Risk factors of metabolic syndrome after liver transplantation

Hangzhou, China

Risk factors of metabolic syndrome after liver transplantation

Jun Zheng and Wei-Lin Wang

Hangzhou, China

BACKGROUND: Liver transplantation is a treatment of choice for both acute and chronic liver failure. Accompanied with the increase of long-term survival rates of recipients, metabolic syndrome and its individual components, including obesity, hyperglycemia, hypertension and hyperlipidemia, have become more frequent post liver transplantation. Here we reviewed the literature concerning the risk factors for the development of metabolic complications in liver recipients.

DATA SOURCES: PubMed was searched for English-language articles published from January 2000 to June 2015. The search criteria focused on risk factors for metabolic syndrome after liver transplantation.

RESULT: The risk factors of metabolic syndrome in liver recipients include older age, obesity, pre-transplantation diabetes mellitus, hepatitis C virus infection, certain genetic polymorphisms and the use of immunosuppressive drugs.

CONCLUSION: Active intervention of the risk factors will reduce the occurrence rate of metabolic syndrome after liver transplantation and improve the recipients' quality of life.

(Hepatobiliary Pancreat Dis Int 2015;14:582-587)

liver transplantation;

risk factors;

hypertension;

hyperlipidemia;

diabetes mellitus

Introduction

Liver transplantation (LT) has been accepted as the most effective treatment for end-stage liver disease for more than two decades.[1]There are now more than 250 LT centers worldwide. Pooled research data suggest that the 1-, 5- and 10-year survival rates after LT are 90%, 80% and 60%, respectively.[2-4]A total of 63% mortalities are liver function unrelated.[5]Complications following LT significantly affect the quality of life in longterm survivors. Metabolic syndrome (MS) is the most common complication after LT, with an incidence of 50%-60%. The incidences of diabetes mellitus (DM), hypertension and hyperlipidemia are 10%-64%, 40%-85% and 40%-66%, respectively. MS is an established risk factor for atherosclerosis and cardiovascular disease which result in high mortality and poor quality of life.

The National Cholesterol Education Program Adult Treatment Panel III criteria are widely accepted for the diagnosis of MS.[6,7]Components of MS include obesity, hyperglycemia, hypertension and hyperlipidemia (Table 1).[8]Other organizations that have published diagnostic criteria are the International Diabetes Federation and the Japan Society for the Study of Obesity. There have been a number of studies on the prevalence of and risk factors for the individual components of MS in living donor liver transplant recipients.[9-11]It appears that the presence of underlying disease states, obesity, older age and certain genetic polymorphisms in the living donor are risk factors for the development of MS in recipients.[12]In addition, treatments given to the recipient, including immunosuppressive drugs, corticosteroids, calcineurin inhibitors (CNIs) and the mammalian target of rapamycin inhibitor (mTORi), are implicated in the development of hyperglycemia, hypertension and hyperlipidemia (Table 2).[8,12-16]

The present review was to categorize the MS, the risk factors and the aspects that the physicians need to pay attention in practice.

Table 1. Criteria for the diagnosis of metabolic syndrome

Table 2. Adverse effects of immunosuppressive drugs on metabolic diseases post liver transplantation

Post LT diabetes mellitus (PTDM)

Fifteen percent of LT patients develop DM. Patients with PTDM have higher morbidity rates than those with DM in the non-liver transplant population.[17,18]PTDM is a risk factor for other diseases, including cardiovascular disease and postoperative infection.

PTDM was categorized as transient and persistent PTDM.[19]Among the 74 patients with PTDM in Ahn and colleagues' analysis,[19]42 (56.8%) showed transient PTDM, while 32 (43.2%) showed persistent one. The mechanism underlying PTDM is not clear; the disturbed carbohydrate metabolism is common immediately after LT. Other risk factors include: male gender; high body mass index; positive family history; hepatitis C virus (HCV) infection; age; drugs including corticosteroids, immunosuppressive agents, CNIs and rapamycin;[17]and gene polymorphisms.

Many publications have demonstrated that age is an independent risk factor for metabolic derangements after transplantation.[20-22]Age ＞45 years is a risk factor for abnormal glucose metabolism [odds ratio (OR) 1.164; 95% confidence intervals (CI): 1.164-3.112], and the effect can persist for up to 3 years post LT. Obesity is closely related to glucose metabolism; research has shown that obesity is a factor associated with disturbed carbohydrate metabolism after transplantation.[21]A meta-analysis of 4580 patients showed that the average pre-transplant body mass index was higher in patients with PTDM than in those without PTDM.[22]The same meta-analysis also showed that male gender was an independent risk factor. Family history of DM significantly increases the risk of PTDM.

There is a relationship between HCV infection and DM in patients with liver disease.[23]Shintani et al[24]proposed that this may be a consequence of a direct effect of the virus on insulin signaling, whereas Petitet al[25]did not verify this notion because there was no correlation between HCV viral load and homeostasis model assessment of insulin resistance (HOMA-IR) of β-cell function. Patients with the combination of post transplantation MS (PTMS) and non-alcoholic fatty liver disease caused by HCV infection are at high risk of progressive liver fibrosis, which itself can alter glucose metabolism.

Immunosuppressive medication is a major risk factor of PTDM. The pro-diabetic effect of corticosteroids is well-known. Corticosteroids cause insulin resistance and enhance gluconeogenesis.[26]High doses of corticosteroids are used in the early phase post transplantation, but whenever possible they should be rapidly tapered. CNIs are also associated with PTDM. The pooled results of 10 studies showed that tacrolimus (TAC) based immunosuppressant therapy is, when compared to that based upon cyclosporine A (CSA), an independent risk factor for the development of PTDM (OR=1.34; 95% CI: 1.03-1.76).[22]It is important to consider this when planning the postoperative immunosuppressive regimen. There is also considerable evidence that appropriately minimizing the use of CNIs improves long-term outcomes without compromizing graft survival.[27-29]Plasma concentration of TAC in excess of 10 ng/mL is an independent risk factor of PTDM.[30]

Within the last five years, scientists found that polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene in liver transplant donors are an independent risk factor of PTDM.[30]The TCF7L2 protein is important in the regulation of cell proliferation and differentiation, including comprising the islets of Langerhans and beta cells,[31]with consequent effects on insulin secretion.

Although the mechanisms and risk factors of PTDM are still not clear, careful use of TAC and corticosteroidsreduce the likelihood of PTDM. Paying attention to the risk factors in individual patient helps identifying the potential patients of PTDM and these patients can be benefited from early interventions. hypertension post LT by careful consideration of the known risk factors. Attention should be paid to ensure that the patient eats a low salt diet, controls weight if appropriate, and appropriately adjusts the immunosuppressive drugs.

Post LT hypertension

Hypertension is an important factor affecting recipient survival. Hypertension is very common (50%-100%) in liver recipients.[32-36]The diagnostic criteria are the same as those universally recognized.

Hypertension develops in the first 6 months after LT as a consequence of systemic vasoconstriction, elevation in plasma endothelin-1 concentrations, and increases in arterial stiffness.[37]There is also a report of hypertension manifested as an increase in blood pressure from 98/60 mmHg to 170/108 mmHg after LT. The pathogenesis of LT-related hypertension is vasoconstriction leading to elevated systemic and renal vascular resistances.[38]

Immunosuppressive medication, particularly CNIs and corticosteroids, plays an important part in the development of hypertension post LT. The primary mechanism of CNI induced hypertension is arterial vasoconstriction with magnification of hemodynamic changes, leading to increased systemic vascular resistance. The effect of vasoconstriction in the kidney is sodium retention and thus, both plasma volume expansion and increased peripheral resistance coexist. It has been reported that the rate of hypertension in patients on TAC may be lower than that in those on CSA during the first year after LT.[34]However, the evidence is conflicting.[39,40]One possible explanation for this is that the dose of steroids was higher in patients treated with CSA than in those treated with TAC. Corticosteroids are considered an essential element of the early post LT immunosuppressive regimen. However, they affect mineralocorticoid metabolism, and cause sodium retention through the renin-angiotensinaldosterone system.

The etiology of hypertension after LT is complicated. It is influenced by body mass index, the occurrence of hyperglycemia following LT, and age. Several studies[35-37]have shown that a body mass index ＞30 kg/m2significantly increases the risk of hypertension pre and post LT. MS has statistical significance in affecting blood pressure before and after LT.[16]Those with high fasting blood glucose levels have a higher prevalence of hypertension 12 months later. Multivariate analysis showed that older age is a risk factor for hypertension after LT. In one study, chronic sympathetic over activity with vasoconstriction and increased sodium sensitivity was found, whether or not patients were on CNIs.[41]

It is relatively straightforward to reduce the risk of

Post LT hyperlipidemia

Hyperlipidemia post LT is not unusual. Its incidence is estimated to be 45%-69%.[42,43]Known risk factors for its development are increased nutrient intake; age; body weight; DM; renal dysfunction; and the use of immunosuppressive drugs, including steroids, CSA and TAC.[44]Hyperlipidemia has a significant impact on the risk of cardiovascular disease post LT and therefore, early recognition is important.

Post-transplant studies have shown that the immunosuppressant regimen is an important determinant for the development of dyslipidemia. The incidence of both hyperlipidemia and hypertriglyceridemia is higher in patients treated with CSA than those with TAC; 14% vs 5% and 49% vs 17%, respectively.[45-49]This may be a consequence of the inhibition of 27-oxycholesterol, with activation of a number of key enzymes involved in cholesterol synthesis leading to hypercholesterolemia.[50]Long-term use of corticosteroids is also associated with the development of hyperlipidemia.[51,52]Steroid-free or sparing immunosuppressant regimens reduce hypertriglyceridemia.[53]However, Neff et al[54]did not get the same results. Another immunosuppressant, sirolimus, is also implicated in the development of dyslipidemia, with a reported incidence as high as 55%.[55]The risk of hyperlipidemia in patients treated with sirolimus was higher than in those with corticosteroids.[34]The mechanism appears to involve changes in the insulin signaling pathway leading to increased triglyceride production and secretion.[56]

Recent research linked polymorphisms of the low density lipoprotein receptor (LDLR) gene in the donor to hyperlipidemia in the recipient.[57]This demonstrates the possibility of transmitting pathogenic mutations of the LDLR gene from donor to recipient.[58,59]

Diet plays an important part in the management of post-transplant hyperlipidemia; this has been appreciated for decades.[60]A study involving 85 LT patients treated with standard triple immunosuppression found that the following factors were predictive of hypercholesterolemia in univariate analysis: female gender, pretransplantation cholesterol levels ＞141 mg/dL, the need for more than three 'boluses' of methylprednisolone, and pre-transplantation cholestatic liver disease. Multivariate analysis revealed that only the pre-transplantationcholesterol level remained significant (OR=5.5; 95% CI: 1.4-21.0). In a different study,[61]multivariate analysis found that the risk of hypertriglyceridemia was associated with pre-transplantation liver disease (OR=6.8; 95% CI: 1.2-40.0) and post-transplantation renal dysfunction (OR=5.4; 95% CI: 1.9-15.4).

Conclusion

Currently, MS after LT is an established risk factor for atherosclerosis and cardiovascular disease, which are important causes of morbidity and mortality in the liver recipients. Taken together, the available evidence suggests that the following are risk factors for PTMS: older age, obesity, pre-transplantation DM, and pre-transplantation liver disease. Certain genetic polymorphisms and the use of immunosuppressive drugs are also important. Active intervention to reduce the impact of risk factors will improve the quality of life in liver recipients. However, there are others that have not been considered, such as the possible contribution made to PTMS by changes in the intestinal microecology after LT.[62]More in depth research aimed to minimize PTMS is required.

Contributors:WWL proposed the study. ZJ wrote the first draft. Both authors contributed to the design and interpretation of the study and to further drafts. WWL is the guarantor.

Funding:This study was supported by a grant from the Public Welfare Technology Application Research Plan of Zhejiang (2015C33117).

Ethical approval:Not needed.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received September 1, 2015

Accepted after revision October 30, 2015

BACKGROUND: The elevation of neutrophil-lymphocyte ratio (NLR) has adverse effects on the prognosis of patients with hepatocellular carcinoma (HCC) who have received liver transplantation (LT). The Hangzhou criteria are set for selecting HCC patients for LT. The present study aimed to establish a set of new criteria combining the NLR and Hangzhou criteria for selecting HCC patients for LT.

METHODS: Receiver operating characteristic (ROC) analysis was done to determine the optimal NLR threshold. Univariate and multivariate analyses were made to evaluate the factors affecting the outcomes of HCC patients after LT. We also proposed new criteria consisting of the elevated NLR and Hangzhou criteria. ROC analysis was carried out to validate the feasibility of the new criteria.

RESULTS: Three hundred and five HCC patients were included in this study. The mean follow-up time of these patients was 5.4 years. Of the 305 patients, 197 (64.6%) showed elevated NLRs (NLR ＞4). The recurrence-free survival rates of the patients with elevated NLRs at 1, 3 and 5 years were lower than those of the patients with normal NLRs (NLR ≤4) (50.1%, 21.7% and 20.2% vs 80.5%, 58.7% and 56.4%, respectively; P＜0.001). The overall survival rate was lower in the patients with elevated NLR than in those with normal NLR at 1, 3 and 5 years (60.8%, 27.0% and 22.5% vs 78.4%, 51.1% and 47.8%,

respectively; P＜0.001). Multivariate analysis demonstrated that an NLR ＞4 (P=0.034), total tumor size ＞8 cm (P=0.005), alpha-fetoprotein level ＞400 μg/L (P=0.007) and the presence of vascular invasion (P=0.003) were independent predictors of HCC recurrence in post-transplant patients. We proposed a set of new criteria based on the elevated NLR and Hangzhou criteria. A ROC analysis demonstrated that the patients with scores ≥1 had an area under the curve of 0.764.

CONCLUSION: The criteria combining the elevated NLR and Hangzhou criteria can be used to select patients with HCC for LT. (Hepatobiliary Pancreat Dis Int 2015;14:588-595)

KEY WORDS: Hangzhou criteria;

hepatocellular carcinoma;

liver transplantation;

neutrophil-lymphocyte ratio;

hepatitis B virus;

biomarker

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common neoplasm worldwide and remains the third leading cause of cancer-related death.[1]Because of the widespread prevalence of HBV infection, China has more than half of the HCC cases and deaths globally.[2]Liver transplantation (LT) is advantageous for the resection of neoplasm together with the dysfunctional organ. The introduction of the Milan criteria has significantly improved the outcome of HCC patients after LT.[1,3]However, the recurrence rate of HCC remains approximately 15%, and some patients with HCC who do not fulfill the Milan criteria cannot benefit from LT. Subsequently, expanded criteria including the UCSF criteria[4]and the Hangzhou criteria[5]have been reported. However, these criteria are merely based on the tumor size, tumor number and macrovascular invasion estimated Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China (Xiao GQ, Yang JY and Yan LN); Department of Biliary-Pancreatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China (Xiao GQ)

Published online September 9, 2015.

Lu-Nan Yan, PhD, Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China (Tel/ Fax: +86-28-85422867; Email: yanlunan688@163.com)

10.1016/S1499-3872(15)60416-7

Author Affiliations:Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine (Zheng J and Wang WL); Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Wang WL), Hangzhou 310003, China; Department of Surgery, The University of Hong Kong, Hong Kong, China (Zheng J)

Corresponding Author:Wei-Lin Wang, MD, PhD, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, No. 79 Qingchun Road, Hangzhou 310003, China (Tel/Fax: +86-571-87236570; Email: wam@zju.edu.cn)

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60037-6

Published online November 18, 2015.

Author Affiliations:

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.