Posttransplant metabolic syndrome: An ... - Wiley Online Library

LIVER TRANSPLANTATION 15:1662-1670, 2009

REVIEW

Posttransplant Metabolic Syndrome: An Epidemic Waiting to Happen Mangesh Pagadala,1 Srinivasan Dasarathy,1 Bijan Eghtesad,2 and Arthur J. McCullough1 Departments of 1Gastroenterology and Hepatology and 2Hepatobiliary Surgery, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH

With increasing survival after orthotopic liver transplantation (OLT), metabolic syndrome and its individual components, including diabetes mellitus, hypertension, dyslipidemia, and obesity, are increasingly being identified and contributing to cardiovascular complications and late morbidity and mortality. The prevalence of posttransplant metabolic syndrome (PTMS) and its individual components has been found to be higher post-OLT versus a comparable population without OLT. The development of nonalcoholic fatty liver disease (NAFLD) after liver transplantation for non-NAFLD cirrhosis is also being increasingly recognized. A number of predictors have been identified as potential risk factors related to these complications. The pretransplant risk factors include immunosuppression, a higher age at transplant, male gender, a history of smoking, the pretransplant body mass index, pre-OLT diabetes, the etiology of the underlying liver disease that resulted in OLT (hepatitis C, cryptogenic cirrhosis, or alcohol), an increased donor body mass index, and marital status. Although there is an increased risk of cardiovascular events, rejection, and infection among patients with PTMS, the overall impact on long-term survival and mortality remains inconclusive. Strategies to reduce the development of metabolic syndrome after transplantation should include lifestyle modifications involving alterations in diet and increased physical activity. Additional measures that may be potentially beneficial include the use of lipid-lowering agents, the optimal control of blood glucose, and the use of tacrolimus instead of cyclosporine. Liver Transpl 15:1662-1670, 2009. © 2009 AASLD. Received June 25, 2009; accepted September 15, 2009.

Metabolic syndrome (MS) is a group of risk factors associated with insulin resistance and an increased risk for the development of diabetes mellitus (DM) and cardiovascular disease. According to the Framingham study, MS alone can predict at least 25% of all newonset cardiovascular diseases.1,2 MS was defined by Adult Treatment Panel III3 as the presence of 3 or more of the following: (1) abdominal obesity (waist circumference ⬎ 102 cm in men and ⬎ 88 cm in women), (2) hypertriglyceridemia [⬎150 mg/dL (1.69 mmol/L)], (3) low high-density lipoprotein levels [HDL; ⬍40 mg/dL (1.04 mmol/L) in men and ⬍50 mg/dL (1.29 mmol/L) in women], (4) high blood pressure (⬎130/85 mm/Hg), and (5) high fasting glucose levels [⬎110 mg/dL (⬎ 6.1 mmol/L)]. The Third National Health and Nutrition Examination

Survey in 1999-2000 estimated the age-adjusted prevalence of MS in the adult US population to be 24%.3 In addition to cardiovascular disease and diabetes, individuals with MS have an increased association with other comorbidities, including fatty liver disease, hyperuricemia, cholelithiasis, polycystic ovary disease, and sleep disorders.1 With the availability of liver transplantation as an effective therapy for chronic end-stage liver disease and with over 90% survival at 1 year and over 70% survival at 5 years, the occurrence of MS after liver transplantation is being increasingly recognized.4 Patients after transplantation can develop a number of well-recognized complications, which include infection, graft rejection, vascular and biliary disorders, renal insufficiency, neurological and psychiatric disorders, chronic

Abbreviations: BMI, body mass index; CC, case control; DM, diabetes mellitus; FBS, fasting blood sugar; HCV, hepatitis C virus; HDL, high-density lipoprotein; HTN, hypertension; MS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NPTDM, no posttransplant diabetes mellitus; NPTMS, no posttransplant metabolic syndrome; NR, not reported; NS, not significant; OLT, orthotopic liver transplantation, PTDM, posttransplant diabetes mellitus, PTMS, posttransplant metabolic syndrome. Address reprint requests to Arthur J. McCullough, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail Code A30, Cleveland, OH 44195. Telephone: 216-444-2766; FAX: 216-445-3889; E-mail: [email protected] DOI 10.1002/lt.21952 Published online in Wiley InterScience (www.interscience.wiley.com).

© 2009 American Association for the Study of Liver Diseases.

POSTTRANSPLANT METABOLIC SYNDROME 1663

TABLE 1. Components of MS After OLT

Authors Stegall et al.6 Laryea et al.7 Hanouneh et al.8 Francioso et al.9 Bianchi et al.10 Navasa et al.14 Guckelberger et al.17 Bigam et al.18 Baid et al.19 Tueche20 John and Thuluvath21 Munoz et al.23 Everhart et al.24 Gisbert et al.25 Contos et al.31 Lim et al.33 Seo et al.34 Trail et al.40 Manzarbeitia et al.44 Wahlstrom et al.51 Levy et al.52

Components of MS Studied After OLT

Year

Number of Patients

DM

HTN

Obesity

Dyslipidemia

1995 2007 2008 2008 2008 1996 1997

123 118 95 75 296 102 197

F F F F F F F

F F F F F

F F F F F

F F F F F

2000 2001 2003 2002

278 47 45 46

F F F F

1991 1998 1997 2001 2007 2007 1996 2001

21 320 85 30 30 68 26 21

1991 1992

169 522

F

F F

Follow-Up (Months) 12 58 ⫾ 21 24 ⫾ 17 72 ⫾ 16 38 36 18

F

60 NR NR 60 ⫾ 36.2 F F

F

NAFLD

F F

F

F F F

32 60 14 ⫾ 6 42 ⫾ 31 44 ⫾ 4 28 ⫾ 18 48 33 ⫾ 18 24 NR

Abbreviations: DM, diabetes mellitus; HTN, hypertension; MS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NR, not reported; OLT, orthotopic liver transplantation. F, Data presented.

rejection, dyslipidemia, and certain types of malignancies.5 With longer survival after liver transplantation, the development of metabolic abnormalities following liver transplantation contributes to the morbidity and mortality. There are no systematic reviews that examine the development of either complete MS or its individual components following liver transplantation. The present review on post–liver transplantation MS evaluates the overall prevalence of MS and its individual components, identifies predictors for posttransplant metabolic syndrome (PTMS), and examines the outcomes of patients who develop MS after orthotopic liver transplantation (OLT).

PREVALENCE OF POSTTRANSPLANT METABOLIC SYNDROME AND ITS COMPONENTS Posttransplant Metabolic Syndrome (PTMS) There are few published studies that have specifically reported the development of individual components of MS following OLT (Table 1).6-10 An early study of 123 patients reported a higher incidence of each component of MS 1 year after OLT (DM, 13%; hypertension, 69%; obesity, 40%; and dyslipidemia, 31%).6 However, the

diagnostic criteria were different from those used by Adult Treatment Panel III. Laryea et al.7 studied the prevalence of PTMS with the Adult Treatment Panel III criteria in 118 adult patients who had a minimum follow-up of 18 months after OLT for various indications. In these patients, the prevalence of DM (13% pre-OLT versus 61% post-OLT), dyslipidemia (pre-OLT 3% versus 46% post-OLT), and hypertension (10% pre-OLT versus 62% post-OLT) was increased after OLT. The overall prevalence of PTMS in these patients was 58%. In a concurrent cohort of hepatitis C virus (HCV) patients, the prevalence of PTMS was reported to be approximately 50% at 1 year postOLT.8 In a subsequent report, Francioso et al.9 found a 43% prevalence of PTMS in 75 patients followed for at least 12 months. In a more recent study of 296 patients who underwent OLT, the prevalence of PTMS was reported to be 45%.10 On the basis of these data, one may conclude that MS develops in 43% to 58% of patients after OLT (Table 2); this is higher than the prevalence of MS reported in the adult US population (24%).3 Although there are no prospective studies, a number of retrospective studies (Table 1) have reported the prevalence of the individual components of MS, which

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

1664 PAGADALA ET AL.

TABLE 2. Prevalence of PTMS Authors 7

Laryea et al. Hanouneh et al.8 Francioso et al.9 Bianchi et al.10

Year

Total Number of Patients

Prevalence of PTMS (%)

2007 2008 2008 2008

118 82 75 296

58 50 43 45

Abbreviation: PTMS, posttransplant metabolic syndrome.

include DM, hypertension, dyslipidemia, and obesity, among patients who have undergone OLT.11-19

OLT, with hypertriglyceridemia being more common than elevated plasma cholesterol. The prevalence of low HDL after transplantation was 48% to 52%.7,23

Posttransplant Diabetes Mellitus (PTDM) Earlier studies reported the prevalence of DM 1 year after OLT to be 13% to 27%.6,14,20,21 Sheiner et al.16 found the prevalence among long-term survivors to be higher after liver transplantation in comparison with a matched control group with a standard prevalence ratio of 5.99 (95% confidence interval ⫽ 4.15-8.38). More recently, the prevalence of post–liver transplant DM was reported to be 61%.7 The variation in the prevalence can be explained, at least in part, by differences in the diagnostic criteria for DM. Earlier studies used a higher fasting plasma glucose level of 140 mg/dL to define DM,6,16 whereas the more recent studies used 126 mg/dL, which was established subsequently by the American Diabetic Association.7,10

Posttransplant Development of Hypertension, Obesity, and Dyslipidemia The prevalence of hypertension following liver transplantation has been reported to range from 62% to 69%.6,8,16,22 In patients followed for at least 1 year after OLT, the incidence of hypertension increased from 19% before transplantation to 64.2% post-transplantation.8 Overall, the prevalence of hypertension after OLT was significantly higher than the prevalence in the general US population (standard prevalence ratio ⫽ 3.07, 95% confidence interval ⫽ 2.35-3.93).16 Obesity [body mass index (BMI) ⬎ 30 kg/m2] develops in 21% to 43% of patients post-OLT.23-25 Everhart et al.24 estimated the incidence of obesity at 2 years posttransplant to be 21.6%. The BMI 2 years after OLT was also found to be slightly higher than that in the US population (P ⫽ 0.04). The prevalence of dyslipidemia post-OLT ranges from 66% to 85%.23,25,26 Gisbert et al.25 reported an increase in the prevalence of dyslipidemia from 8% before liver transplantation to 66% afterwards in 85 transplanted patients followed for over 14 months. In the same study, elevated cholesterol and hypertriglyceridemia developed in 19% and 59%, respectively. Another study reported an increase in the prevalence of both elevated total cholesterol (2.9% pre-OLT versus 15.3%) and triglycerides (18.2% pre-OLT versus 70%) at 6 months post-transplant.26 These data indicate that there is an increased prevalence of dyslipidemia post-

Posttransplant Development of Nonalcoholic Fatty Liver Disease (NAFLD) NAFLD is a spectrum of diseases ranging from simple hepatic steatosis to the more severe form, nonalcoholic steatohepatitis (NASH), and NASH cirrhosis. Both recurrent NAFLD and de novo NAFLD have been recognized post-OLT. A number of case reports initially suggested the recurrence of NAFLD post-transplant.27-29 Among 16 patients transplanted for NASH cirrhosis, the development of posttransplant NAFLD at the end of 1 year post-OLT was reported in 60%, and a third of these patients developed NASH, with progression to cirrhosis in 12.5%.30 In a cohort of patients transplanted for cryptogenic cirrhosis, the development of fatty liver at the end of 1 year after OLT was observed in 52% of the subjects. In the same study, the time-dependent risk of developing allograft steatosis was 100% by 5 years versus 25% among those transplanted for alcoholic or cholestatic disease.31 The development of NAFLD after liver transplantation for non-NASH cirrhosis is also being increasingly recognized. The occurrence of NAFLD post-OLT was first reported in 4 patients transplanted for a disease other than NAFLD.32 This finding was confirmed in subsequent studies,33,34 which found NAFLD in 18% and 40% of the patients post–liver transplantation. Of particular concern was the finding of NASH in 9% to 13% of these patients.

Posttransplant Insulin Resistance The primary abnormality in MS is the development of insulin resistance. Although up to 60% to 80% of patients with cirrhosis have glucose intolerance and 20% of these patients may develop DM, the presence of insulin resistance is virtually universal in patients with cirrhosis.35 Measures of insulin sensitivity, including the homeostasis model assessment, the quantitative insulin sensitivity check index, and the glucose insulin clamp technique, have all shown objective evidence of insulin resistance in patients with cirrhosis pre-transplant.36,37 In the posttransplant state, case control studies indicate that insulin sensitivity, as measured by the glycemic insulin clamp method, improves significantly.36-38 In addition, there was a 45% reduction in



TABLE 3. Predictors of PTMS Reported Predictors of PTMS

Authors

Age†

Laryea et al.7 Francioso et al.9* Bianchi et al.10

F F

Indication for OLT‡

Comorbidities Pre-OLT§

Post-OLT㛳

F

F

F

Cyclosporine Use¶

History of Smoking#

F

F

Abbreviations: OLT, orthotopic liver transplantation, PTMS, posttransplant metabolic syndrome. *This study found a family history of cardiovascular disease to be a predictor of PTMS. †Higher age at transplant (P ⫽ 0.02). ‡Indications included hepatitis C, cryptogenic, and alcohol (odds ratio ⫽ 3.43, P ⬍ 0.001). §Pretransplant predictors included the pre-OLT body mass index (odds ratio ⫽ 1.2, P ⬍ 0.001) and pre-OLT diabetes mellitus (odds ratio ⫽ 2.36, P ⫽ 0.048). 㛳Posttransplant predictors included an increase in the body mass index after OLT (odds ratio ⫽ 1.18, P ⬍ 0.001). ¶P ⫽ 0.01. #P ⫽ 0.009. F, Data presented.

fasting plasma insulin and c-peptide levels as well as improved peripheral nonoxidative glucose metabolism (P ⬍ 0.0001) after liver transplantation.38 However, after liver transplantation, insulin resistance, as measured by a homeostasis model assessment score ⬎ 2.7, was observed in up to 41% of these patients.10 It should be noted that any improvement in sensitivity posttransplant occurs despite the presence of immunosuppressive therapy, which may adversely affect insulin resistance. It is likely that this improved insulin sensitivity post-transplant is a result of an increase in peripheral glucose utilization and the correction of insulin resistance in the periphery.

PREDICTORS OF PTMS The high prevalence of PTMS and its accompanying cardiovascular and metabolic abnormalities makes it important to identify the predictors for the development of PTMS. The predictive factors of PTMS identified from the published data are shown in Table 3. A higher age at transplant, an increase in BMI post-OLT, pre-OLT diabetes, a history of smoking, the immunosuppressant regimen used, and the indication for OLT (hepatitis C, alcohol, or cryptogenic cirrhosis) are the highest risk factors for PTMS.7,9,10 Laryea et al.7 also found significantly higher pretransplant and posttransplant BMI, fasting blood glucose, triglycerides, and abnormal HDL among patients with MS compared to those who did not develop PTMS. The type of immunosuppressant therapy used has also been implicated in the development of various components of MS.25,39,40 Although Francioso et al.9 demonstrated an association between the use of cyclosporine and the development of PTMS (P ⫽ 0.01), a number of other studies have not observed this association.7,8,10 Predictors and risk factors for the individual components of MS after OLT have been reported (Table 4). Factors associated with PTDM include HCV and alco-

hol-related cirrhosis as the indication for OLT (P ⬍ 0.05), pretransplant DM (odds ratio ⫽ 24.4, P ⬍ 0.001), male gender, HCV infection, and steroid use (P ⬍ 0.05).18-20,40 Decreasing the dose of prednisone from 10 to 5 mg decreased the incidence of PTDM (P ⫽ 0.045).6 In another study, the prevalence of PTDM declined from 27% at 1 year to 7% at 3 years. This reduction was directly related to a decrease in the daily prednisone dose from 13 ⫾ 4 mg at 1 year to 2 ⫾ 4 mg at 3 years (P ⬍ 0.001) and additionally to a significant reduction in blood levels of cyclosporine from 249 ⫾ 129 ng/mL at 1 year to 171 ⫾ 84 ng/mL at 3 years (P ⬍ 0.05).14 A higher number of steroid boluses also increased the risk of PTDM (hazard ratio ⫽ 1.09/bolus, P ⫽ 0.02).19 On the basis of these observations, it may be concluded that the use of steroids during postoperative immunosuppression is associated with a higher risk of developing PTDM in a dose-dependent manner. Both cyclosporine and tacrolimus are associated with an increased risk of DM after kidney transplantation, although the use of tacrolimus has been reported to be 5 times more diabetogenic then cyclosporine in that population.41 Although some studies of patients after OLT have reported an increased incidence of PTDM with tacrolimus,10,20,21 one study42 found the diabetogenic effects of tacrolimus and cyclosporine to be similar. Neal et al.43 found no difference in patient blood glucose levels between tacrolimus and cyclosporine therapy. Both tacrolimus and cyclosporine can cause DM post-OLT, with the incidence possibly being higher with the use of tacrolimus.10,21,42 Risk factors of hypercholesterolemia post-OLT include pre-OLT hypercholesterolemia (⬎141 mg/dL; odds ratio ⫽ 5.5, P ⫽ 0.05) and cyclosporine and steroid use (P ⫽ 0.05).23,25 The conversion from cyclosporine to tacrolimus decreases the incidence of dyslipidemia (P ⬍ 0.001).44 Predictors of posttransplant triglyceridemia are pre-OLT hepatocellular disease, including cirrhosis due to HCV, hepatitis B virus, alcohol, and cryptogenic



TABLE 4. Predictors and Risk Factors of Individual Components of MS Post–Liver Transplantation Predictors and Risk Factors Cyclosporine use Steroid use Pretransplant DM and FBS Pre-OLT cholesterol ⬎ 141 mg/dL HCV infection and alcoholic cirrhosis Pre-OLT hepatocellular disease Increased donor BMI Higher BMI preOLT Higher BMI at last biopsy Post-OLT weight gain (⬎10% pre-OLT) Married recipients Acute rejection Male gender Renal dysfunction post-OLT

Components of MS Diabetes‡

Cholesterolemia§

F F F

F F

Triglyceride㛳

Obesity¶

Hypertension#

F F

F

NAFLD**

References

F

23, 24,* 40, 42 19, 24, 25,* 31 18, 20, 40

F

25

F

18-20

F

25

F F

F

F F F

24* F

24,* 33†

F

33†

F

34

24* 24 18, 20 25

Abbreviations: BMI, body mass index; DM, diabetes mellitus; FBS, fasting blood sugar; HCV, hepatitis C virus; MS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; OLT, orthotopic liver transplantation. *Univariate analysis. †Steatohepatitis. ‡Induction with cyclosporine versus OKT3 (P ⫽ 0.009), methyl prednisolone bolus (hazard ratio ⫽ 1.09/bolus, P ⬍ 0.02), pretransplant DM (odds ratio ⫽ 24.4, P ⬍ 0.001), pre-OLT DM (P ⬍ 0.05), higher pre-OLT FBS (P ⫽ 0.04), HCV-related liver failure (odds ratio ⫽ 5.8, P ⫽ 0.002), HCV reinfection of the allograft (P ⫽ 0.008), alcoholic cirrhosis (P ⬍ 0.05), male gender (P ⬍ 0.05). §The use of cyclosporine correlated with the development of cholesterol (r ⫽ 0.50, P ⫽ 0.05), more than 3 boluses of methyl prednisolone after OLT (P ⫽ 0.02), and pre-OLT cholesterol ⬎ 141 mg/dL (odds ratio ⫽ 5.5, P ⬍ 0.05). 㛳Pre-OLT hepatocellular disease (odds ratio ⫽ 6.8, P ⫽ 0.03) and post-OLT renal dysfunction (odds ratio ⫽ 5.4, P ⬍ 0.01). ¶Patients treated with cyclosporine at the end of the first year (P ⬍ 0.025), a higher dose of prednisone in the second year (P ⫽ 0.01), donor BMI (odds ratio ⫽ 3.76, P ⫽ 0.03), pre-OLT BMI (odds ratio ⫽ 5.11, P ⬍ 0.001), recipient BMI (P ⬍ 0.001), married recipients (odds ratio ⫽ 2.65, P ⫽ 0.02), and absence of acute rejection (odds ratio ⫽ 0.49, P ⫽ 0.02). #Hypertension was associated with the use of cyclosporine versus tacrolimus (P ⬍ 0.05). **Cumulative steroid exposure (odds ratio ⫽ 1.7, P ⬍ 0.02), pretransplant BMI (32.3 versus 23 kg/m2, P ⫽ 0.02), higher BMI at last biopsy (32.5 versus 22.9 kg/m2, P ⫽ 0.01), and post-OLT weight gain ⬎ 10% of the pre-OLT BMI (odds ratio ⫽ 19.3, P ⫽ 0.001). F, Data presented.

causes (odds ratio ⫽ 6.8, P ⱕ 0.007), and post-OLT renal insufficiency (odds ratio ⫽ 5.4, P ⬍ 0.01).25 Canzanello et al.42 found elevated plasma cholesterol (33% versus 0%), hypertension (82% versus 33%), and obesity (46% versus 29%) in patients treated with cyclosporine versus tacrolimus by 12 months post-OLT (all P ⬍ 0.05). Weight gain post-transplant also correlated positively with an increase in triglyceride levels (P ⬍ 0.05) in patients treated with cyclosporine. A follow-up study of 26 patients over 8 months post-OLT found a similar improvement in hypercholesterolemia (P ⫽

0.01), body weight gain (P ⫽ 0.02), and hypertension (P ⫽ 0.015) when patients were switched from cyclosporine to tacrolimus.43 Consequently, it appears that cyclosporine treatment, in comparison with tacrolimus, is associated with a greater incidence of hypertension along with an increase in plasma triglyceride and total cholesterol levels within the first year after OLT.42-44 The development of posttransplant hypertension may result from increased renal vasoconstriction and impaired sodium excretion induced by cyclosporine use.45 Some studies in the past have suggested that the lower



incidence of dyslipidemia in patients treated with tacrolimus-based regimens may be the result of its steroid-sparing effect.46,47 Predictors of low HDL after OLT have not yet been identified but are probably similar to those that result in elevated triglycerides. Risk factors for post-OLT obesity include increased donor BMI (odds ratio ⫽ 3.76, P ⬍ 0.03), absence of acute rejection, the immunosuppressive regimen used, and the marital status of the recipient (P ⬍ 0.05); however, in multivariate analysis, only acute rejection and steroid use remained predictors for posttransplant obesity.24 The mechanism by which donor BMI correlates with increased obesity post-transplant is unclear. The paucity of donor livers makes it difficult to control by matching the donor weight with the recipient body size. A higher dose of steroids in the second year post-transplant (P ⫽ 0.01) and the continued use of cyclosporine at the end of the first year (P ⫽ 0.025) have also been associated with obesity.24 Obesity at 12 months was also significantly higher with cyclosporine treatment versus tacrolimus treatment (46% versus 29%).42 The higher incidence of obesity in the cyclosporine group could also be explained by the increased rates of rejection in the cyclosporine regimen and the subsequent greater steroid requirement in comparison with primary tacrolimus use.46 Increased body weight seen among married recipients was similar to that seen in the general population.48 The development of de novo NAFLD post-OLT, including steatohepatitis, was associated with a pretransplant BMI ⬎ 30 kg/m2 (32 versus 23, P ⫽ 0.02), a higher BMI at the last biopsy (P ⫽ 0.01), and a higher posttransplant BMI (P ⬍ 0.01).33,34 Patients with a posttransplant increase in body weight greater than 10% of the pretransplant BMI had a significantly higher risk of developing de novo NAFLD in comparison with patients who had no weight gain (odds ratio ⫽ 19.38, P ⫽ 0.001). The use of angiotensin converting enzyme inhibitors to treat hypertension was seen to have a beneficial effect on the development of posttransplant steatosis in comparison with patients who were not treated with this class of antihypertensives (P ⬍ 0.05).34 In a small study, patients with preexisting NAFLD in the native liver or donor liver had a higher chance of having posttransplant NAFLD.33 The recurrence of posttransplant fatty liver in the allograft was associated with the cumulative steroid exposure over time (P ⬍ 0.02).31 It is possible that the development of insulin resistance from weight gain and steroid use could result in the development of steatosis post–liver transplant.49

Outcome in Patients with PTMS (Table 5) Patients undergoing OLT had a greater risk of cardiovascular and ischemic events in comparison with an age-matched and sex-matched population obtained from the database of the Office for National Statistic (relative risk ⫽ 3.07, confidence interval ⫽ 1.98-4.53), and the relative risk of cardiovascular death in the transplant group was 2.5 (95% confidence interval ⫽ 1.52-4.05).22 After OLT, patients with PTMS had signif-

icantly more cardiovascular events than those without PTMS (30% versus 8%, P ⫽ 0.003).7 Progression of recurrent liver disease post-OLT has been reported in patients with hepatitis C infection. The presence of PTMS has been associated with progression to fibrosis beyond 1 year after OLT in comparison with those without PTMS (odds ratio ⫽ 6.3, P ⫽ 0.017).8 In addition, patients who developed PTDM had an increased number of cardiovascular events in comparison with those without diabetes.21,50 Patients with PTDM had higher all-cause mortality in the second postoperative year (17% versus 3%, P ⬍ 0.05).14 In another study following a cohort of HCV patients, there was an increased risk for death (hazard ratio ⫽ 3.67, P ⬍ 0.001) among patients who developed diabetes after transplantation.19 The impact of PTDM on posttransplant mortality remains unclear because some of the subsequent studies have shown no difference in survival rates between the 2 groups.21,40,51 The number of episodes of rejection at 1 year postOLT was greater among patients with PTDM (1.5 ⫾ 1.1 versus 1.1 ⫾ 0.7, P ⬍ 0.05).14 This was similar to another study in which the acute rejection rates were higher among patients with PTMS compared to controls without diabetes (50% versus 30%, P ⫽ 0.03).21 An increased incidence of early but not late rejection (74% versus 56%, P ⫽ 0.015) was seen in a PTDM group versus nondiabetic patients.52 The greater incidence of PTDM in patients with increased rates of rejection may have been related to the greater use of steroid boluses.14 Patients with PTDM had more episodes of both bacterial and fungal infections (2.3 versus 0.6 per patient, P ⬍ 0.01) and viral infections (1.3 versus 0.35 per patient, P ⬍ 0.001) within 2 years post-transplant.51 However, 2 other studies found infection rates to be comparable between patients with PTDM and nondiabetic controls.40,52

DISCUSSION On the basis of the published data, it is apparent that MS and its components (DM, hypertension, obesity, and dyslipidemia) are more common among liver transplant patients post-OLT than in the general adult population.16 The increased prevalence of components of MS is of particular concern because of the increased incidence of cardiovascular mortality and other comorbidities associated with MS.3,6,7,14,19,21,52 MS in the general population has been associated with increased cardiovascular morbidity, and similar effects of MS in the transplant population have been reported.53 However, the impact of PTMS on overall post-OLT mortality is not yet clear.9,18,21 Furthermore, in contrast to MS in the general population, no relationship has been observed between hyperlipidemia, diabetes, or immunosuppressants and posttransplant steatosis.33,34 This is contrary to the findings in the nontransplant population, in which dyslipidemia and diabetes increase the risk of steatosis.54 Strategies to reduce the development of PTMS should



TABLE 5. Various Outcomes of Patients Developing PTMS

Authors

Group 7

Laryea et al.

Francioso et al.9 Navasa et al.14

Sutedja et al.15 Bigam et al.18

Baid et al.19 John and Thuluvath21

Trail et al.40 Guckelberger et al.50 Wahlstrom et al.51

Levy et al.52

Cardiovascular Events

Mortality

Rejection

Infection

Survival at 5 years (P ⫽ NS) Survival at 10 years (P ⫽ NS) Mortality at 2 years (P ⬍ 0.05)

NR

NR

NR

NR

Rejection episodes (P ⬍ 0.05) P ⫽ NS

Bacterial and fungal infections (P ⫽ NS)

Acute rejection (P ⫽ NS) NR

NR

PTMS versus NPTMS PTMS versus NPTMS PTDM versus NPTDM

P ⫽ 0.003

PTDM versus NPTDM PTDM versus NPTDM

NR

NR

NR

Survival at 5 years (P ⫽ NS)

PTDM versus CC PTDM versus CC

NR

Risk of death (P ⬍ 0.001) Survival at 5 years (P ⫽ NS)

PTDM versus CC PTDM versus NPTDM PTDM versus NPTDM

PTDM versus NPTDM

NR NR

P ⫽ 0.005

NR

Acute rejection (P ⫽ 0.03)

Survival at 1 years (P ⫽ NS) NR

Rejection (P ⫽ NS) NR

NR


P ⫽ NS

NR


Early rejection (P ⫽ 0.015) Late rejection (P ⫽ NS)

P ⫽ 0.017*

NR

Increased bacterial and fungal infections Major infection (P ⫽ 0.07) Minor infection (P ⫽ 0.001) P ⫽ NS NR Increased episodes of bacterial/fungal and viral infections (P ⬍ 0.01) P ⫽ NS

NOTE: One study (Hanouneh et al.8) noted increased progression to fibrosis with PTMS (odds ratio ⫽ 6.3, P ⫽ 0.017). Abbreviations: CC, case control; NPTDM, no posttransplant diabetes mellitus; NPTMS, no posttransplant metabolic syndrome; NR, not reported; NS, not significant, PTDM, posttransplant diabetes mellitus, PTMS, posttransplant metabolic syndrome. *Univariate analysis

include careful screening of patients for diabetes, dyslipidemia, and obesity. It is important to reiterate the importance of weight reduction before and after transplantation with a carefully constructed program including diet modification and exercise. Additionally, the use of lipid-lowering agents to control dyslipidemia, the optimal management of blood glucose, and the use of a tacrolimus-based regimen instead of cyclosporine should also help to prevent the development of PTMS. The results of recent studies on the prevention of DM suggest that similar studies are needed in this population of patients at high risk of developing the disease.55,56 In summary, the prevalence of MS and its components are increased post-OLT. Although there is controversy regarding the impact of PTMS on the overall survival rates following OLT, these patients are at an increased risk for cardiovascular morbidity and mortality. Although survival among transplant patients continues to improve with advances in medical and surgi-

cal techniques, cardiovascular mortality along with higher infection rates among patients with PTMS continues to remain a concern. Although immunosuppressants have been largely implicated, there are a number of other predictors for the development of PTMS. There is clearly a need for prospective studies to help identify and validate these risk factors and thereby develop interventional strategies. Prevention of PTMS will help improve posttransplant survival, and these strategies need to be developed before OLT and modified post-OLT according to the specific risk factors identified.

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