the general population. In this Review, we discuss the management of the components of metabolic syndrome following liver transplantation and provide practical stepwise guidance. We also emphasise the need for adequately powered studies for the treatment of metabolic comorbidities in liver transplant recipients.
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5
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Wong T, Bloom RD. Management and treatment of the HCV-infected kidney transplant patient. Semin Dial 2018; 32:169-178. [PMID: 30536995 DOI: 10.1111/sdi.12766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The prevalence of hepatitis C virus infection is increased in patients with end stage kidney disease compared to the general population and is an adverse outcome determinant. Direct-acting antiviral therapy for hepatitis C virus is changing the management paradigm of infected kidney transplant candidates and recipients, with potential to reduce patient morbidity and mortality. This review describes the hepatic and nonhepatic manifestations of hepatitis C virus in kidney transplant patients as well as management and treatment strategies to optimize transplant outcomes, highlighting the importance of direct-acting antivirals in this population.
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Affiliation(s)
- Tiffany Wong
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Roy D Bloom
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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6
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Agarwal K, Brown SE. Achieving Cure From Hepatitis C Virus Is Good for More Than Just the Liver Graft. Liver Transpl 2018; 24:997-998. [PMID: 30028069 DOI: 10.1002/lt.25298] [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: 06/25/2018] [Accepted: 06/25/2018] [Indexed: 01/13/2023]
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7
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Beig J, Orr D, Harrison B, Gane E. Hepatitis C Virus Eradication with New Interferon-Free Treatment Improves Metabolic Profile in Hepatitis C Virus-Related Liver Transplant Recipients. Liver Transpl 2018; 24:1031-1039. [PMID: 29577581 DOI: 10.1002/lt.25060] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 04/22/2018] [Accepted: 05/20/2018] [Indexed: 12/15/2022]
Abstract
Interferon (IFN)-free, direct-acting antiviral (DAA) therapy agents provide a safe and efficacious treatment for liver transplant recipients with recurrent hepatitis C virus (HCV) infection. The aim of this study is to evaluate the impact of HCV eradication on the metabolic factors in liver transplant recipients. We completed a retrospective single-center study on HCV-related liver transplant recipients treated with IFN-free DAAs including both treatment-naive and treatment-experienced patients. IFN-free DAAs impact on the metabolic profile were assessed at baseline and sustained virological response (SVR) between 24 and 48 weeks. In total, 91 liver transplant recipients with recurrent HCV infection received IFN-free DAA treatment, 62 patients had IFN-based treatment failure, and 29 were treatment-naïve, of whom 87 (96%) achieved SVR. Eradication of recurrent HCV infection was associated with reduction in the treatment of diabetes and hypertension by 38% and 22% from the baseline respectively. Hemoglobin A1c (HbA1c) levels declined from mean 35.5 ± 4.3 mmol/mol to 33.3 ±3.6 mmol/mol at 44 weeks posttreatment (P = 0.03). Total cholesterol levels increased from 3.8 ± 0.9 mmol/L to 4.9 ± 0.9 mmol/L at 41 weeks posttreatment (P < 0.0001), reflecting a significant increase in serum low-density lipoprotein (LDL) levels (2.0 ± 0.8 to 2.9 ± 0.8; P < 0.0001). Estimated glomerular filtration rate (eGFR) levels increased from 64.9 ± 20 mL/minute to 69.6 ± 20 mL/minute at 24 weeks posttreatment (P = 0.0004). Glucose, lipid profile, and eGFR changes were independent of weight changes and immunosuppression dosage and trough levels. In conclusion, eradication of recurrent HCV infection by DAA therapy has beneficial impacts on glucose metabolism and renal profile and reverses the hypolipidemic effect of HCV in liver transplant recipients. These extrahepatic effects of DAA therapy need to be validated by larger prospective studies.
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Affiliation(s)
- Junaid Beig
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - David Orr
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Barry Harrison
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Edward Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
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8
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Castedal M, Skoglund C, Axelson C, Bennet W. Steroid-free immunosuppression with low-dose tacrolimus is safe and significantly reduces the incidence of new-onset diabetes mellitus following liver transplantation. Scand J Gastroenterol 2018; 53:741-747. [PMID: 29688072 DOI: 10.1080/00365521.2018.1463390] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Corticosteroids (CS) are traditionally used as part of the basal immunosuppression (IS) following liver transplantation (LT) but are known to be associated with an increased risk of new-onset diabetes mellitus (NODM), cardiovascular morbidity and mortality. The aim of this study was to retrospectively compare the incidence of transient as well as persistent NODM, rejection rate and patient- and graft survival between patients receiving steroid-based and steroid-free maintenance IS. MATERIALS AND METHODS A total of 238 patients liver transplanted (2008-2011) with deceased donor livers were divided into two groups, one group that received steroid-based IS (tacrolimus (TAC), corticosteroids (CS), ± mycophenolate mofetil (MMF); n = 155) (2008-2011) and another group of non-autoimmune recipients that received steroid-free IS (TAC, MMF; n = 83) according to our new maintenance IS-protocol starting January 2010. The primary and secondary end-points were patient- and graft survival, rejection rates and the incidence of NODM. The median follow-up times were 1248 days and 681 days, respectively. RESULTS The one-year patient- and graft survival in the steroid-based and steroid-free group was 92.7% and 93.3% (ns) and 87.6% and 84.9% (ns), respectively. The incidence of biopsy proven acute rejection (BPAR) was 27.7% in both groups (ns) during follow-up. The overall incidence of persistent NODM in the two groups were 16.8% and 2.9%, respectively (p < .01). CONCLUSIONS The results show that steroid-free low-dose tacrolimus-based IS following LT is safe and decreases the incidence of NODM significantly.
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Affiliation(s)
- M Castedal
- a The Transplant Institute , Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - C Skoglund
- a The Transplant Institute , Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - C Axelson
- a The Transplant Institute , Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - W Bennet
- a The Transplant Institute , Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
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9
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Peláez-Jaramillo MJ, Cárdenas-Mojica AA, Gaete PV, Mendivil CO. Post-Liver Transplantation Diabetes Mellitus: A Review of Relevance and Approach to Treatment. Diabetes Ther 2018; 9:521-543. [PMID: 29411291 PMCID: PMC6104273 DOI: 10.1007/s13300-018-0374-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Indexed: 02/08/2023] Open
Abstract
Post-liver transplantation diabetes mellitus (PLTDM) develops in up to 30% of liver transplant recipients and is associated with increased risk of mortality and multiple morbid outcomes. PLTDM is a multicausal disorder, but the main risk factor is the use of immunosuppressive agents of the calcineurin inhibitor (CNI) family (tacrolimus and cyclosporine). Additional factors, such as pre-transplant overweight, nonalcoholic steatohepatitis and hepatitis C virus infection, may further increase risk of developing PLTDM. A diagnosis of PLTDM should be established only after doses of CNI and steroids are stable and the post-operative stress has been overcome. The predominant defect induced by CNI is insulin secretory dysfunction. Plasma glucose control must start immediately after the transplant procedure in order to improve long-term results for both patient and transplant. Among the better known antidiabetics, metformin and DPP-4 inhibitors have a particularly benign profile in the PLTDM context and are the preferred oral agents for long-term management. Insulin therapy is also an effective approach that addresses the prevailing pathophysiological defect of the disorder. There is still insufficient evidence about the impact of newer families of antidiabetics (GLP-1 agonists, SGLT-2 inhibitors) on PLTDM. In this review, we summarize current knowledge on the epidemiology, pathogenesis, course of disease and medical management of PLTDM.
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Affiliation(s)
| | | | - Paula V Gaete
- Universidad de los Andes School of Medicine, Bogotá, Colombia
| | - Carlos O Mendivil
- Universidad de los Andes School of Medicine, Bogotá, Colombia.
- Endocrinology Section, Department of Internal Medicine, Fundación Santa Fe de Bogotá, Bogotá, Colombia.
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10
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Wagener G. Immunosuppression. LIVER ANESTHESIOLOGY AND CRITICAL CARE MEDICINE 2018. [PMCID: PMC7123053 DOI: 10.1007/978-3-319-64298-7_32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Gebhard Wagener
- Department of Anesthesiology, Columbia University Medical Center, New York, New York USA
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11
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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12
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Salam OMA, Sleem AA, Omara EA, Hassan NS. Effect of Ribavirin Alone or Combined with Silymarin on Carbon Tetrachloride Induced Hepatic Damage in Rats. Drug Target Insights 2017. [DOI: 10.1177/117739280700200014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Omar M.E. Abdel Salam
- Department of Pharmacology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
| | - Amany A. Sleem
- Department of Pharmacology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
| | - Enayat A. Omara
- Department of Pathology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
| | - Nabila S. Hassan
- Department of Pathology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
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13
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Lerat H, Imache MR, Polyte J, Gaudin A, Mercey M, Donati F, Baudesson C, Higgs MR, Picard A, Magnan C, Foufelle F, Pawlotsky JM. Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice. J Biol Chem 2017; 292:12860-12873. [PMID: 28559285 DOI: 10.1074/jbc.m117.785030] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 05/18/2017] [Indexed: 12/15/2022] Open
Abstract
Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.
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Affiliation(s)
- Hervé Lerat
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France; Université Paris-Est Créteil Val de Marne, 94010 Créteil, France.
| | - Mohamed Rabah Imache
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Jacqueline Polyte
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Aurore Gaudin
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Marion Mercey
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Flora Donati
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Camille Baudesson
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Martin R Higgs
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Alexandre Picard
- Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, 75013 Paris, France
| | - Christophe Magnan
- Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, 75013 Paris, France
| | - Fabienne Foufelle
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 75006 Paris, France
| | - Jean-Michel Pawlotsky
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France; Université Paris-Est Créteil Val de Marne, 94010 Créteil, France; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, AP-HP, 94010 Créteil, France
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14
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Yagi S, Kaido T, Iida T, Yoshizawa A, Okajima H, Uemoto S. New-onset diabetes mellitus after living-donor liver transplantation: association with graft synthetic function. Surg Today 2016; 47:733-742. [PMID: 27837276 DOI: 10.1007/s00595-016-1444-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 09/20/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND PURPOSE It is now known that post-transplant graft function after deceased-donor liver transplantation and living-donor liver transplantation (LDLT) differ; however, there is no report assessing the relationship between graft function and the development of new-onset diabetes mellitus after transplantation (NODAT). We conducted this study to identify the predictive risk factors for NODAT, including graft function after LDLT. METHODS The subjects of this study were 175 adult recipients who underwent LDLT at Kyoto University Hospital between 2006 and 2010, and survived for more than 3 months (median observation period, 1046 days). RESULTS The 1-, 2-, and 3-year incidences of NODAT after LDLT were 26.1, 32.0, and 33.4%, respectively. Pre-transplant diabetes was associated with poor survival (p = 0.0048), whereas NODAT was not associated with patient survival. In the multivariate analysis, recipient age ≥40, a tacrolimus trough level ≥8 ng/mL 3 months after LDLT, and cholinesterase (ChE) <185 IU/L 3 months after LDLT were the independent risk factors for NODAT. CONCLUSIONS Poor graft synthetic function 3 months after LDLT as well as older age of the recipient and a higher tacrolimus concentration were strongly associated with NODAT development after LDLT.
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Affiliation(s)
- Shintaro Yagi
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Toshimi Kaido
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Taku Iida
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Atsushi Yoshizawa
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Hideaki Okajima
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Shinji Uemoto
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
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15
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Loftfield E, Freedman ND, Lai GY, Weinstein SJ, McGlynn KA, Taylor PR, Männistö S, Albanes D, Stolzenberg-Solomon RZ. Higher Glucose and Insulin Levels Are Associated with Risk of Liver Cancer and Chronic Liver Disease Mortality among Men without a History of Diabetes. Cancer Prev Res (Phila) 2016; 9:866-874. [PMID: 27574287 DOI: 10.1158/1940-6207.capr-16-0141] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 08/22/2016] [Indexed: 12/23/2022]
Abstract
Insulin resistance likely increases the risk of chronic liver disease (CLD) and liver cancer, but long-term prospective studies with measured fasting glucose and insulin are lacking. We evaluated the associations of prediagnostic fasting glucose, insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR) with liver cancer and CLD mortality in a prospective study of Finnish male smokers with extended follow-up time (≤22 years) and information on known risk factors using data from 138 incident primary liver cancer cases, 216 CLD deaths, and 681 matched controls. Fasting glucose and insulin were measured in baseline serum. We used unconditional logistic regression to estimate ORs and 95% confidence intervals adjusted for age, alcohol, education, smoking, body mass index, and hepatitis B and C viral status. Among those without self-reported diabetes, glucose was positively associated with liver cancer [quartile 3 vs. quartile 1 (Q3/Q1): OR = 1.88; 1.03-3.49; Q4/Q1: OR = 2.40; 1.33-4.35; Ptrend = 0.002], and undiagnosed, biochemically defined, diabetes was associated with higher risk of liver cancer (OR = 2.95; 1.46-5.96) and CLD mortality (OR = 1.88; 1.00-3.56). Serum insulin and HOMA-IR were also positively associated with liver cancer (Q4/Q1: OR = 3.41; 1.74-6.66; Ptrend < 0.0001; OR = 3.72; 1.89-7.32, Ptrend < 0.0001, respectively) and CLD (OR = 2.51; 1.44-4.37; Ptrend = 0.0002; OR = 2.31; 1.34-3.97; Ptrend = 0.001, respectively), with stronger associations observed for liver cancer diagnosed >10 years after baseline. In conclusion, elevated fasting glucose and insulin and insulin resistance were independently associated with risk of liver cancer and CLD mortality, suggesting a potentially important etiologic role for insulin and glucose dysregulation even in the absence of diagnosed diabetes. Cancer Prev Res; 9(11); 866-74. ©2016 AACR.
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Affiliation(s)
- Erikka Loftfield
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland.
| | - Neal D Freedman
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland
| | - Gabriel Y Lai
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland
| | | | | | - Philip R Taylor
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland
| | - Satu Männistö
- National Institute for Health and Welfare, Helsinki, Finland
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland
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16
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Xue M, Lv C, Chen X, Huang X, Sun Q, Wang T, Liang J, Zhang Y, He S, Gao J, Zhou J, Yu M, Fan J, Gao X. Effect of interleukin-2 receptor antagonists on new-onset diabetes after liver transplantation: A retrospective cohort study. J Diabetes 2016; 8:579-87. [PMID: 26588180 DOI: 10.1111/1753-0407.12356] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 09/28/2015] [Accepted: 11/10/2015] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The aim of the present retrospective observational study was to examine the effect of interleukin-2 receptor antagonists (IL-2Ra) on new-onset diabetes after transplantation (NODAT) in liver transplant recipients. METHODS Pre- and postoperative clinical data of 781 patients undergoing liver transplantation between April 2001 and December 2014 at Zhongshan Hospital, Fudan University, were analyzed. Patients were divided into two groups depending on the use of IL-2Ra (IL-2Ra and non-IL-2Ra). The cumulative incidence of NODAT was compared between the IL-2Ra and non-IL-2Ra groups and the effect of IL-2Ra on the incidence of NODAT in liver transplant recipients was evaluated. RESULTS Of the 781 patients in the study, 451 received IL-2Ra. During follow-up, 138 (41.8%) and 137 (30.4%) patients in the non-IL-2Ra and IL-2Ra groups, respectively, developed NODAT (P = 0.001). The cumulative incidence of NODAT at 1, 3, 5, and 8 years after transplantation in the IL-2Ra group was 30%, 38%, 45%, and 54%, respectively; these values were substantially lower than corresponding values for the non-IL-2Ra group (P < 0.05). Cox regression analyses showed that IL-2Ra was a protective factor against NODAT development (odds ratio 0.685; 95% confidence interval 0.473-0.991; P = 0.044). This was independent of age, sex, donor type, hepatitis virus infection, body mass index, history of hypertension, preoperative liver function, preoperative fasting plasma glucose, total cholesterol, and total triglyceride levels, severity of liver cirrhosis, acute rejection, initial immunosuppressant regimen type, and postoperative immunosuppressant levels. CONCLUSION In conclusion, IL-2Ra reduces the risk of NODAT in liver transplant recipients.
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Affiliation(s)
- Mengjuan Xue
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Chaoyang Lv
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Xianying Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
- Department of Endocrinology and Metabolism, Hainan Provincial Nong Ken Hospital, Hainan, China
| | - Xiaowu Huang
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Qiman Sun
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Ting Wang
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Jing Liang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Yao Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Shunmei He
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Jian Gao
- Center of Clinical Epidemiology and Evidence-Based Medicine, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Mingxiang Yu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
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Shivaswamy V, Boerner B, Larsen J. Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes. Endocr Rev 2016; 37:37-61. [PMID: 26650437 PMCID: PMC4740345 DOI: 10.1210/er.2015-1084] [Citation(s) in RCA: 215] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM.
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Affiliation(s)
- Vijay Shivaswamy
- Division of Diabetes, Endocrinology, and Metabolism (V.S., B.B., J.L.), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198; and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105
| | - Brian Boerner
- Division of Diabetes, Endocrinology, and Metabolism (V.S., B.B., J.L.), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198; and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105
| | - Jennifer Larsen
- Division of Diabetes, Endocrinology, and Metabolism (V.S., B.B., J.L.), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198; and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105
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18
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Burra P, De Martin E, Zanetto A, Senzolo M, Russo FP, Zanus G, Fagiuoli S. Hepatitis C virus and liver transplantation: where do we stand? Transpl Int 2016; 29:135-152. [PMID: 26199060 DOI: 10.1111/tri.12642] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/06/2015] [Accepted: 07/15/2015] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Eleonora De Martin
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Centre Hepato-Biliaire Paul Brousse, Villejuif, France
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Giacomo Zanus
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
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19
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Lv C, Zhang Y, Chen X, Huang X, Xue M, Sun Q, Wang T, Liang J, He S, Gao J, Zhou J, Yu M, Fan J, Gao X. New-onset diabetes after liver transplantation and its impact on complications and patient survival. J Diabetes 2015; 7:881-90. [PMID: 25676209 DOI: 10.1111/1753-0407.12275] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 01/13/2015] [Accepted: 01/27/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The aim of the present study was to investigate the incidence and risk factors of new-onset diabetes after transplantation (NODAT) in liver transplant recipients and the influence of NODAT on complications and long-term patient survival. METHODS We examined 438 patients who underwent liver transplantation between April 2001 and December 2008 and were not diabetic before transplantation. RESULTS The mean (± SD) follow-up duration was 2.46 ± 1.62 years. The incidence of NODAT 3, 6, 9, 12, 36, and 60 months after transplantation was 44.24%, 25.59%, 23.08%, 25.17%, 17.86%, and 18.18%, respectively. Multifactor analysis indicated that preoperative fasting plasma glucose (FPG) levels and donor liver steatosis were independent risk factors for NODAT, whereas administration of an interleukin-2 receptor (IL-2R) antagonist reduced the risk of NODAT. Compared with the no NODAT group (N-NODAT), the NODAT group had a higher rate of sepsis and chronic renal insufficiency. Mean survival was significantly longer in the N-NODAT than NODAT group. Cox regression analysis showed that pre- and/or postoperative FPG levels, tumor recurrence or metastasis, and renal insufficiency after liver transplantation were independent risk factors of mortality. Pulmonary infection or multisystem failure were specific causes of death in the NODAT group, whereas patients in both groups died primarily from tumor relapse or metastasis. CONCLUSIONS Preoperative FPG levels and donor liver steatosis were independent risk factors for NODAT, whereas administration of an IL-2R antagonist reduced the risk of NODAT. Patients with NODAT had reduced survival and an increased incidence of sepsis and chronic renal insufficiency. Significant causes of death in the NODAT group were pulmonary infection and multisystem failure.
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Affiliation(s)
- Chaoyang Lv
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Yao Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Xianying Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
- Department of Endocrinology and Metabolism, Hainan Provincial Nong Ken Hospital, Hainan, China
| | - Xiaowu Huang
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Mengjuan Xue
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Qiman Sun
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Ting Wang
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Jing Liang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Shunmei He
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Jian Gao
- Center of Clinical Epidemiology and Evidence-based Medicine, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Mingxiang Yu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
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20
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Kukla M, Piotrowski D, Waluga M, Hartleb M. Insulin resistance and its consequences in chronic hepatitis C. Clin Exp Hepatol 2015; 1:17-29. [PMID: 28856251 PMCID: PMC5421163 DOI: 10.5114/ceh.2015.51375] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized.
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Affiliation(s)
- Michał Kukla
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Damian Piotrowski
- Department of Infectious Diseases in Bytom, Medical University of Silesia in Katowice, Poland
| | - Marek Waluga
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
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21
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Abstract
Chronic HCV infection is the leading indication for liver transplantation. However, as a result of HCV recurrence, patient and graft survival after liver transplantation are inferior compared with other indications for transplantation. HCV recurrence after liver transplantation is associated with considerable mortality and morbidity. The development of HCV-related fibrosis is accelerated after liver transplantation, which is influenced by a combination of factors related to the virus, donor, recipient, surgery and immunosuppression. Successful antiviral therapy is the only treatment that can attenuate fibrosis. The advent of direct-acting antiviral agents (DAAs) has changed the therapeutic landscape for the treatment of patients with HCV. DAAs have improved tolerability, and can potentially be used without PEG-IFN for a shorter time than previous therapies, which should result in better outcomes. In this Review, we describe the important risk factors that influence HCV recurrence after liver transplantation, highlighting the mechanisms of fibrosis and the integral role of hepatic stellate cells. Indirect and direct assessment of fibrosis, in addition to new antiviral therapies, are also discussed.
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22
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Campos-Varela I, Esteban JI, Bes M, Caralt M, Allende H, Rodríguez-Frías F, Salcedo MT, Sauleda S, Charco R, Guardia J, Esteban R, Castells L. Early predictors of antiviral treatment response in liver transplant recipients with recurrent hepatitis C genotype 1. J Viral Hepat 2014; 21:e118-e128. [PMID: 24620835 DOI: 10.1111/jvh.12246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 01/14/2014] [Indexed: 12/09/2022]
Abstract
The success of current antiviral treatment for hepatitis C virus (HCV) recurrence in liver transplant (LT) recipients remains limited. We aimed at evaluating the value of IL28B genotype and early viral kinetics to predict response to standard treatment in the transplant setting. We retrospectively evaluated 104 LT recipients treated for HCV genotype 1 recurrence between 2001 and 2010. Baseline variables, including IL28B genotype, and early viral kinetics were compared among patients who did or did not achieve a sustained virological response (SVR). Logistic regression analyses of candidate variables were conducted to generate a reliable predictive model based on the minimum set of variables. Twenty-nine (28%) achieved an SVR. On multivariate analysis, the magnitude of HCV RNA decline at 4 weeks (OR: 3.74, 95% CI: 1.64-9.39; P = 0.003) and treatment compliance (OR: 35.27, 95% CI: 3.35-365.54; P = 0.003) were the only independent predictors of SVR. Favourable recipient IL28B genotype significantly correlates with virological response at week 4 (OR 3.23; 95% CI, 1.12-9.15; P = 0.03). By logistic regression analysis, a model including donor age, recipient rs12979860 genotype and viral load at 4 weeks showed the best predictive value for SVR with an area under the receiver operating curve of 0.861. Favourable recipient IL28B genotype strongly correlates with the viral response at week 4 which is the strongest predictor of response. The combination of recipient IL28B genotype and donor age with the week 4 response reliably estimates the probability of SVR early on-treatment and may facilitate therapeutic strategies incorporating new antiviral agents.
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Affiliation(s)
- I Campos-Varela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Liu Z, Chen Y, Tao R, Xv J, Meng J, Yong X. Tacrolimus-based versus cyclosporine-based immunosuppression in hepatitis C virus-infected patients after liver transplantation: a meta-analysis and systematic review. PLoS One 2014; 9:e107057. [PMID: 25198195 PMCID: PMC4157850 DOI: 10.1371/journal.pone.0107057] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Accepted: 08/05/2014] [Indexed: 02/06/2023] Open
Abstract
Background Most liver transplant recipients receive calcineurin inhibitors (CNIs), especially tacrolimus and cyclosporine, as immunosuppressant agents to prevent rejection. A controversy exists as to whether the outcomes of hepatitis C virus (HCV)-infected liver transplant patients differ based on the CNIs used. This meta-analysis compares the clinical outcomes of tacrolimus-based and cyclosporine-based immunosuppression, especially cases of HCV recurrence in liver transplant patients with end-stage liver disease caused by HCV infection. Methods Related articles were identified from the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, and Embase. Meta-analyses were performed for the results of homogeneous studies. Results Nine randomized or quasi-randomized controlled trials were included. The total effect size of mortality (RR = 0.98, 95% CI: 0.77–1.25, P = 0.87) and graft loss (RR = 1.05, 95% CI: 0.83–1.33, P = 0.67) showed no significant difference between the two groups irrespective of duration of immunosuppressant therapy after liver transplantation. In addition, the HCV recurrence-induced mortality (RR = 1.11, 95% CI: 0.66–1.89, P = 0.69), graft loss (RR = 1.62, 95% CI: 0.64–4.07, P = 0.31) and retransplantation (RR = 1.40, 95% CI: 0.48–4.09, P = 0.54), as well as available biopsies, confirmed that histological HCV recurrences (RR = 0.92, 95% CI: 0.71–1.19, P = 0.51) were similar. Conclusion These results suggested no difference in posttransplant HCV recurrence-induced mortality, graft loss and retransplantation, as well as histological HCV recurrence in patients treated with tacrolimus-based and cyclosporine-based immunosuppresion.
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Affiliation(s)
- Zhenmin Liu
- Department of Periodontology and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Yi Chen
- Department of Periodontology and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Renchuan Tao
- Department of Periodontology and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
- * E-mail:
| | - Jing Xv
- Department of Hepato-biliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jianyuan Meng
- Department of Hepato-biliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiangzhi Yong
- Department of Periodontology and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
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Dumortier J, Boillot O, Scoazec JY. Natural history, treatment and prevention of hepatitis C recurrence after liver transplantation: Past, present and future. World J Gastroenterol 2014; 20:11069-11079. [PMID: 25170196 PMCID: PMC4145750 DOI: 10.3748/wjg.v20.i32.11069] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 03/07/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related liver disease, including cirrhosis and hepatocellular carcinoma is the main indication for liver transplantation (LT) worldwide. Post-transplant HCV re-infection is almost universal and results in accelerated progression from acute hepatitis to chronic hepatitis, and liver cirrhosis. Comprehension and treatment of recurrent HCV infection after LT have been major issues for all transplant hepatologists and transplant surgeons for the last decades. The aim of this paper is to review the evolution of our knowledge on the natural history of HCV recurrence after LT, including risk factors for disease progression, and antiviral therapy. We will focus our attention on possible ways (present and future) to improve the final long-term results of LT for HCV-related liver disease.
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25
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Khullar V, Dolganiuc A, Firpi RJ. Pre-and-post transplant considerations in patients with nonalcoholic fatty liver disease. World J Transplant 2014; 4:81-92. [PMID: 25032097 PMCID: PMC4094954 DOI: 10.5500/wjt.v4.i2.81] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 02/17/2014] [Accepted: 03/12/2014] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the third most common indication for liver transplantation in the United States. With the growing incidence of obesity, NAFLD is expected to become the most common indication for liver transplantation over the next few decades. As the number of patients who have undergone transplantation for NAFLD increases, unique challenges have emerged in the management and long-term outcomes in patients. Risk factors such as obesity, hypertension, diabetes, and hyperlipidemia continue to play an important role in the pathogenesis of the disease and its recurrence. Patients who undergo liver transplantation for NAFLD have similar long-term survival as patients who undergo liver transplantation for other indications. Research shows that post-transplantation recurrence of NAFLD is commonplace with some patients progressing to recurrent non-alcoholic steatohepatitis and cirrhosis. While treatment of comorbidities is important, there is no consensus on the management of modifiable risk factors or the role of pharmacotherapy and immunosuppression in patients who develop recurrent or de novo NAFLD post-transplant. This review provides an outline of NAFLD as indication for liver transplantation with a focus on the epidemiology, pathophysiology and risk factors associated with this disease. It also provides a brief review on the pre-transplant considerations and post-transplant factors including patient characteristics, role of obesity and metabolic syndrome, recurrence and de novo NAFLD, outcomes post-liver transplantation, choice of medications, and options for immunosuppression.
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26
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Morbitzer KA, Taber DJ, Pilch NA, Meadows HB, Fleming JN, Bratton CF, McGillicuddy JW, Baliga PK, Chavin KD. The impact of diabetes mellitus and glycemic control on clinical outcomes following liver transplant for hepatitis C. Clin Transplant 2014; 28:862-8. [PMID: 24893750 DOI: 10.1111/ctr.12391] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2014] [Indexed: 12/15/2022]
Abstract
Hepatitis C is the leading indication for liver transplantation in the USA and recurrence is universal. The impact of preexisting diabetes, new-onset diabetes after transplant (NODAT), and glycemic control on fibrosis progression has not been studied. This retrospective longitudinal cohort study included adult liver recipients with hepatitis C transplanted between 2000 and 2011. Patients were divided into three groups: preexisting diabetes (n = 41), NODAT (n = 59), and no diabetes (n = 103). Patients with preexisting diabetes (70%) or NODAT (59%) were more likely to develop hepatitis C recurrence (≥stage 1 fibrosis), as compared to non-diabetics (36%, p = 0.006). There was also a trend toward a higher incidence of at least Stage 2 fibrosis (36% and 48% vs. 23%, respectively; p = 0.063). Patients with tight glycemic control had a lower rate of Stage 2 fibrosis development (78% vs. 60%, p = 0.027), while those with good control (<150 mg/dL) also had lower rates of Stage 2 fibrosis (84% vs. 62%, p = 0.004). Multivariable analysis verified a decreased rate of recurrence for patients with blood glucose <138 mg/dL (p = 0.021), after controlling for confounders. These results demonstrate that diabetes is strongly associated with an increased risk of hepatitis C virus-related fibrosis development and glycemic control may reduce the risk and severity of recurrence.
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Affiliation(s)
- Kathryn A Morbitzer
- Division of Practice Advancement and Clinical Education, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacy Services, Medical University of South Carolina, Charleston, SC, USA
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Joshi D, Carey I, Foxton M, Al-Freah M, Bruce M, Heaton N, Quaglia A, O'Grady J, Aluvihare V, Agarwal K. CXCL10 levels identify individuals with rapid fibrosis at 12 months post-transplant for hepatitis C virus and predict treatment response. Clin Transplant 2014; 28:569-78. [DOI: 10.1111/ctr.12354] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2014] [Indexed: 01/14/2023]
Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies; King's College Hospital; London UK
| | - Ivana Carey
- Institute of Liver Studies; King's College Hospital; London UK
| | - Matthew Foxton
- Institute of Liver Studies; King's College Hospital; London UK
| | | | - Matthew Bruce
- Institute of Liver Studies; King's College Hospital; London UK
| | - Nigel Heaton
- Institute of Liver Studies; King's College Hospital; London UK
| | - Alberto Quaglia
- Institute of Liver Studies; King's College Hospital; London UK
| | - John O'Grady
- Institute of Liver Studies; King's College Hospital; London UK
| | | | - Kosh Agarwal
- Institute of Liver Studies; King's College Hospital; London UK
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28
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Cho J, Oh S, Kim K, Namgung J, Kim D, Song G, Ha T, Moon D, Ahn C, Kim K, Hwang S, Lee S. Prevalence and Treatment of New-Onset Diabetes Mellitus After Liver Transplantation in Korean Children: A Single-Center Study. Transplant Proc 2014; 46:873-5. [DOI: 10.1016/j.transproceed.2013.11.065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 11/22/2013] [Indexed: 11/30/2022]
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29
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Levy G, Villamil FG, Nevens F, Metselaar HJ, Clavien PA, Klintmalm G, Jones R, Migliaccio M, Prestele H, Orsenigo R. REFINE: a randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C. Am J Transplant 2014; 14:635-46. [PMID: 24456049 DOI: 10.1111/ajt.12620] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 12/09/2013] [Accepted: 12/09/2013] [Indexed: 01/25/2023]
Abstract
REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.
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Affiliation(s)
- G Levy
- Multi Organ Transplant Program, University of Toronto Transplant Institute, Toronto, ON, Canada
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30
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Loria P, Marchesini G, Nascimbeni F, Ballestri S, Maurantonio M, Carubbi F, Ratziu V, Lonardo A. Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology. Atherosclerosis 2014; 232:99-109. [PMID: 24401223 DOI: 10.1016/j.atherosclerosis.2013.10.030] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 10/23/2013] [Accepted: 10/24/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Liver regulates lipid metabolism in health and disease states. Nevertheless, the entity of cardiovascular risk (CVR) resulting from dysregulation of lipid metabolism secondary to liver disease is poorly characterized. AIM AND METHODS To review, based on a PubMed literature search, the features and the determinants of serum lipid phenotype and its correlation with hepatic steatosis, insulin resistance (IR) and CVR across the wide spectrum of the most common chronic liver diseases due to different etiologies. RESULTS Alcoholic liver disease (ALD) is associated with steatosis, IR and a typical lipid profile. The relationship between alcohol intake, incident type 2 diabetes (T2D) and CVR describes a J-shaped curve. Non-alcoholic fatty liver disease (NAFLD), and probably nonalcoholic steatohepatitis (NASH) in particular, is associated with IR, atherogenic dyslipidemia and increased CVR independent of traditional risk factors. Moreover, NASH-cirrhosis and T2D contribute to increasing CVR in liver transplant recipients. HBV infection is generally free from IR, steatosis and CVR. HCV-associated dysmetabolic syndrome, featuring steatosis, hypocholesterolemia and IR, appears to be associated with substantially increased CVR. Hyperlipidemia is an almost universal finding in primary biliary cirrhosis, a condition typically spared from steatosis and associated with neither subclinical atherosclerosis nor excess CVR. Finally, little is known on CVR in patients with hepatocellular carcinoma. CONCLUSIONS CVR is increased in ALD, NAFLD and chronic HCV infection, all conditions featuring IR and steatosis. Therefore, irrespective of serum lipid phenotype, hepatic steatosis and IR may be major shared determinants in amplifying CVR in common liver disease due to varying etiology.
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Affiliation(s)
- P Loria
- University of Modena and Reggio Emilia, Italy; Azienda USL MODENA, Italy.
| | | | - F Nascimbeni
- University of Modena and Reggio Emilia, Italy; Azienda USL MODENA, Italy
| | - S Ballestri
- University of Modena and Reggio Emilia, Italy; Azienda USL MODENA, Italy
| | - M Maurantonio
- University of Modena and Reggio Emilia, Italy; Azienda USL MODENA, Italy
| | - F Carubbi
- University of Modena and Reggio Emilia, Italy; Azienda USL MODENA, Italy
| | | | - A Lonardo
- University of Modena and Reggio Emilia, Italy; Azienda USL MODENA, Italy.
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31
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Howell J, Angus P, Gow P. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis 2013; 16:1-16. [PMID: 24372756 DOI: 10.1111/tid.12173] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 06/12/2013] [Accepted: 08/03/2013] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is the most common indication for liver transplantation worldwide; however, recurrence post transplant is almost universal and follows an accelerated course. Around 30% of patients develop aggressive HCV recurrence, leading to rapid fibrosis progression (RFP) and culminating in liver failure and either death or retransplantation. Despite many advances in our knowledge of clinical risks for HCV RFP, we are still unable to accurately predict those most at risk of adverse outcomes, and no clear consensus exists on the best approach to management. This review presents a critical overview of clinical factors shown to influence the course of HCV recurrence post transplant, with particular focus on recent data identifying the important role of metabolic factors, such as insulin resistance, in HCV recurrence. Emerging data for genetic markers of HCV recurrence and their usefulness for predicting adverse outcomes will also be explored.
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Affiliation(s)
- J Howell
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia
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Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis 2013; 45 Suppl 5:S349-54. [PMID: 24091115 DOI: 10.1016/j.dld.2013.07.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 07/01/2013] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus infection is a leading cause of end stage liver disease and one of the leading indications for liver transplantation. Furthermore, hepatitis C virus recurrence is universal post-transplant leading to decreased graft and patient survival. Recurrent disease related to hepatitis C virus can lead to between 20 and 30% of patients developing recurrent cirrhosis within 5 years. Treatment options with antiviral therapy are limited and are associated with a significant side-effect profile, suboptimal tolerability and inferior response rates. Attention has therefore turned to strategies that can reduce hepatitis C virus recurrence rates post-transplant. Approximately only 30% of patients will achieve a sustained virologic response with current therapy with pegylated interferon and ribavirin. Successful hepatitis C virus eradication is the only factor associated with improved graft and patient survival post liver transplantation. Here we provide an overview of antiviral treatment in patients in the transplant arena and the potential opportunities and challenges with the introduction of new directly acting antivirals in G1 patients.
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Affiliation(s)
- Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK.
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Harada N, Sugawara Y, Akamatsu N, Kaneko J, Tamura S, Aoki T, Sakamoto Y, Hasegawa K, Yamashiki N, Kokudo N. New-onset diabetes mellitus developing in Asian adult living donor liver transplant recipients: a single-center experience. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2013; 20:634-638. [PMID: 23564193 DOI: 10.1007/s00534-013-0602-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND New-onset diabetes mellitus (NODM) after liver transplantation is a common complication with a potentially negative impact on patient outcome. METHODS To evaluate the incidence of NODM and its impact on Asian adult living donor liver transplant (LDLT) recipients, we investigated 369 adult LDLT cases in our institute. RESULTS Preoperative diabetes mellitus (DM) was diagnosed in 38 (9 %) patients. NODM was observed in 128/331 (38 %) patients, 56 (44 %) with persistent NODM and 72 (56 %) with transient NODM. The mean interval between LDLT and the development of NODM was 0.6 ± 1.8 (range 0-1.4) months. Multivariate analyssis revealed that older age, being male and having a higher body mass index were independent risk factors among recipients for developing NODM, while hepatitis C virus infection was not a significant risk factor, and DM had no impact on patient outcome. CONCLUSIONS Although the long-term effect of DM on outcome remains to be investigated, the presence of DM after liver transplant, whether it was NODM or preexisting DM, had no impact on LDLT recipients' outcomes in mid-term.
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Affiliation(s)
- Nobuhiro Harada
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Satapathy SK, Nair S, Vanatta JM. Nonalcoholic fatty liver disease following liver transplantation. Hepatol Int 2013; 7:400-412. [PMID: 26201774 DOI: 10.1007/s12072-013-9434-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Accepted: 03/16/2013] [Indexed: 12/17/2022]
Abstract
Post-transplant, nonalcoholic hepatic steatosis and steatohepatitis are increasingly recognized as a complication of liver transplantation, and the progression of the latter through fibrosis to cirrhosis has been clearly shown. Non-alcoholic steatohepatitis (NASH) is independently associated with an increased risk of death from cardiovascular and liver diseases. While optimal therapy is not yet available in the post-liver transplant setting, knowledge gained in the therapy of NASH in the non-transplant setting can be used to design therapeutic interventions. In addition, early recognition with protocol liver biopsies and an effective preventive strategy by modifying known risk factors implicated in the recurrence of NASH would be the most effective way to curtail the progression of NASH before an effective treatment can be found. Additional rigorous research aimed at elucidating the pathogenesis, natural history, and selection of immunosuppressants for NASH is clearly warranted.
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Affiliation(s)
- Sanjaya Kumar Satapathy
- Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Science Center, 1211 Union Avenue, Suite 340, Memphis, TN, 38104, USA.
| | - Satheesh Nair
- Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Science Center, 1211 Union Avenue, Suite 340, Memphis, TN, 38104, USA
| | - Jason M Vanatta
- Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Science Center, 1211 Union Avenue, Suite 340, Memphis, TN, 38104, USA
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35
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Ciria R, Pleguezuelo M, Khorsandi SE, Davila D, Suddle A, Vilca-Melendez H, Rufian S, de la Mata M, Briceño J, Cillero PL, Heaton N. Strategies to reduce hepatitis C virus recurrence after liver transplantation. World J Hepatol 2013; 5:237-50. [PMID: 23717735 PMCID: PMC3664282 DOI: 10.4254/wjh.v5.i5.237] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2012] [Revised: 11/16/2012] [Accepted: 12/01/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.
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Affiliation(s)
- Ruben Ciria
- Ruben Ciria, Shirin Elizabeth Khorsandi, Diego Davila, Abid Suddle, Hector Vilca-Melendez, Nigel Heaton, Institute of Liver Studies, King's College Hospital, London SE5 9RS, United Kingdom
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36
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Manousou P, Burroughs AK, Tsochatzis E, Isgro G, Hall A, Green A, Calvaruso V, Ma GL, Gale J, Burgess G, O'Beirne J, Patch D, Thorburn D, Leandro G, Dhillon AP, Dhillon AP. Digital image analysis of collagen assessment of progression of fibrosis in recurrent HCV after liver transplantation. J Hepatol 2013; 58:962-8. [PMID: 23262247 DOI: 10.1016/j.jhep.2012.12.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 11/11/2012] [Accepted: 12/07/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Histological assessment of fibrosis progression is currently performed by staging systems which are not continuous quantitative measurements. We aimed at assessing a quantitative measurement of fibrosis collagen proportionate area (CPA), to evaluate fibrosis progression and compare it to Ishak stage progression. METHODS We studied a consecutive cohort of 155 patients with recurrent HCV hepatitis after liver transplantation (LT), who had liver biopsies at one year and were subsequently evaluated for progression of fibrosis using CPA and Ishak staging, and correlated with clinical decompensation. The upper quartile of distribution of fibrosis rates (difference in CPA or Ishak stage between paired biopsies) defined fast fibrosers. RESULTS Patients had 610 biopsies and a median follow-up of 116 (18-252) months. Decompensation occurred in 29 (18%) patients. Median Ishak stage progression rate was 0.42 units/year: (24 (15%) fast fibrosers). Median CPA fibrosis progression rate was 0.71%/year (36 (23%) fast fibrosers). Clinical decompensation was independently associated by Cox regression only with CPA (p=0.007), with AUROCs of 0.81 (95% CI 0.71-0.91) compared to 0.68 (95% CI 0.56-0.81) for Ishak stage. Fast fibrosis defined by CPA progression was independently associated with histological de novo hepatitis (OR: 3.77), older donor age (OR: 1.03) and non-use/discontinuation of azathioprine before 1 year post-LT (OR: 3.85), whereas when defined by Ishak progression, fast fibrosers was only associated with histological de novo hepatitis. CONCLUSIONS CPA fibrosis progression rate is a better predictor of clinical outcome than progression by Ishak stage. Histological de novo hepatitis, older donor age and non-use/discontinuation of azathioprine are associated with rapid fibrosis progression in recurrent HCV chronic hepatitis after liver transplantation.
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Affiliation(s)
- Pinelopi Manousou
- The Royal Free Sheila Sherlock Liver Centre and Division of Surgery & Interventional Sciences, University College London, UK
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37
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Joshi D, Carey I, Agarwal K. Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients. Aliment Pharmacol Ther 2013; 37:659-71. [PMID: 23432320 DOI: 10.1111/apt.12260] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 12/20/2012] [Accepted: 02/03/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently, the therapeutic landscape with regard to anti-HCV therapy has changed dramatically. The new directly acting anti-virals (DAAs) have demonstrated improved sustained virological response (SVR) compared with pegylated-interferon and ribavirin. AIM To examine and present the latest data with regard to anti-viral therapy in genotype 1 HCV-positive transplant candidates and recipients. METHODS An electronic search using Medline was performed. Search terms included 'HCV, DAA and protease inhibitor' in combination with 'treatment pre-transplantation' and 'treatment post-transplantation'. RESULTS Patients with advanced fibrosis and cirrhosis have inferior SVR rates compared with patients with minimal fibrosis. A low accelerating dose regimen (LADR) of pegylated interferon and ribavirin (PR) appears to be a safe therapeutic option. Side effects also appear to be more pronounced in patients with advanced disease. Data from the large registration studies with triple therapy (boceprevir or telaprevir plus PR) demonstrated improved SVR rates even in patients with advanced disease, although virological relapse rates were highest amongst these patients. In transplant recipients, initial data are being reported on the use of triple therapy, and although no SVR data are available, promising results are accruing. The drug-drug interactions appear to be manageable. Side effects in particular anaemia appear to be markedly increased in the posttransplant setting. CONCLUSIONS The use of the new DAAs in patients with advanced fibrosis/cirrhosis pretransplant and posttransplant appears possible, with manageable side effects and drug-drug interactions, and improved early virological response rates. We recommend that these patients are managed in centres with the appropriate expertise.
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Affiliation(s)
- D Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
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Logge C, Vettorazzi E, Fischer L, Nashan B, Sterneck M. Cost-effectiveness analysis of antiviral treatment in liver transplant recipients with HCV infection. Transpl Int 2013; 26:527-34. [PMID: 23517333 DOI: 10.1111/tri.12085] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2012] [Revised: 07/11/2012] [Accepted: 02/11/2013] [Indexed: 01/21/2023]
Abstract
Within 5-10 years, 20-40% of hepatitis C virus (HCV)-infected liver transplant recipients can be expected to develop cirrhosis. Here, cost-effectiveness of antiviral therapy was assessed. A Markov model was developed to simulate disease progression and calculate outcome and costs of treatment. In the baseline analysis, Peg-IFN/RBV treatment prevented organ loss/death, gained quality-adjusted life-years (QALYs) and undercut the limit of cost-effectiveness of €50 000/QALY with an incremental cost-effectiveness ratio of approximately €40 400/QALY and €21 000/QALY for HCV genotype 1 and 2/3 patients, respectively. Furthermore, sensitivity analysis testing modified model parameters according to extreme data described in the literature confirmed cost-effectiveness for a lower or higher rate of fibrosis progression, increased non-HCV-related mortality, lower limits of utilities, a time horizon of 30 years, and additional costs in the year of death. On the other hand, cost-effectiveness was lost for patients with genotype 1 in case of doubled antiviral or life-time costs or an increased discount rate of 7%. New treatment strategies for HCV genotype 1 infected patients remained on the same level cost-effective, if additional costs did not exceed €10 774 per 10% sustained virologic response gain. We conclude that Peg-IFN/RBV treatment is cost-effective post transplant. This may support treatment decision in individual cases.
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Affiliation(s)
- Christoph Logge
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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39
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Duvoux C, Firpi R, Grazi GL, Levy G, Renner E, Villamil F. Recurrent hepatitis C virus infection post liver transplantation: impact of choice of calcineurin inhibitor. Transpl Int 2013; 26:358-72. [PMID: 23413991 DOI: 10.1111/tri.12065] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 03/23/2012] [Accepted: 12/23/2012] [Indexed: 02/06/2023]
Abstract
Recurrence of hepatitis C virus infection following liver transplantation (LT) for hepatitis C is universal. After LT, hepatitis C is associated with accelerated fibrosis progression and reduced graft and patient survival. Furthermore, responses to antiviral therapy in patients with recurrent hepatitis C virus post-transplant are consistently sub-optimal. Calcineurin inhibitors (CNIs) like cyclosporine A (CsA) and tacrolimus continue to dominate immunosuppressive regimens in this population; however, there is still uncertainty as to whether either offers an advantage in terms of patient outcomes. Although tacrolimus demonstrates improved efficacy in the general LT population, differences have begun to emerge between these agents regarding diabetogenic potential, antiviral activity, and fibrosis progression in patients with hepatitis C. This review critically evaluates the existing literature, providing an overview of the reported differences, concluding that despite conflicting evidence, a potential benefit of CsA in patients with hepatitis C is supported by the data and warrants further investigation. Future studies examining the role of CNIs in hepatitis C virus-positive LT recipients are required to accurately examine the effects of CNIs on outcomes such as fibrosis progression, survival, and effects on response to antiviral therapy, to provide robust information that allows clinicians to make an informed choice concerning which CNI is best for their patients.
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Akamatsu N, Sugawara Y. Living-donor liver transplantation and hepatitis C. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2013; 2013:985972. [PMID: 23401640 PMCID: PMC3564275 DOI: 10.1155/2013/985972] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 01/01/2013] [Indexed: 12/19/2022]
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompression. In areas with low deceased-donor organ availability like Japan, living-donor liver transplantation (LDLT) is similarly indicated for HCV cirrhosis as deceased-donor liver transplantation (DDLT) in Western countries and accepted as an established treatment for HCV-cirrhosis, and the results are equivalent to those of DDLT. To prevent graft failure due to recurrent hepatitis C, antiviral treatment with pegylated-interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. In contrast to DDLT, many Japanese LDLT centers have reported modified treatment regimens as best efforts to secure first graft, such as aggressive preemptive antiviral treatment, escalation of dosages, and elongation of treatment duration.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-cho, Kamoda, Kawagoe, Saitama 350-8550, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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41
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Brennan DC, Aguado JM, Potena L, Jardine AG, Legendre C, Säemann MD, Mueller NJ, Merville P, Emery V, Nashan B. Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence and potential mechanisms. Rev Med Virol 2012; 23:97-125. [PMID: 23165654 DOI: 10.1002/rmv.1733] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Revised: 09/07/2012] [Accepted: 09/20/2012] [Indexed: 12/11/2022]
Abstract
Recent evidence suggesting a potential anti-CMV effect of mTORis is of great interest to the transplant community. However, the concept of an immunosuppressant with antiviral properties is not new, with many accounts of the antiviral properties of several agents over the years. Despite these reports, to date, there has been little effort to collate the evidence into a fuller picture. This manuscript was developed to gather the evidence of antiviral activity of the agents that comprise a typical immunosuppressive regimen against viruses that commonly reactivate following transplant (HHV1 and 2, VZV, EBV, CMV and HHV6, 7, and 8, HCV, HBV, BKV, HIV, HPV, and parvovirus). Appropriate immunosuppressive regimens posttransplant that avoid acute rejection while reducing risk of viral reactivation are also reviewed. The existing literature was disparate in nature, although indicating a possible stimulatory effect of tacrolimus on BKV, potentiation of viral reactivation by steroids, and a potential advantage of mammalian target of rapamycin (mTOR) inhibition in several viral infections, including BKV, HPV, and several herpesviruses.
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42
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Manzia TM, Angelico R, Toti L, Lai Q, Ciano P, Angelico M, Tisone G. Hepatitis C virus recurrence and immunosuppression-free state after liver transplantation. Expert Rev Clin Immunol 2012; 8:635-644. [PMID: 23078061 DOI: 10.1586/eci.12.66] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
HCV-related disease is the most common indication for liver transplantation (LT). HCV recurrence, which is almost universal, has a significant impact on patient and graft survival after LT and still represents a great unsolved issue for the liver transplant community. Several treatment strategies have been proposed. Since antiviral therapy has limited efficacy and can be administrated only in selected transplant recipients and additionally that immunosuppressive drugs have a negative impact on HCV re-infection, the achievement of an immunosuppression-free state after LT could play a central role in the avoidance of rapid HCV recurrence.
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43
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Garcia-Saenz-de-Sicilia M, Mukherjee S. The adverse pharmacology of calcineurin inhibitors and their impact on hepatitis C recurrence after liver transplantation: implications for clinical practice. Expert Rev Clin Pharmacol 2012; 5:587-593. [PMID: 23121280 DOI: 10.1586/ecp.12.49] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Abstract
Calcineurin inhibitors are widely used as maintenance immunosuppressants in solid-organ transplantation to minimize the risk of allograft rejection. Although the use of these agents has transformed the outcomes for patient and graft survival, this has come at a cost, notably the well-known adverse events of nephrotoxicity and metabolic abnormalities, to name a few. Over the last decade, tremendous interest has also focused on the impact of these medications on the replication of hepatitis C virus (HCV), with cyclosporine in particular having a negative effect on viral replication in vitro. Although small retrospective studies suggested that there may be a beneficial effect with cyclosporine on the progression of recurrent HCV and response to interferon, these findings have not been validated in several well-designed randomized controlled trial studies. The authors will review the pharmacology and pharmacokinetics of these well-known drugs and discuss the impact of these medications on the natural history of HCV recurrence after liver transplantation.
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44
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Akamatsu N, Sugawara Y. Liver transplantation and hepatitis C. Int J Hepatol 2012; 2012:686135. [PMID: 22900194 PMCID: PMC3412106 DOI: 10.1155/2012/686135] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 05/21/2012] [Indexed: 02/07/2023] Open
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompensation. The use of poor quality organs, particularly from older donors, has a highly negative impact on the severity of recurrence and patient/graft survival. Although immunosuppressive regimens have a considerable impact on the outcome, the optimal regimen after liver transplantation for HCV-infected patients remains unclear. Disease progression monitoring with protocol biopsy and new noninvasive methods is essential for predicting patient/graft outcome and starting antiviral treatment with the appropriate timing. Antiviral treatment with pegylated interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. Living-donor liver transplantation is now widely accepted as an established treatment for HCV cirrhosis and the results are equivalent to those of deceased donor liver transplantation.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-cho, Kamoda, Kawagoe, Saitama 350-8550, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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45
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Germani G, Tsochatzis E, Papastergiou V, Burroughs AK. HCV in liver transplantation. Semin Immunopathol 2012; 35:101-10. [PMID: 22829333 DOI: 10.1007/s00281-012-0329-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 07/01/2012] [Indexed: 12/23/2022]
Abstract
HCV-related cirrhosis represents the leading indication for liver transplantation in the Western countries. HCV reinfection after liver transplantation occurs in virtually all patients transplanted for HCV-related liver disease Histological evidence of chronic HCV infection develops in 50 to 90 % of patients by 12 months after liver transplantation, and cirrhosis occurs in about 20 % of patients within 5 years after transplant. Several studies have evaluated host, viral, and transplant-related factors that might be associated with the severity of HCV recurrence. Among host factors, immunosuppression is one of the major factors that accounts for accelerated HCV recurrence and it has been an area of extensive research and controversy. Donor age, steatosis, and immunogenetic factors are also relevant in determining the outcome in patients transplanted for HCV-related cirrhosis. A major step to prevent complications of HCV recurrence related to the rapid fibrosis is the posttransplant antiviral treatment. Two strategies have been tried: pre-emptive or other strategies as soon as possible after liver transplantation or elective therapy once there is histological evidence of recurrent hepatitis C. Retransplantation due to graft failure from recurrent hepatitis C is rarely an option in the era of organ shortage as it is associated with poor outcome, but many case needs to be considered early in the evolution of disease. New antivirals may change the outcome dramatically of patients transplanted for HCV cirrhosis.
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Affiliation(s)
- Giacomo Germani
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital and UCL, London, UK
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46
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Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter? J Hepatol 2012; 56 Suppl 1:S56-65. [PMID: 22300466 DOI: 10.1016/s0168-8278(12)60007-5] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Given the pandemic spread of the hepatitis C virus (HCV) infection and the metabolic syndrome (MS), the burden of their interaction is a major public health issue, bound to increase in the near term. A better appreciation of the clinical consequences of the relationship between HCV and MS is needed, not only due to their potential synergism on liver disease severity, but also because of the multifaceted interactions between HCV and glucose and lipid metabolism. HCV infection per se does not carry an increased risk of MS, but is able to perturb glucose homeostasis through several direct and indirect mechanisms, leading to both hepatic and extrahepatic insulin resistance. This translates into accelerated liver disease progression (including the development of hepatocellular carcinoma), reduced response to antivirals and, in susceptible individuals, increased risk of developing full-blown type 2 diabetes. HCV may also cause hepatic steatosis, especially in patients infected with genotype 3, although the clinical impact of viral steatosis is debated. Possibly as a result of HCV-induced insulin resistance, and despite a paradoxically favourable lipid profile, the cardiovascular risk is moderately increased in chronic hepatitis C. In addition, the interaction with the MS further increases the risks of cirrhosis, hepatocellular carcinoma, diabetes, and cardiovascular events. Thus, targeted lifestyle and pharmacological measures are urgently warranted in chronic hepatitis C with metabolic alterations.
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47
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Berenguer M, Charco R, Manuel Pascasio J, Ignacio Herrero J. Spanish society of liver transplantation (SETH) consensus recommendations on hepatitis C virus and liver transplantation. Liver Int 2012; 32:712-31. [PMID: 22221843 DOI: 10.1111/j.1478-3231.2011.02731.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 11/23/2011] [Indexed: 02/06/2023]
Abstract
In November 2010, the Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation.
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Affiliation(s)
- Marina Berenguer
- Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH)
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48
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Crespo G, Mariño Z, Navasa M, Forns X. Viral hepatitis in liver transplantation. Gastroenterology 2012; 142:1373-1383.e1. [PMID: 22537446 DOI: 10.1053/j.gastro.2012.02.011] [Citation(s) in RCA: 144] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2011] [Revised: 01/30/2012] [Accepted: 02/08/2012] [Indexed: 12/11/2022]
Abstract
Liver transplantation is the only alternative for patients with end-stage liver disease. Viral hepatitis B and C are among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent indication for liver transplantation. Hepatitis B virus immunoglobulin and nucleot(s)ide analogues have facilitated the management of patients with hepatitis B who have received liver transplants and resulted in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Current therapeutic approaches are far from optimal, because sustained virologic responses are only achieved in one-third of treated patients, and adverse effects are common and severe. However, the rapid development of direct-acting antivirals against hepatitis C virus will change the management of this disease and in a few years prevent graft infection with this virus.
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Affiliation(s)
- Gonzalo Crespo
- Liver Unit, Hospital Clinic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
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49
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Sheiner P, Rochon C. Recurrent Hepatitis C After Liver Transplantation. ACTA ACUST UNITED AC 2012; 79:190-8. [DOI: 10.1002/msj.21300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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50
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Gane EJ. Diabetes mellitus following liver transplantation in patients with hepatitis C virus: risks and consequences. Am J Transplant 2012; 12:531-8. [PMID: 22123496 DOI: 10.1111/j.1600-6143.2011.03854.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recurrent hepatitis C virus (HCV) infection of the allograft occurs universally following liver transplantation. Longitudinal natural history studies have identified several pre- and posttransplant factors associated with more rapid fibrosis progression, including baseline host and viral factors, donor factors and posttransplant immunosuppression effects, such as metabolic syndrome. Evidence accumulated over the past two decades indicates that HCV has metabolic associations, in particular insulin resistance and diabetes mellitus. Approximately half of HCV-positive liver transplant recipients develop posttransplant diabetes mellitus (PTDM), which is associated with accelerated fibrosis progression and poorer graft and patient survival outcomes. This review summarizes the risks and consequences of insulin resistance and PTDM in HCV-positive liver transplant recipients. Risk for developing PTDM is one factor that should be considered when choosing the primary immunosuppressive regimen following liver transplantation. Comparative studies suggest that cyclosporine A-based immunosuppression may provide improved responses to antiviral therapy and reduced incidence of PTDM compared with tacrolimus-based immunosuppression. Addressing insulin resistance and PTDM in HCV-positive liver transplant recipients may have the potential to slow HCV complications and improve survival outcomes.
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Affiliation(s)
- E J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
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