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• W2073202578 abstract "BMI, body mass index; CNI, calcineurin inhibitor; DL, dyslipidemia; HCV, hepatitis C virus; LT, liver transplantation; MS, metabolic syndrome; N/A, not applicable; NR, not reported; PTMS, posttransplant metabolic syndrome. The success of liver transplantation (LT) is one of the great achievements of modern medicine. Advances in medical management and surgical techniques have resulted in sequential improvements in outcomes, with overall 5-year survival rates approaching 70% (http://www.unos.org). The last 2 decades have witnessed an evolution in the causes of death and graft loss after LT. Perhaps most impressively, step wise improvements in the efficacy and tolerability of immunosuppression have reduced chronic rejection to a relatively minor cause of graft loss.1 As the frequency of immunological causes of graft loss and mortality has declined, other causes have become increasingly important. Cardiovascular disease, renal insufficiency, and malignancies are among the emerging important causes of mortality and graft loss after LT. Metabolic syndrome (MS) is a common thread of risk for each of these. The prevalence and etiology of posttransplant metabolic syndrome (PTMS) are thus of increasing interest to the transplant community. The report by Laish et al.2 in this issue of Liver Transplantation is very welcome in this regard. Laish et al. studied the records of 252 transplant recipients (mean age = 54.5 ± 2.8 years, proportion of men = 57.9%) for pretransplant and posttransplant clinical and laboratory parameters of MS. Among the primary observations was the fact that rates of obesity [body mass index (BMI) > 30 kg/m2], hypertriglyceridemia (>150 mg/dL), high-density lipoprotein cholesterol levels less than 40 (men) or 50 mg/dL (women), hypertension, and diabetes were significantly higher after transplantation than before transplantation. Most striking, however, was the finding that PTMS was diagnosed in 5.4% of patients before transplantation and in 51.9% afterward. By and large, transplant recipients with PTMS had risk profiles similar to those of nontransplant patients: they were older and heavier than patients without PTMS. PTMS conveyed a greater than 3-fold increase in the relative risk of major vascular and cardiac events. Significant independent predictors of PTMS included age (odds ratio = 1.04) and pretransplant nonalcoholic fatty liver disease (odds ratio = 3.4). How do these findings compare to what is known about MS and LT? The prevalence of MS in the West is approximately 34%, and increases with advancing age and BMI.3 The prevalence of MS in patients with cirrhosis and end-stage liver disease is not well established and varies with the etiology of the underlying liver disease, with an increased prevalence reported among patients with cryptogenic cirrhosis.4 The associations of pretransplantation cryptogenic cirrhosis and hepatitis C virus (HCV) infection as etiologies of liver disease with the development of PTMS may not be entirely unexpected because both of these conditions are associated with MS in the nontransplant setting. In the same vein, an increase in the relative risk of mortality and heart disease in men with MS in a nontransplant setting has been well described5 and appears to be similar to that reported by Laish et al.2 What is striking in Laish et al.'s report is the relatively short period of time in which MS and subsequent complications develop after LT. The diagnosis of MS is typically defined by a set of variables including 3 or more of the following: increased waist circumference, elevated fasting serum triglyceride level, elevated blood pressure, abnormally high fasting serum glucose level, high BMI, and low high-density lipoprotein cholesterol level. With these criteria, the prevalence of MS in patients awaiting LT is likely to be low because patients with cirrhosis are frequently malnourished and may have lower triglyceride and high-density lipoprotein cholesterol levels,6 abnormal glucose metabolism, and systemic vasodilatation leading to lower arterial blood pressures.7 The increase in the prevalence of MS after LT that was observed by Laish et al. might conceivably reflect the effects of restoring liver and vascular function, compounded by the effects of immunosuppression, on the features of PTMS. In addition, the authors used modified criteria [BMI > 30 kg/m2 or waist circumference > 102 (men) or 88 cm (women)] so that they could include all their recipients from a retrospective database. Both BMI and waist circumference can be inappropriately increased by ascites in the pretransplant setting; this limitation is acknowledged by the authors. It is likely that the increase in the prevalence of MS after LT has been underestimated. The relationship between PTMS and major vascular complications is difficult to determine because of the retrospective nature of the study. A prospectively designed study would more reliably address these issues. Nonetheless, an important inference from the current study is the rapid development of MS with subsequent major vascular events after LT. An increased relative risk of ischemic cardiac events and cardiovascular death has been reported in LT recipients in comparison with an age-matched and sex-matched general population.8-12 Perhaps surprisingly, Laish et al.2 did not find an association between PTMS and increased cardiovascular mortality; they explained that this might be due to the relatively short duration of follow-up. The lack of an association of PTMS with cardiovascular mortality is inconclusive. What are the practical implications of the study by Laish et al.?2 Caveats aside, PTMS is likely to be causatively associated with posttransplant morbidity and mortality. It is likely that aspects of PTMS are modifiable, just as they are in the nontransplant setting. Screening, prevention, and treatment strategies (eg, nutritional counseling, lipid-lowering therapy, optimal control of hypertension, and immunosuppressants less likely to cause PTMS) are needed. PTMS screening, prevention, and treatment might be particularly important in patients with HCV. An association of MS and fibrosis progression in patients with recurrent hepatitis C has been reported.13 Insulin resistance and diabetes are intricately linked to hepatitis C and are established risk factors for fibrosis progression in patients with HCV infection.13-15 Insulin resistance is also associated with the diminished efficacy of antiviral therapy16 and the development of new-onset diabetes.17 HCV infection has complex effects on lipid metabolism that result in reduced serum lipid levels and paradoxically increased hepatic lipid content.18 The eradication of HCV can result in increased serum lipid levels.19 Steroid use after LT has been associated with diabetes, hypertension, hyperlipidemia, obesity, and HCV recurrence.20 Tacrolimus may be toxic to beta cells and has been significantly associated with the development of diabetes mellitus.21 In addition to increasing oxidative stress and lipid peroxidation, calcineurin inhibitors (CNIs) in general can cause hypertension as well as acute and chronic nephrotoxicity. Sirolimus, in addition to being associated with excess death rates, infections, and hepatic artery thrombosis, is a potent inducer of dyslipidemia. In lieu of randomized studies to determine optimal immunosuppression, steroid avoidance and minimization of calcineurin inhibition should be considered in recipients with PTMS. There is increasing evidence that steroid avoidance, minimization of CNIs, or both are safe and, moreover, reduce the frequency of metabolic complications post-LT.22 Although Laish et al.2 did not find a significant association of PTMS with the choice of immunosuppression, the methodological approach, which included a small number of study subjects, raises the possibility of a β error. We summarize in Tables 1 and 2 the published studies specifically examining the development of MS or its components in the posttransplant period and its relationship to pretransplant and posttransplant factors. The most significant effect of the study of Laish et al.2 and the studies preceding it (Tables 1 and 2) should be to highlight the urgent need for studies of the impact of more aggressive recourse to early diagnosis and sustained implementation of interventions for the prevention, diagnosis, and treatment of PTMS. Unfortunately, the management of PTMS after LT has been not well defined and is largely based on experience in the nontransplant setting. The management of weight gain after transplantation is fraught with the same difficulties found in the general population. The only drug investigated for the management of weight loss is orlistat (tetrahydrolipstatin), a reversible inhibitor of pancreatic lipase, which appears to be of limited efficacy and may interfere with immunosuppression absorption.32 Bariatric surgery before transplantation is a difficult proposition in patients with portal hypertension but may be an option in carefully selected transplant recipients and patients with portal hypertension.33 The goals of treatment of post-LT diabetes should not be different from those for the general population, and the target glycosylated hemoglobin level should be <7%.34 Thiazolidinediones are generally well tolerated and may temporarily improve features of post-LT nonalcoholic fatty liver disease35, 36 but cause weight gain and may be associated with hepatotoxicity37 and cardiotoxicity.38 Transplant recipients with diabetes should be presumed to have the same long-term risks of diabetic complications that the nontransplant population has, and consideration should be given to annual retinal examinations, urinary protein screening, and foot care. Statins have been used commonly in solid organ transplant recipients for decades and are well tolerated.39 A small reduction in cyclosporine levels during statin therapy has been suggested. Similar effects have been seen with tacrolimus and statins.40 Reasonable starting doses for post-LT hypercholesterolemia include 40 mg/day for simvastatin, 40 mg/day for atorvastatin, and 20 mg/day for pravastatin. It is important to remember that the effects of statin therapy are additive to those of a controlled diet (eg, a Mediterranean diet rich in omega 3 fatty acids, fruits, vegetables, and dietary fiber). Isolated hypertriglyceridemia responds to fish oil (omega 3), which has very few side effects and drug interactions.41 Alternative agents include the fibric acid derivatives (gemfibrozil, clofibrate, and fenofibrate), which are generally well tolerated but have occasionally been associated with muscle injury, particularly in combination with statins. Fibrates are highly protein-bound and cytochrome P450–metabolized, and there is some evidence of a mild effect of increasing CNI levels.42 Ezetimibe, an agent that inhibits the enterohepatic recirculation of lipids and has minimal cytochrome P450 metabolism, was shown to be well tolerated and effective when it was used in combination with statin drugs in a small retrospective study of LT patients.43 There is a theoretical concern of hepatotoxicity for ezetimibe, particularly when it is used with statins; thus, caution should be exercised until more data are available for LT recipients. Blood pressure goals are not established specifically for LT patients, but <130/80 is a suggested goal for all patients with diabetes, chronic renal disease, or known cardiovascular disease (or a risk for cardiovascular disease); these patients would encompass the majority of posttransplant patients.44 Up to 30% of transplant recipients require 2 or more antihypertensives to achieve these goals.10 Because of the contribution of renal arteriolar vasoconstriction to post-LT hypertension, calcium channel blockers (amlodipine, isradipine, and felodipine) are often used as first-line agents. Nifedipine is an inhibitor of intestinal cytochrome P450, predictably increases CNI levels with a potential for CNI toxicity, and may cause leg edema. Second-line therapies include specific beta-blockers (nonspecific beta-blockers may reduce portal blood flow), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and loop diuretics.45 Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may exacerbate CNI-induced hyperkalemia but also may provide antifibrotic properties for patients with a high risk of liver fibrosis (eg, recurrent hepatitis C or steatohepatitis) and possibly protect against calcineurin-induced renal injury.46 Thiazides and other diuretics are problematic in transplant recipients because of the potentiation of electrolyte abnormalities. In summary, the study by Laish et al.2 provides new evidence for the increasingly high prevalence and important associated outcomes of PTMS. Well-designed, prospective studies are needed to validate these new observations and to establish optimal strategies for the diagnosis, prevention, and management of PTMS." @default.
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• W2073202578 title "Posttransplant metabolic syndrome: New evidence of an epidemic and recommendations for management" @default.
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• W2073202578 doi "https://doi.org/10.1002/lt.22222" @default.
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