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Metabolic syndrome after liver transplantation: Short-term prevalence and pre- and post-operative risk factors
Digestive and Liver Disease 45 (2013) 833–839
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Metabolic syndrome after liver transplantation: Short-term prevalence and preand post-operative risk factors Maria Elena Lunati a , Valeria Grancini a , Francesca Agnelli b,1 , Stefano Gatti c , Benedetta Masserini a , Dario Zimbalatti a , Giuseppe Pugliese d , Giorgio Rossi c , Maria Francesca Donato b , Massimo Colombo b , Paolo Beck-Peccoz a , Emanuela Orsi a,∗ a
Endocrinology and Diabetes Unit, University of Milan, Milan (MI), Italy A.M. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, University of Milan, Milan (MI), Italy c General Surgery Unit, IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation, University of Milan, Milan (MI), Italy d Department of Clinical and Molecular Medicine, “La Sapienza” University, Rome (RM), Italy b
a r t i c l e
i n f o
Article history: Received 11 August 2012 Accepted 17 March 2013 Available online 29 June 2013 Keywords: Hypertension New-onset diabetes after transplantation Obesity Orthotopic liver transplantation Post-transplantation metabolic syndrome
a b s t r a c t Background: The metabolic syndrome is a common condition among liver transplanted patients and contributes to morbidity and mortality by favouring the development of cardiovascular diseases. Aims: This prospective study assessed the prevalence of metabolic syndrome in the first year after orthotopic liver transplantation, the associated pre-operative and post-operative risk factors and the influence of nutritional factors. Methods: 84 cirrhotic patients (75% male, mean age 53.9 ± 9.3 years) were evaluated at baseline and after liver transplantation. Metabolic syndrome was defined according to 2004 Adult Treatment Panel-III criteria. Nutritional habits were assessed using 3-day food records. Results: Prevalence of metabolic syndrome before orthotopic liver transplantation was 14/84 (16.6%); at 3, 6 and 12 months post-orthotopic liver transplantation it was 27/84 (32.1%), 30/84 (35.7%), and 32/81 (39.5%), respectively. Diabetes, family history of diabetes, and excess body weight at baseline independently correlated with incidence of metabolic syndrome. After orthotopic liver transplantation, patients with metabolic syndrome showed a higher increase in the intake of total energy and saturated fats and a higher prevalence of complications, especially cardiovascular events, than subjects without metabolic syndrome. Conclusion: Occurrence of metabolic syndrome is an early phenomenon after liver transplantation. Preoperative and post-operative factors predispose patients to metabolic syndrome, which may be reduced by controlling modifiable risk factors, such as body weight and dietary intake. © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Liver transplantation is the elective therapy for cirrhosis. It has improved life quality and expectancy of patients with end-stage liver disease, with 1-year and 5-year survival rates of approximately 85% and 75%, respectively [1]. As longer survival rates have been achieved, the incidence of metabolic derangements clustering in the metabolic syndrome (MS), such as hyperglycaemia, hypertension, dyslipidaemia and central obesity, has also increased [2,3].
∗ Corresponding author at: Endocrinology and Diabetes Unit, Department of Medical Sciences, University of Milan, IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation, Via F Sforza 35, 20122 Milan, Italy. Tel.: +39 3385238279; fax: +39 0250320605. E-mail addresses: [email protected], emanuela [email protected] (E. Orsi). 1 Current address: Unit of Internal Medicine, Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milan (MI), Italy.
Retrospective studies have shown that post-transplantation MS (PTMS) develops in 43% to 58% of patients over a period of 2–6 years after orthotopic liver transplantation (OLT) [4], a prevalence higher than that of the general population [5]. Unfortunately, prospective studies are lacking; therefore, the prevalence of PTMS during the first few months after OLT and the OLT-related and unrelated factors favouring the early development of this condition are poorly defined. Immunosuppressant regimens required for organ acceptance may account for a large proportion of the increased risk for the development of PTMS. It is recognized that corticosteroids have a diabetogenic action, mainly by increasing insulin resistance; moreover, there is also evidence of a dose–response relationship between steroids and the development of new-onset diabetes after transplantation (NODAT) [6]. Both cyclosporine and tacrolimus are associated with hypertension, dyslipidaemia and hyperglycaemia, the latter due to reduced insulin synthesis and secretion, insulin
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resistance and hyperinsulinemia [2]. Other potential pathogenic factors are lifestyle modifications with return to unrestricted food intake and consequent weight gain driving the metabolic abnormalities associated with central obesity [7]. Predictors of PTMS include older age, male gender, excess pre-OLT body weight, pre-OLT diabetes, and the aetiology of underlying liver disease, particularly hepatitis C virus (HCV) infection, alcohol-related liver disease, and cryptogenic cirrhosis [4,8]. As a result of the increased incidence of MS, cardiovascular diseases (CVD) have been emerging as a major cause of both morbidity and mortality in these subjects [9]. The aim of the present study was to prospectively assess the prevalence of MS early after OLT, as well as the associated pre-operative and post-operative modifiable risk factors, with particular reference to changes in anthropometric parameters, body composition, and nutritional intake that occur soon after OLT. 2. Materials and methods 2.1. Study population One-hundred and eighty-three patients on the waiting list for liver transplantation were consecutively recruited and evaluated at the IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation of Milan from 2006 to 2010. Eighty-four of these patients underwent OLT during that period, whereas the remaining subjects (99/183) were excluded from the waiting list (11/183), died before OLT (19/183) or are still awaiting transplantation (69/183). Transplanted patients were re-evaluated at 3, 6 and 12 months after OLT. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008), as reflected in a priori approval by the institution’s human research committee. All patients gave written informed consent to participate in the study. According to the 2001 guidelines of the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) [10] and their 2004 revision [11], MS was defined as the presence of 3 or more of the following: central obesity (waist circumference >102 cm in men and >88 cm in women); high fasting glucose levels [>110 mg/dL (>6.1 mmol/L)]; hypertriglyceridemia [>150 mg/dL (1.69 mmol/L)]; low high-density lipoprotein (HDL) levels [<40 mg/dL (1.04 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women]; high blood pressure (>130/85 mmHg) or specific treatment for each of these conditions. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2 . NODAT was diagnosed according to the American Diabetes Association guidelines [12]. 2.2. Clinical parameters Body weight and height were measured with scale and stadiometer whereas body mass index (BMI) was calculated as patient’s weight in kg divided by patient height (in metres) squared. Waist circumference was taken at the umbilicus. Blood pressure was measured with a mercury sphygmomanometer after the patient had been lying supine for at least 5 min. Fat mass and fatfree mass were measured using an impedance method (Maltron BioScan® ). All subjects underwent a strict nutritional surveillance and counselling, aimed at assessing usual dietary intake and identifying areas where change was needed and possible barriers to changes. Food and alcohol intake were assessed by the use of a food record method. Types and amounts of food and beverages consumed during 3 consecutive days (2 weekdays and 1 weekend day) were recorded in a food diary. Patients were given oral and written instructions by the medical staff on how to keep a food diary.
Food estimates were facilitated by the use of photographs showing portion sizes and corresponding weights. Total calories and percent of nutrients were then calculated using a computer software (Dieta Ragionata® 7.0). At each visit, records were examined by a dietician, who provided nutritional counselling, information, educational material, and support to achieve or maintain targets. Complications, including major CVD events, infections and acute graft rejection, as well as type and dosage of immunosuppressive agents were recorded. 2.3. Biochemical parameters All patients were evaluated at baseline and after transplantation for fasting glucose, triglycerides, total and HDL cholesterol, with calculation of low-density lipoprotein (LDL) cholesterol by the Friedwald formula, aspartate transaminase, alanine transaminase, ␥-glutamyl transferase, alkaline phosphatase, total and conjugated bilirubin, pseudocholinesterase, serum creatinine, urea, uric acid and complete blood count using standard methods. Estimated glomerular filtration rate was calculated from serum creatinine using the Modification of Diet in Renal Disease 6-variable equation [13]. Haemoglobin A1c (HbA1c ) was assessed by the use of a high performance liquid chromatography, National Glycohaemoglobin Standardisation Program-certified and Diabetes Control and Complications Trial-standardized method. Non-diabetic patients were also evaluated for insulin levels by immunoenzymetric one-step assay (Medgenics Diagnostics, Belgium) and electrochemiluminescence immunoassay (Roche Diagnostics, Germany). Insulin resistance was then estimated by the homeostatic model assessment-insulin resistance (HOMA-IR) index (http://www.dtu.ox.ac.uk/homacalculator/index.php). 2.4. Statistical analysis Statistical analysis was performed with the statistical package SPSS for Windows version 17.0 (SPPS Inc. Chicago, IL). Data are expressed as mean ± standard deviation for continuous variables and as number of cases and percentage for categorical variables. Groups were compared using the Student’s t test for parametric continuous variables, and the Mann–Whitney test for nonparametric continuous variables. Normality of distribution was preliminary assessed by the Kolmogorov–Smirnov test. The 2 test or the Fischer’s exact test, when applicable, were used for categorical variables. One-way analysis of variance for repeated measures or the McNemar’s test were applied to analyse post-OLT changes of continuous and categorical variables, respectively. Logistic regression analysis with stepwise backward variable selection was performed to identify independent predictors of PTMS, using a p value < 0.05 as criteria to include and a p > 0.10 as criteria to remove variables from the model. p values < 0.05 were considered statistically significant. 3. Results Overall 84 patients who underwent OLT were enrolled (75% male, mean age 53.9 ± 9.3 years). Underlying liver disease was: HCV infection in 45/84 (53.6%), hepatitis B virus infection in 15/84 (17.8%), delta virus infection in 5/84 (6.0%), autoimmune disorders (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis) in 8/84 (9.5%), alcohol-related in 8/84 (9.5%), and metabolic (Wilson disease, haemochromatosis) in 3/84 (3.6%). Superimposed hepatocellular carcinoma (HCC) was diagnosed in 21 (25%) of the 84 patients. All subjects received calcineurin inhibitors (58.3% tacrolimus and 41.7% cyclosporine) associated with tapered
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Table 1 Prevalence of the metabolic syndrome and its components before and after orthotopic liver transplantation.
N Metabolic syndrome Central obesity Obesity IFG Diabetes mellitus Hypertriglyceridemia Low HDL Arterial hypertension
Pre-OLT
3 months post-OLT
P*
6 months post-OLT
P*
12 months post-OLT
P*
84 14 (16.6) 35 (41.6) 8 (9.5) 14 (16.6) 35 (41.7) 4 (4.8) 21 (25.0) 11 (13.1)
84 27 (32.1) 24 (28.5) 6 (7.1) 10 (11.9) 35 (41.6) 20 (23.8) 20 (23.8) 34 (40.4)
0.015 0.035 0.687 0.515 1.0 0.001 0.908 <0.001
84 30 (35.7) 29 (34.5) 8 (9.5) 10 (11.9) 35 (41.6) 22 (26.2) 21 (23.8) 40 (47.6)
0.004 0.242 1.0 0.515 1.0 0.001 0.845 <0.001
81 32 (39.5) 34 (42.0) 12 (14.8) 12 (14.8) 36 (44.4) 21 (25.9) 28 (34.5) 46 (56.5)
0.001 1.0 0.344 0.607 0.508 0.001 0.243 <0.001
All values are n (%). OLT: orthotopic liver transplantation; IFG: impaired fasting glucose; HDL: high-density lipoprotein. * McNemar’s test, vs. pre-OLT.
corticosteroids. Three patients were lost to follow-up before the 12month post-OLT evaluation: 2 patients died from acute liver failure 8 months after OLT and 1 subject moved elsewhere. At baseline, 35/84 patients (41.6%) had diabetes. Moreover, 35 subjects (41.6%) had central obesity and 21 (25.0%) had low HDL cholesterol, 8 individuals (9.5%) were obese, 11 (13.1%) had hypertension and 4 (4.8%) had hypertriglyceridemia. As a result, only 14/84 (16.6%) patients fulfilled the criteria for the diagnosis of MS (Table 1). After OLT, while prevalence of diabetes, impaired fasting glucose (IFG), low HDL cholesterol, and obesity did not change significantly, the percentage of patients with hypertriglyceridemia and arterial hypertension markedly increased. As a consequence, MS was diagnosed in 27/84 patients (32.1%) at 3 months, 30/84 (35.7%) at 6 months, and 32/81 (39.5%) at 12 months (Table 1). Interestingly, 5 of the 35 patients with diabetes and 6 of the 14 patients with MS at baseline, had reversed these conditions at 3 months post-OLT, when 5 cases of NODAT and 19 of PTMS were diagnosed. Subsequently, only 2 subjects developed NODAT (and 1 reversed it), whereas 9
and 10 patients developed PTMS at 6 and 12 months, respectively, when 6 and 7 individuals reversed it. One of the 2 subjects who died had diabetes and MS. Subjects with MS at 6 months post-OLT were older and had significantly higher BMI, waist circumference and fat mass, as well as higher prevalence of diabetes, family history of diabetes, obesity, dyslipidaemia, and hypertension than patients without MS (Table 2). Similar results were obtained at 3 and 12 months (not shown). The mean daily dose of prednisone did not differ between patients with and without MS at 3 months after OLT (8.9 ± 4.8 mg vs. 9.1 ± 4.9 mg; p = 0.537). At 6 and 12 months post-OLT, respectively 19/30 (63.3%) and 28/32 (87.5%) patients with MS and 24/54 (44.5%) and 36/49 (73.5%) patients without MS discontinued corticosteroid therapy. Regarding immunosuppressive therapy, at 12 months postOLT patients on cyclosporine vs. patients receiving tacrolimus had significantly higher prevalence of hypertension (71% vs. 44%, respectively; p = 0.013), hypertriglyceridemia (37% vs. 16%
Table 2 Characteristics of liver transplant recipients with (n = 30) and without (n = 54) metabolic syndrome 6 months after orthotopic liver transplantation.
Mean age (years) Male gender, n (%) HCV positive, n (%) Tacrolimus therapy, n (%) Family history of diabetes Fasting glucose level (mg/dL) HbA1c (%) Triglycerides (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) BMI (kg/m2 ) Waist (cm) FAT (kg) FFM (kg) Uric acid (mg/dL) Serum creatinine (mg/dL) eGFR (mL/min/1.73 m2 ) Obesity, n (%) Central obesity, n (%) IFG, n (%) Diabetes mellitus, n (%) Hypertriglyceridemia, n (%) Low HDL cholesterol, n (%) Hypertension, n (%)
Non-MS
MS
P*
51.6 ± 10 40 (72.7) 27 (50) 32 (59.2) 17 (31.6) 99.8 ± 23 5.5 ± 0.8 106.3 ± 44 165 ± 39 57.4 ± 18 90.4 ± 37.5 125.5 ± 15 77 ± 9 24.8 ± 2.8 91.4 ± 9.6 18 ± 7.2 53.4 ± 9.2 5.9 ± 2.0 1.1 ± 0.3 65.8 ± 25 2 (3.7) 9 (17) 5 (9.2) 15 (28) 4 (7.5) 8 (15) 16 (31)
58 ± 6.3 23 (79) 18 (60) 13 (43) 17 (56) 108.5 ± 18.5 6.0 ± 0.9 174 ± 96 169 ± 43.6 44 ± 14.2 94.8 ± 38.1 125 ± 15 75.8 ± 7.5 27.1 ± 4 100.4 ± 11.2 22 ± 8.6 55 ± 11 6.4 ± 1.8 1.23 ± 0.3 54.7 ± 17.2 6 (20) 20 (66) 5 (16.6) 20 (66) 18 (60) 13 (43) 24 (79)
0.003 0.505 0.258 0.120 0.022 0.088 0.037 <0.001 0.640 0.002 0.710 0.874 0.602 0.004 <0.001 0.04 0.409 0.371 0.130 0.056 0.022 <0.001 0.030 0.002 <0.001 0.007 <0.001
Values are mean ± SD or n (%). MS: metabolic syndrome; HCV: hepatitis C virus; HbA1: chemoglobin A1c; HDL: high-density cholesterol; LDL: low-density cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; FAT: fat mass; FFM: fat free mass; eGFR: estimated glomerular filtration rate; IFG: impaired fasting glucose; SD: standard deviation. * Student’s t test/Mann–Whitney test for continue variables, 2 test for categorical variables.
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respectively; p = 0.03), and MS (76% vs. 39.5% respectively; p = 0.01). Patients who had MS at any time during the study period vs. subjects who did not display any features of MS showed a higher prevalence of acute graft rejection (40.8% vs. 28.6%, respectively; p = 0.178), infections (38.8% vs. 22.9%, respectively; p = 0.095) and major CVD events (16.3% vs. 0%, respectively; p = 0.01). CVD events included hospitalization for acute heart failure, acute coronary syndrome, and ischaemic or haemorrhagic stroke. Before OLT, 20/35 (57.2%) of diabetic subjects were treated with diet alone whereas 11/35 (31.4%) were treated with insulin and 4/35 (11.4%) received oral hypoglycaemic agents. At 3 months, 31/35 (88.5%) diabetic subjects were receiving intensive insulin treatment (mean daily dose, 45 ± 20 UI). Subsequently, both the number of subjects on insulin therapy (77.1% at 6 months, 58.3% at 12 months) and the daily insulin dose (37 ± 22 UI/day at 6 months, 29 ± 20 UI/day at 12 months) decreased. Conversely, the number of patients treated with diet alone increased from 4/35 (11.4%) at 3 months to 7/35 (20%) at 6 months and to 14/36 (38.8%) at 12 months. In non-diabetic patients, both insulin levels (pre-OLT: 17.8 ± 17.3 UI/mL; 3 months: 13.3 ± 9.5 UI/mL; 6 months 10.5 ± 5.6 UI/mL; 12 months: 9.7 ± 6.2 UI/mL; p = 0.006), and HOMA-IR index (pre-OLT: 4.5 ± 5.0; 3 months: 3.01 ± 2.2; 6 months: 2.3 ± 1.3; 12 months: 2.24 ± 1.6; p = 0.016) decreased significantly after OLT. We then excluded from the analysis subjects presented with MS before OLT and those who were lost during the follow-up and thus compared the pre- and post-transplant characteristics of patients who never developed PTMS with those who did at any time post-OLT (Table 3). Patients who developed PTMS were older and showed higher pre-OLT values of BMI, waist circumference and fat mass, and prevalence of diabetes, family history of diabetes, and obesity, but not higher levels of IFG, dyslipidaemia or hypertension, than subjects who did not develop PTMS. A multivariate logistic regression model with stepwise backward variable selection was applied to analyse baseline variables associated with development of PTMS, including age, gender, presence of HCV infection, HCC and alcohol intake, family history of diabetes, BMI and pre-OLT diabetes mellitus. Only family history of diabetes (p = 0.005), presence of diabetes (p = 0.013), and BMI (p = 0.001) at baseline were identified as independent variables associated with PTMS. When included in the model, immunosuppressive therapy did not correlate with PTMS occurrence. After OLT, total cholesterol, triglycerides, uric acid, and systolic and diastolic blood pressure increased significantly both in subjects who did and did not develop PTMS, whereas HbA1c and creatinine increased only in PTMS individuals (Supplemental Table S1). Moreover, prevalence of hypertriglyceridemia, low HDL cholesterol and hypertension increased in PTMS patients, whereas only the rate of hypertension was significantly higher in non-PTMS subjects at 12 months vs. baseline (Supplemental Table S2). After OLT, HbA1c , triglycerides, BMI, waist circumference, fat mass and, except at 6 months, systolic blood pressure were significantly higher in PTMS than in non-PTMS subjects. In addition, prevalence rates of diabetes, hypertriglyceridemia, hypertension and, except at 3 months, obesity were higher in PTMS than in non-PTMS subjects (Table 3). The analysis of daily food intake in transplanted patients showed an initial increase in caloric intake, with redistribution of macronutrients, i.e. reduced consumption of carbohydrates and increased consumption of fats, saturated fats and cholesterol, expressed as percentage of total energy intake (Table 4). Before transplantation, no significant differences were found in energy intake and distribution of macronutrients between patients with and without MS (not shown). Conversely, after OLT, patients with MS showed a higher intake of total energy, with an increased consumption of saturated fats. Moreover, intake of fibres was lower in MS patients vs.
non-MS patients at 12 months (Table 5). Similar results were observed when only the subjects not affected by MS before transplantation were considered (Supplemental Table S3).
4. Discussion This is the first prospective study assessing the prevalence and determinants of PTMS occurring within 1 year post-OLT. Although the prevalence of MS rapidly increased from 16.6% pre-OLT to 32.1%, 35.7% and 39.5% at 3, 6 and 12 months post-OLT, respectively, the 1-year figures are higher than the estimated prevalence reported in the general Western population [5] and somewhat lower than those from previous retrospective surveys using the NCEP-ATP III criteria and examining longer time periods [4]. In particular, Laryea et al. found that 58% of 118 patients who had undergone OLT developed MS [9]. Similar findings were observed by Laish et al. in 252 subjects, with a 5.4% prevalence before and 51.9% after transplantation [14]. The mean observation times were approximately of 5 and 6 years, respectively. Another study evaluating 296 subjects reported a slightly lower prevalence of MS (45%) over a shorter time period (38 months on average) [15]. High rates (50% at 1 year) were also reported by Hanouneh et al. in 95 patients with HCV infection [16], a high-risk condition for MS [4,8]. There are several potential explanations for the apparently lower prevalence of MS in our study. Firstly, although PTMS is an early phenomenon, its prevalence might further increase in longer follow-up periods. This is supported by a trend towards an increased prevalence of PTMA in longer follow-up periods, as observed in the retrospective studies mentioned above [9,14–16]. However, a preliminary report showed that MS prevalence at 12 months was only slightly lower than that at 6 years (39% vs. 46%) [17]. Secondly, the prospective design of our study, specifically focused on MS, may have favoured a reduced occurrence of this condition. In fact, our patients underwent a strict follow-up and nutritional counselling during the study period, which could have reduced post-OLT weight gain and its metabolic consequences. This interpretation is consistent with the finding that, while prevalence of diabetes, hypertension and dyslipidaemia in our cohort were similar, obesity, but not central obesity, was present in a much lower percentage of patients (7–15% vs. 27.5%, respectively), than in previous reports [9,14,15], including a study with a short followup [16]. Further follow-up of our patients will answer this question. Finally, another factor might be the low pre-OLT MS frequency (16.6%). MS prevalence in patients with cirrhosis is not well established and may vary with aetiology, with higher rates observed in cryptogenic cirrhosis (29%) than in other liver disorders (6%) [18]. However, low prevalence rates are consistent with malnutrition and the haemodynamic and metabolic changes characterizing liver cirrhosis, which reduce the frequency of hypertension and dyslipidaemia [8] but favour the occurrence of “hepatogenous” diabetes, as shown by a case control study [19]. Multiple regression analysis of pre-operative risk factors showed, in contrast to a previous report [9], that aetiology of liver disease was not an independent predictor of PTMS in our cohort. In contrast, we found that family history of diabetes, pre-OLT diabetes and excess weight were independently associated with the development of PTMS, consistently with previous studies [9,14,15]. Among the post-OLT risk factors, the overall prevalence of diabetes and obesity did not significantly change after OLT. However, there was a trend towards an increase of central obesity from 3 to 12 months. Additionally HbA1c , BMI, and waist circumference were significantly higher in subjects who developed PTMS than those who did not. This is consistent with previous reports showing that the greatest relative weight gain occurs during the first year [7,20]. In contrast to the prevalence of diabetes and obesity,
Table 3 Baseline and 3-, 6- and 12-month characteristics of patients who did (n = 32) and did not (n = 35) develop post-transplantation metabolic syndrome. Pre-OLT Non-PTMS
PTMS
P
Non-PTMS
PTMS
50.5 ± 11 9 (26) 26 (74) 13 (37) 96 ± 37 4.7 ± 1.2 77 ± 40 138 ± 51 57.6 ± 22 73 ± 44.5 111 ± 15 69 ± 11 24 ± 2.6 90.7 ± 8.5 16 ± 5.1 52.4 ± 9.2 4.3 ± 1.7 0.85 ± 0.23 0 (0) 5 (14) 5 (14) 7 (20) 2 (5.7) 5 (14) 5 (14)
56 ± 7 16 (50) 25 (78) 19 (54) 107 ± 27 5.4 ± 1.2 84.5 ± 27.5 129 ± 31.4 54 ± 15.3 60 ± 29 116 ± 11 73 ± 8 27.2 ± 4 98.8 ± 10.5 23.5 ± 7.0 54.0 ± 9.0 4.9 ± 1.3 0.9 ± 0.3 5 (15.5) 18 (56) 5 (15.5) 17 (53) 0 (0) 4 (12.5) 2 (6.2)
0.028 0.036 0.469 0.057 0.159 0.061 0.421 0.394 0.581 0.252 0.102 0.083 0.001 0.001 0.001 0.452 0.092 0.414 0.021 0.001 0.220 0.005 0.269 0.559 0.220
– – – – 96.6 ± 27 5.0 ± 0.7 99 ± 27 170.5 ± 40 61.0 ± 21.5 90.7 ± 27 126 ± 14 78 ± 9 23 ± 2.3 90.0 ± 8.1 15.3 ± 5.4 51 ± 9.5 5.3 ± 1.8 0.98 ± 0.3 0 (0) 6 (17) 4 (11.4) 5 (14) 1 (2.8) 4 (11.5) 5 (14)
– – – – 111.5 ± 34 6.0 ± 0.9 145.3 ± 55 188 ± 45 50.5 ± 17 114 ± 33 131 ± 11 80 ± 8.5 26.4 ± 3.5 97 ± 9.3 23 ± 12.1 56.5 ± 8 6.0 ± 1.4 1.08 ± 0.3 5 (15.5) 14 (44) 3 (9.4) 20 (62.5) 13 (40.6) 11 (34.5) 18 (56)
6 months post-OLT *
P
Non-PTMS
PTMS
0.054 0.001 0.001 0.105 0.057 0.014 0.170 0.343 0.001 0.001 0.003 0.018 0.073 0.176 0.021 0.017 0.312 0.001 0.001 0.033 0.001
– – – – 94 ± 17 5.3 ± 0.7 104 ± 48.5 160 ± 40.5 54.5 ± 17 92.2 ± 35 121 ± 14.5 74 ± 6.6 24.0 ± 2.3 90 ± 7.8 15.9 ± 4.8 52.4 ± 8.9 5.6 ± 1.8 1.06 ± 0.3 0 (0) 5 (14) 4 (11.4) 5 (14) 3 (8.5) 6 (17) 8 (23)
– – – – 108 ± 23 6.0 ± 0.8 163 ± 96 171 ± 41.5 49 ± 17.5 90 ± 36 129 ± 13 79 ± 8.5 27.0 ± 3.9 98 ± 11.6 22 ± 7.8 56.1 ± 9.4 6.1 ± 1.7 1.2 ± 0.3 6 (19) 18 (56) 4 (12.5) 20 (62.5) 14 (44) 10 (31.2) 20 (62.5)
12 months post-OLT *
P
Non-PTMS
PTMS
P*
0.078 0.001 0.002 0.292 0.244 0.904 0.019 0.023 0.001 0.003 0.002 0.132 0.200 0.084 0.010 0.001 0.177 0.001 0.001 0.164 0.001
– – – – 96.6 ± 19.4 5.2 ± 0.7 92 ± 38 162.7 ± 40 51 ± 14 93 ± 24 122 ± 15 77 ± 9 24 ± 2.8 90 ± 9.8 15.5 ± 5.8 53.2 ± 10 5.6 ± 1.7 1.08 ± 0.2 0 (0) 7 (20) 5 (14) 6 (17) 3 (8.5) 9 (25.7) 13 (37)
– – – – 108 ± 17 5.8 ± 0.7 148 ± 62 172.6 ± 41 46 ± 17 98 ± 33.2 131.5 ± 12 80 ± 6.5 28 ± 4 102 ± 9.6 22.3 ± 6.2 58 ± 9.8 6.6 ± 1.4 1.07 ± 0.2 10 (31) 20 (62.5) 5 (15.5) 20 (62.5) 14 (44) 14 (44) 22 (68.7)
0.012 0.001 0.001 0.329 0.242 0.626 0.009 0.080 0.001 0.001 0.001 0.102 0.024 0.858 0.001 0.001 0.106 0.001 0.001 0.091 0.009
M.E. Lunati et al. / Digestive and Liver Disease 45 (2013) 833–839
Age (years) Family history of diabetes, n (%) Male gender, n (%) HCV positive, n (%) Fasting glucose level (mg/dL) HbA1c (%) Triglycerides (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) SBP (mmHg) DBP (mmHg) BMI (kg/mt2 ) Waist (cm) FAT (kg) FFM (kg) Uric acid (mg/dL) Serum creatinine (mg/dL) Obesity, n (%) Central obesity, n (%) IFG, n (%) Diabetes mellitus, n (%) Hypertriglyceridemia, n (%) Low HDL cholesterol, n (%) Hypertension, n (%)
3 months post-OLT *
Values are mean ± SD or n (%). PTMS: post-transplantation metabolic syndrome; OLT: orthotopic liver transplantation; HCV: hepatitis C virus; HbA1c : haemoglobin A1c ; HDL: high-density cholesterol; LDL: low-density cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; FAT: fat mass; FFM: fat free mass; IFG: impaired fasting glucose; SD: standard deviation. * Student’s t test/Mann–Whitney test for continue variables, 2 test for categorical variables.
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Table 4 Total energy daily intake and macronutrients distribution pre-OLT and 3 and 6 and 12 months after OLT (n = 81). Pre-OLT Total energy (kcal/day) Carbohydrates (%) Proteins (%) Fats (%) Saturated fats (%) Cholesterol (mg) Fibres (g)
2006 57 15 28 8.3 211 18.5
± ± ± ± ± ± ±
3 months post-OLT
624 27 4.7 8.2 3.7 155 7.8
2516 49 15.5 35.5 10.8 332 21.0
± ± ± ± ± ± ±
6 months post-OLT
763 7.5 3.5 8.1 3.3 174 6.4
2069 49.5 15.5 35 10.0 248 18.9
± ± ± ± ± ± ±
P*
12 months post-OLT
466 8.3 2.9 7.4 3.5 104 7.5
2100 50 14.5 35.5 9.2 241.5 18.5
± ± ± ± ± ± ±
506 9.9 3.0 9.2 3.9 185 6.5
<0.001 0.002 0.768 <0.001 <0.001 <0.001 0.126
Values are mean ± SD. OLT: orthotopic liver transplantation; SD: standard deviation. * One-way analysis of variance for repeated measures. Table 5 Total energy daily intake and macronutrient distribution between patients with (n = 46) and without (n = 35) the metabolic syndrome, at 3, 6 and 12 months after orthotopic liver transplantation. 3 months post-OLT Non-MS Total energy (kcal/day) Carbohydrates (%) Proteins (%) Fats (%) Saturated fats (%) Cholesterol (mg) Fibres (g)
2417 50 15.2 34.5 9.9 330 21.5
± ± ± ± ± ± ±
533 7.8 3.5 7.3 2.7 179 7.4
6 months post-OLT
MS 2584 49 15.5 35.5 11.4 336 20.7
± ± ± ± ± ± ±
887 7.3 3.8 8.7 3.5 167 6.5
P*
Non-MS
0.35 0.26 0.99 0.73 0.05 0.88 0.625
1980 48.8 15.5 35 8.5 230 19.3
± ± ± ± ± ± ±
12 months post-OLT
MS
604 10.6 2.3 8.8 2.5 82 7.7
2112 48.5 16 36 10.7 257 18.2
± ± ± ± ± ± ±
389 7.2 3.9 6.7 3.7 113 7.3
P*
Non-MS
0.35 0.99 0.48 0.71 0.03 0.39 0.63
1912 50.5 14.5 34 7.7 238 24.4
± ± ± ± ± ± ±
534 5.0 3.3 7.9 2.8 193 5.2
P*
MS 2433 48.5 15.5 36 11.8 247 14.8
± ± ± ± ± ± ±
190 12 2.5 11.3 4.4 183 4.2
0.01 0.70 0.39 0.50 0.01 0.91 0.01
Values are mean ± SD. MS: metabolic syndrome; OLT: orthotopic liver transplantation; SD: standard deviation. * Student’s t test/Mann–Whitney test.
the rates of hypertriglyceridemia and hypertension increased dramatically after OLT according to previous reports [4,8,21], thus favouring the fulfilment of the criteria for MS diagnosis, especially in subjects who gained weight after OLT. These different trends in prevalence rates of MS components after OLT might be explained by the different effects that the restoration of liver function has on metabolic and haemodynamic parameters. In fact, OLT is associated with a reduction of insulin resistance due to improvement of hepatic insulin clearance. This is confirmed by the finding that, after OLT, non-diabetic patients showed reduced HOMA-IR index [20]; nevertheless, it cannot be ruled out that a toxic effect of immunosuppressive drugs may have contributed, at least in part, to the reduced insulin levels. On the other hand, a functioning liver graft favours an increase of lipid and blood pressure levels, as mentioned above. Other post-operative risk factors, i.e. immunosuppressive drugs and nutritional changes, may adversely affect all components of the MS. According to previous publications [7,14,15], despite the fact that immunosuppressive regimen was not included in the regression model, subjects on cyclosporine had a higher prevalence of MS and of some of its components than those on tacrolimus, thus suggesting the need for tailoring the immunosuppressive drugs. Moreover, tapering of corticosteroids was associated with a reduction of the number of subjects on insulin and of the daily insulin dose. Finally, the most intriguing findings of our study derive from the analysis of food diaries, which showed a modification of the nutritional habits after OLT, with higher intake of calories, saturated fat and cholesterol, despite strict nutritional surveillance and counselling. These changes were more pronounced in MS patients, who also showed a lower intake of fibres than non-MS subjects, thus supporting the concept that nutritional factors play a major role in the development of PTMS. In this view, it can be speculated that obese and/or overweight patients before transplantation are at higher risk of developing obesity and MS after OLT because they may return to their previous unbalanced diet. Multiple factors may contribute to changes in nutritional habits. First, the improvements in general health and well-being stimulate appetite and food intake. Additionally, many patients complain of constant hunger
after transplantation, which may be related to the use of prednisone or to emotional issues. Previous long-term retrospective studies showed that the risk of complications, and particularly of major CVD events, is higher in subjects developing MS after OLT. In fact, Laryea et al. reported a higher rate of CVD events in MS than in non-MS subjects (30% vs. 8%; p = 0.003) [9], and similar findings were reported by Laish et al. (15.2% vs. 4.9%; p < 0.007) [14]. A relevant finding of our study is the demonstration that this risk was already increased in the early post-OLT period in MS subjects. Strengths of this study are the prospective design, the focus on the early post-OLT period, and the strict nutritional surveillance and counselling. A possible limitation is the smaller number of subjects compared to previous reports [14,15]. Moreover, assessment of body weight and waist circumference may have been confounded by the presence of ascites and oedema in some patients with cirrhosis, thus affecting pre-OLT prevalence rate of MS. In fact, the percentage of subjects with an increased waist circumference decreased from 41.6% to 28.5% at 3 months post-OLT, when excess fluids were no longer observed. In conclusion, these data show that the development of PTMS is an early phenomenon and is related to pre-OLT diabetes and obesity and to nutritional changes after OLT. Lifestyle modifications, especially in overweight and/or obese patients, should be recommended to transplanted individuals starting in the early post-OLT period [22]. This would facilitate prevention of body weight gain and the associated abnormalities, including dyslipidaemia and hypertension, thus reducing the incidence of PTMS and the related CVD complications [23]. Conflict of interest statement None declared. Acknowledgements This work was supported by the IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation, Milan (MI), Italy.
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2013.03.009. References [1] Verdonk RC, van den Berg AP, Slooff MJ, et al. Liver transplantation: an update. Netherlands Journal of Medicine 2007;65:372–80. [2] Satapathy SK, Charlton MR. Posttransplant metabolic syndrome: new evidence of an epidemic and recommendations for management. Liver Transplantation 2011;17:1–6. [3] Correia TD, Rego MI, Lima LOAS. Post-liver transplant obesity and diabetes. Current Opinion in Clinical Nutrition and Metabolic Care 2003;6:457–60. [4] Pagadala M, Dasarathy S, Eghtesad B, et al. Posttransplant metabolic syndrome: an epidemic waiting to happen. Liver Transplantation 2009;15:1662–70. [5] Ford ES, Li C, Zhao G. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adult in the US. Journal of Diabetes 2010;2:180–93. [6] Bodziak KA, Hricik DE. New-onset diabetes mellitus after solid organ transplantation. Transplant International 2009;22:519–30. [7] Richards J, Gunson B, Johnson J, et al. Weight gain and obesity after liver transplantation. Transplant International 2005;18:461–6. [8] Watt KDS, Charlton MR. Metabolic syndrome and liver transplantation: a review and guide to management. Journal of Hepatology 2010;53:199–206. [9] Laryea M, Watt K, Molinari M, et al. Metabolic syndrome in liver transplant recipients: prevalence and association with major vascular events. Liver Transplantation 2007;13:1109–14. [10] Expert Panel on detection, evaluation and treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection. Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Journal of the American Medical Association 2001;285:2486–97.
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[11] Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung and Blood Institute Scientific Statement. Circulation 2005;112:2735–52. [12] American Diabetes Association. Standards of medical care in diabetes – 2010. Diabetes Care 2010;33(Suppl. 1):S11–61. [13] Yu-Wei C, Han-Hsiang C, Tsang-En W, et al. Difference between CKD-EPI and MDRD equations in calculating glomerular filtration rate in patients with cirrhosis. World Journal of Gastroenterology 2011;17:4532–8. [14] Laish I, Braun M, Mor E, et al. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transplantation 2011;17:15–22. [15] Bianchi G, Marchesini G, Marzocchi R, et al. Metabolic syndrome in liver transplantation: relation to etiology and immunosuppression. Liver Transplantation 2008;14:1648–54. [16] Hanouneh IA, Feldstein AE, McCollough AJ, et al. The significance of metabolic syndrome in the setting of recurrent hepatitis C after liver transplantation. Liver Transplantation 2008;14:1287–93. [17] Francioso S, Angelico F, Baiocchi L, et al. High prevalence of metabolic syndrome and long-term survival after liver transplantation. Journal of Hepatology 2008;48:S82. [18] Tellez-Avila F, Sanchez-Avila F, Garcia-Saenz-de-Socolia M, et al. Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis. World Journal of Gastroenterology 2008;14:4771–5. [19] Poonawala A, Nair S, Thuluvath P. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case–control study. Hepatology 2000;32:689–92. [20] Perseghin G, Mazzaferro V, Sereni LP, et al. Contribution to reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation. Hepatology 2000;31:694–703. [21] Martínez-Saldivar B, Prieto J, Berenguer M, et al. Control of blood pressure in liver transplant recipients. Transplantation 2012;93:1031–7. [22] Krasnoff JB, Vintro AQ, Ascher NL, et al. A randomized trial of exercise and dietary counseling after liver transplantation. American Journal of Transplantation 2006;6:1896–905. [23] Mells G, Neuberger J. Reducing the risks of cardiovascular disease in liver allograft recipients. Transplantation 2007;83:1141–50.
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Metabolic syndrome after liver transplantation: Short-term prevalence and preand post-operative risk factors Maria Elena Lunati a , Valeria Grancini a , Francesca Agnelli b,1 , Stefano Gatti c , Benedetta Masserini a , Dario Zimbalatti a , Giuseppe Pugliese d , Giorgio Rossi c , Maria Francesca Donato b , Massimo Colombo b , Paolo Beck-Peccoz a , Emanuela Orsi a,∗ a
Endocrinology and Diabetes Unit, University of Milan, Milan (MI), Italy A.M. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, University of Milan, Milan (MI), Italy c General Surgery Unit, IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation, University of Milan, Milan (MI), Italy d Department of Clinical and Molecular Medicine, “La Sapienza” University, Rome (RM), Italy b
a r t i c l e
i n f o
Article history: Received 11 August 2012 Accepted 17 March 2013 Available online 29 June 2013 Keywords: Hypertension New-onset diabetes after transplantation Obesity Orthotopic liver transplantation Post-transplantation metabolic syndrome
a b s t r a c t Background: The metabolic syndrome is a common condition among liver transplanted patients and contributes to morbidity and mortality by favouring the development of cardiovascular diseases. Aims: This prospective study assessed the prevalence of metabolic syndrome in the first year after orthotopic liver transplantation, the associated pre-operative and post-operative risk factors and the influence of nutritional factors. Methods: 84 cirrhotic patients (75% male, mean age 53.9 ± 9.3 years) were evaluated at baseline and after liver transplantation. Metabolic syndrome was defined according to 2004 Adult Treatment Panel-III criteria. Nutritional habits were assessed using 3-day food records. Results: Prevalence of metabolic syndrome before orthotopic liver transplantation was 14/84 (16.6%); at 3, 6 and 12 months post-orthotopic liver transplantation it was 27/84 (32.1%), 30/84 (35.7%), and 32/81 (39.5%), respectively. Diabetes, family history of diabetes, and excess body weight at baseline independently correlated with incidence of metabolic syndrome. After orthotopic liver transplantation, patients with metabolic syndrome showed a higher increase in the intake of total energy and saturated fats and a higher prevalence of complications, especially cardiovascular events, than subjects without metabolic syndrome. Conclusion: Occurrence of metabolic syndrome is an early phenomenon after liver transplantation. Preoperative and post-operative factors predispose patients to metabolic syndrome, which may be reduced by controlling modifiable risk factors, such as body weight and dietary intake. © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Liver transplantation is the elective therapy for cirrhosis. It has improved life quality and expectancy of patients with end-stage liver disease, with 1-year and 5-year survival rates of approximately 85% and 75%, respectively [1]. As longer survival rates have been achieved, the incidence of metabolic derangements clustering in the metabolic syndrome (MS), such as hyperglycaemia, hypertension, dyslipidaemia and central obesity, has also increased [2,3].
∗ Corresponding author at: Endocrinology and Diabetes Unit, Department of Medical Sciences, University of Milan, IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation, Via F Sforza 35, 20122 Milan, Italy. Tel.: +39 3385238279; fax: +39 0250320605. E-mail addresses: [email protected], emanuela [email protected] (E. Orsi). 1 Current address: Unit of Internal Medicine, Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milan (MI), Italy.
Retrospective studies have shown that post-transplantation MS (PTMS) develops in 43% to 58% of patients over a period of 2–6 years after orthotopic liver transplantation (OLT) [4], a prevalence higher than that of the general population [5]. Unfortunately, prospective studies are lacking; therefore, the prevalence of PTMS during the first few months after OLT and the OLT-related and unrelated factors favouring the early development of this condition are poorly defined. Immunosuppressant regimens required for organ acceptance may account for a large proportion of the increased risk for the development of PTMS. It is recognized that corticosteroids have a diabetogenic action, mainly by increasing insulin resistance; moreover, there is also evidence of a dose–response relationship between steroids and the development of new-onset diabetes after transplantation (NODAT) [6]. Both cyclosporine and tacrolimus are associated with hypertension, dyslipidaemia and hyperglycaemia, the latter due to reduced insulin synthesis and secretion, insulin
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resistance and hyperinsulinemia [2]. Other potential pathogenic factors are lifestyle modifications with return to unrestricted food intake and consequent weight gain driving the metabolic abnormalities associated with central obesity [7]. Predictors of PTMS include older age, male gender, excess pre-OLT body weight, pre-OLT diabetes, and the aetiology of underlying liver disease, particularly hepatitis C virus (HCV) infection, alcohol-related liver disease, and cryptogenic cirrhosis [4,8]. As a result of the increased incidence of MS, cardiovascular diseases (CVD) have been emerging as a major cause of both morbidity and mortality in these subjects [9]. The aim of the present study was to prospectively assess the prevalence of MS early after OLT, as well as the associated pre-operative and post-operative modifiable risk factors, with particular reference to changes in anthropometric parameters, body composition, and nutritional intake that occur soon after OLT. 2. Materials and methods 2.1. Study population One-hundred and eighty-three patients on the waiting list for liver transplantation were consecutively recruited and evaluated at the IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation of Milan from 2006 to 2010. Eighty-four of these patients underwent OLT during that period, whereas the remaining subjects (99/183) were excluded from the waiting list (11/183), died before OLT (19/183) or are still awaiting transplantation (69/183). Transplanted patients were re-evaluated at 3, 6 and 12 months after OLT. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008), as reflected in a priori approval by the institution’s human research committee. All patients gave written informed consent to participate in the study. According to the 2001 guidelines of the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) [10] and their 2004 revision [11], MS was defined as the presence of 3 or more of the following: central obesity (waist circumference >102 cm in men and >88 cm in women); high fasting glucose levels [>110 mg/dL (>6.1 mmol/L)]; hypertriglyceridemia [>150 mg/dL (1.69 mmol/L)]; low high-density lipoprotein (HDL) levels [<40 mg/dL (1.04 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women]; high blood pressure (>130/85 mmHg) or specific treatment for each of these conditions. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2 . NODAT was diagnosed according to the American Diabetes Association guidelines [12]. 2.2. Clinical parameters Body weight and height were measured with scale and stadiometer whereas body mass index (BMI) was calculated as patient’s weight in kg divided by patient height (in metres) squared. Waist circumference was taken at the umbilicus. Blood pressure was measured with a mercury sphygmomanometer after the patient had been lying supine for at least 5 min. Fat mass and fatfree mass were measured using an impedance method (Maltron BioScan® ). All subjects underwent a strict nutritional surveillance and counselling, aimed at assessing usual dietary intake and identifying areas where change was needed and possible barriers to changes. Food and alcohol intake were assessed by the use of a food record method. Types and amounts of food and beverages consumed during 3 consecutive days (2 weekdays and 1 weekend day) were recorded in a food diary. Patients were given oral and written instructions by the medical staff on how to keep a food diary.
Food estimates were facilitated by the use of photographs showing portion sizes and corresponding weights. Total calories and percent of nutrients were then calculated using a computer software (Dieta Ragionata® 7.0). At each visit, records were examined by a dietician, who provided nutritional counselling, information, educational material, and support to achieve or maintain targets. Complications, including major CVD events, infections and acute graft rejection, as well as type and dosage of immunosuppressive agents were recorded. 2.3. Biochemical parameters All patients were evaluated at baseline and after transplantation for fasting glucose, triglycerides, total and HDL cholesterol, with calculation of low-density lipoprotein (LDL) cholesterol by the Friedwald formula, aspartate transaminase, alanine transaminase, ␥-glutamyl transferase, alkaline phosphatase, total and conjugated bilirubin, pseudocholinesterase, serum creatinine, urea, uric acid and complete blood count using standard methods. Estimated glomerular filtration rate was calculated from serum creatinine using the Modification of Diet in Renal Disease 6-variable equation [13]. Haemoglobin A1c (HbA1c ) was assessed by the use of a high performance liquid chromatography, National Glycohaemoglobin Standardisation Program-certified and Diabetes Control and Complications Trial-standardized method. Non-diabetic patients were also evaluated for insulin levels by immunoenzymetric one-step assay (Medgenics Diagnostics, Belgium) and electrochemiluminescence immunoassay (Roche Diagnostics, Germany). Insulin resistance was then estimated by the homeostatic model assessment-insulin resistance (HOMA-IR) index (http://www.dtu.ox.ac.uk/homacalculator/index.php). 2.4. Statistical analysis Statistical analysis was performed with the statistical package SPSS for Windows version 17.0 (SPPS Inc. Chicago, IL). Data are expressed as mean ± standard deviation for continuous variables and as number of cases and percentage for categorical variables. Groups were compared using the Student’s t test for parametric continuous variables, and the Mann–Whitney test for nonparametric continuous variables. Normality of distribution was preliminary assessed by the Kolmogorov–Smirnov test. The 2 test or the Fischer’s exact test, when applicable, were used for categorical variables. One-way analysis of variance for repeated measures or the McNemar’s test were applied to analyse post-OLT changes of continuous and categorical variables, respectively. Logistic regression analysis with stepwise backward variable selection was performed to identify independent predictors of PTMS, using a p value < 0.05 as criteria to include and a p > 0.10 as criteria to remove variables from the model. p values < 0.05 were considered statistically significant. 3. Results Overall 84 patients who underwent OLT were enrolled (75% male, mean age 53.9 ± 9.3 years). Underlying liver disease was: HCV infection in 45/84 (53.6%), hepatitis B virus infection in 15/84 (17.8%), delta virus infection in 5/84 (6.0%), autoimmune disorders (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis) in 8/84 (9.5%), alcohol-related in 8/84 (9.5%), and metabolic (Wilson disease, haemochromatosis) in 3/84 (3.6%). Superimposed hepatocellular carcinoma (HCC) was diagnosed in 21 (25%) of the 84 patients. All subjects received calcineurin inhibitors (58.3% tacrolimus and 41.7% cyclosporine) associated with tapered
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Table 1 Prevalence of the metabolic syndrome and its components before and after orthotopic liver transplantation.
N Metabolic syndrome Central obesity Obesity IFG Diabetes mellitus Hypertriglyceridemia Low HDL Arterial hypertension
Pre-OLT
3 months post-OLT
P*
6 months post-OLT
P*
12 months post-OLT
P*
84 14 (16.6) 35 (41.6) 8 (9.5) 14 (16.6) 35 (41.7) 4 (4.8) 21 (25.0) 11 (13.1)
84 27 (32.1) 24 (28.5) 6 (7.1) 10 (11.9) 35 (41.6) 20 (23.8) 20 (23.8) 34 (40.4)
0.015 0.035 0.687 0.515 1.0 0.001 0.908 <0.001
84 30 (35.7) 29 (34.5) 8 (9.5) 10 (11.9) 35 (41.6) 22 (26.2) 21 (23.8) 40 (47.6)
0.004 0.242 1.0 0.515 1.0 0.001 0.845 <0.001
81 32 (39.5) 34 (42.0) 12 (14.8) 12 (14.8) 36 (44.4) 21 (25.9) 28 (34.5) 46 (56.5)
0.001 1.0 0.344 0.607 0.508 0.001 0.243 <0.001
All values are n (%). OLT: orthotopic liver transplantation; IFG: impaired fasting glucose; HDL: high-density lipoprotein. * McNemar’s test, vs. pre-OLT.
corticosteroids. Three patients were lost to follow-up before the 12month post-OLT evaluation: 2 patients died from acute liver failure 8 months after OLT and 1 subject moved elsewhere. At baseline, 35/84 patients (41.6%) had diabetes. Moreover, 35 subjects (41.6%) had central obesity and 21 (25.0%) had low HDL cholesterol, 8 individuals (9.5%) were obese, 11 (13.1%) had hypertension and 4 (4.8%) had hypertriglyceridemia. As a result, only 14/84 (16.6%) patients fulfilled the criteria for the diagnosis of MS (Table 1). After OLT, while prevalence of diabetes, impaired fasting glucose (IFG), low HDL cholesterol, and obesity did not change significantly, the percentage of patients with hypertriglyceridemia and arterial hypertension markedly increased. As a consequence, MS was diagnosed in 27/84 patients (32.1%) at 3 months, 30/84 (35.7%) at 6 months, and 32/81 (39.5%) at 12 months (Table 1). Interestingly, 5 of the 35 patients with diabetes and 6 of the 14 patients with MS at baseline, had reversed these conditions at 3 months post-OLT, when 5 cases of NODAT and 19 of PTMS were diagnosed. Subsequently, only 2 subjects developed NODAT (and 1 reversed it), whereas 9
and 10 patients developed PTMS at 6 and 12 months, respectively, when 6 and 7 individuals reversed it. One of the 2 subjects who died had diabetes and MS. Subjects with MS at 6 months post-OLT were older and had significantly higher BMI, waist circumference and fat mass, as well as higher prevalence of diabetes, family history of diabetes, obesity, dyslipidaemia, and hypertension than patients without MS (Table 2). Similar results were obtained at 3 and 12 months (not shown). The mean daily dose of prednisone did not differ between patients with and without MS at 3 months after OLT (8.9 ± 4.8 mg vs. 9.1 ± 4.9 mg; p = 0.537). At 6 and 12 months post-OLT, respectively 19/30 (63.3%) and 28/32 (87.5%) patients with MS and 24/54 (44.5%) and 36/49 (73.5%) patients without MS discontinued corticosteroid therapy. Regarding immunosuppressive therapy, at 12 months postOLT patients on cyclosporine vs. patients receiving tacrolimus had significantly higher prevalence of hypertension (71% vs. 44%, respectively; p = 0.013), hypertriglyceridemia (37% vs. 16%
Table 2 Characteristics of liver transplant recipients with (n = 30) and without (n = 54) metabolic syndrome 6 months after orthotopic liver transplantation.
Mean age (years) Male gender, n (%) HCV positive, n (%) Tacrolimus therapy, n (%) Family history of diabetes Fasting glucose level (mg/dL) HbA1c (%) Triglycerides (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) BMI (kg/m2 ) Waist (cm) FAT (kg) FFM (kg) Uric acid (mg/dL) Serum creatinine (mg/dL) eGFR (mL/min/1.73 m2 ) Obesity, n (%) Central obesity, n (%) IFG, n (%) Diabetes mellitus, n (%) Hypertriglyceridemia, n (%) Low HDL cholesterol, n (%) Hypertension, n (%)
Non-MS
MS
P*
51.6 ± 10 40 (72.7) 27 (50) 32 (59.2) 17 (31.6) 99.8 ± 23 5.5 ± 0.8 106.3 ± 44 165 ± 39 57.4 ± 18 90.4 ± 37.5 125.5 ± 15 77 ± 9 24.8 ± 2.8 91.4 ± 9.6 18 ± 7.2 53.4 ± 9.2 5.9 ± 2.0 1.1 ± 0.3 65.8 ± 25 2 (3.7) 9 (17) 5 (9.2) 15 (28) 4 (7.5) 8 (15) 16 (31)
58 ± 6.3 23 (79) 18 (60) 13 (43) 17 (56) 108.5 ± 18.5 6.0 ± 0.9 174 ± 96 169 ± 43.6 44 ± 14.2 94.8 ± 38.1 125 ± 15 75.8 ± 7.5 27.1 ± 4 100.4 ± 11.2 22 ± 8.6 55 ± 11 6.4 ± 1.8 1.23 ± 0.3 54.7 ± 17.2 6 (20) 20 (66) 5 (16.6) 20 (66) 18 (60) 13 (43) 24 (79)
0.003 0.505 0.258 0.120 0.022 0.088 0.037 <0.001 0.640 0.002 0.710 0.874 0.602 0.004 <0.001 0.04 0.409 0.371 0.130 0.056 0.022 <0.001 0.030 0.002 <0.001 0.007 <0.001
Values are mean ± SD or n (%). MS: metabolic syndrome; HCV: hepatitis C virus; HbA1: chemoglobin A1c; HDL: high-density cholesterol; LDL: low-density cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; FAT: fat mass; FFM: fat free mass; eGFR: estimated glomerular filtration rate; IFG: impaired fasting glucose; SD: standard deviation. * Student’s t test/Mann–Whitney test for continue variables, 2 test for categorical variables.
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respectively; p = 0.03), and MS (76% vs. 39.5% respectively; p = 0.01). Patients who had MS at any time during the study period vs. subjects who did not display any features of MS showed a higher prevalence of acute graft rejection (40.8% vs. 28.6%, respectively; p = 0.178), infections (38.8% vs. 22.9%, respectively; p = 0.095) and major CVD events (16.3% vs. 0%, respectively; p = 0.01). CVD events included hospitalization for acute heart failure, acute coronary syndrome, and ischaemic or haemorrhagic stroke. Before OLT, 20/35 (57.2%) of diabetic subjects were treated with diet alone whereas 11/35 (31.4%) were treated with insulin and 4/35 (11.4%) received oral hypoglycaemic agents. At 3 months, 31/35 (88.5%) diabetic subjects were receiving intensive insulin treatment (mean daily dose, 45 ± 20 UI). Subsequently, both the number of subjects on insulin therapy (77.1% at 6 months, 58.3% at 12 months) and the daily insulin dose (37 ± 22 UI/day at 6 months, 29 ± 20 UI/day at 12 months) decreased. Conversely, the number of patients treated with diet alone increased from 4/35 (11.4%) at 3 months to 7/35 (20%) at 6 months and to 14/36 (38.8%) at 12 months. In non-diabetic patients, both insulin levels (pre-OLT: 17.8 ± 17.3 UI/mL; 3 months: 13.3 ± 9.5 UI/mL; 6 months 10.5 ± 5.6 UI/mL; 12 months: 9.7 ± 6.2 UI/mL; p = 0.006), and HOMA-IR index (pre-OLT: 4.5 ± 5.0; 3 months: 3.01 ± 2.2; 6 months: 2.3 ± 1.3; 12 months: 2.24 ± 1.6; p = 0.016) decreased significantly after OLT. We then excluded from the analysis subjects presented with MS before OLT and those who were lost during the follow-up and thus compared the pre- and post-transplant characteristics of patients who never developed PTMS with those who did at any time post-OLT (Table 3). Patients who developed PTMS were older and showed higher pre-OLT values of BMI, waist circumference and fat mass, and prevalence of diabetes, family history of diabetes, and obesity, but not higher levels of IFG, dyslipidaemia or hypertension, than subjects who did not develop PTMS. A multivariate logistic regression model with stepwise backward variable selection was applied to analyse baseline variables associated with development of PTMS, including age, gender, presence of HCV infection, HCC and alcohol intake, family history of diabetes, BMI and pre-OLT diabetes mellitus. Only family history of diabetes (p = 0.005), presence of diabetes (p = 0.013), and BMI (p = 0.001) at baseline were identified as independent variables associated with PTMS. When included in the model, immunosuppressive therapy did not correlate with PTMS occurrence. After OLT, total cholesterol, triglycerides, uric acid, and systolic and diastolic blood pressure increased significantly both in subjects who did and did not develop PTMS, whereas HbA1c and creatinine increased only in PTMS individuals (Supplemental Table S1). Moreover, prevalence of hypertriglyceridemia, low HDL cholesterol and hypertension increased in PTMS patients, whereas only the rate of hypertension was significantly higher in non-PTMS subjects at 12 months vs. baseline (Supplemental Table S2). After OLT, HbA1c , triglycerides, BMI, waist circumference, fat mass and, except at 6 months, systolic blood pressure were significantly higher in PTMS than in non-PTMS subjects. In addition, prevalence rates of diabetes, hypertriglyceridemia, hypertension and, except at 3 months, obesity were higher in PTMS than in non-PTMS subjects (Table 3). The analysis of daily food intake in transplanted patients showed an initial increase in caloric intake, with redistribution of macronutrients, i.e. reduced consumption of carbohydrates and increased consumption of fats, saturated fats and cholesterol, expressed as percentage of total energy intake (Table 4). Before transplantation, no significant differences were found in energy intake and distribution of macronutrients between patients with and without MS (not shown). Conversely, after OLT, patients with MS showed a higher intake of total energy, with an increased consumption of saturated fats. Moreover, intake of fibres was lower in MS patients vs.
non-MS patients at 12 months (Table 5). Similar results were observed when only the subjects not affected by MS before transplantation were considered (Supplemental Table S3).
4. Discussion This is the first prospective study assessing the prevalence and determinants of PTMS occurring within 1 year post-OLT. Although the prevalence of MS rapidly increased from 16.6% pre-OLT to 32.1%, 35.7% and 39.5% at 3, 6 and 12 months post-OLT, respectively, the 1-year figures are higher than the estimated prevalence reported in the general Western population [5] and somewhat lower than those from previous retrospective surveys using the NCEP-ATP III criteria and examining longer time periods [4]. In particular, Laryea et al. found that 58% of 118 patients who had undergone OLT developed MS [9]. Similar findings were observed by Laish et al. in 252 subjects, with a 5.4% prevalence before and 51.9% after transplantation [14]. The mean observation times were approximately of 5 and 6 years, respectively. Another study evaluating 296 subjects reported a slightly lower prevalence of MS (45%) over a shorter time period (38 months on average) [15]. High rates (50% at 1 year) were also reported by Hanouneh et al. in 95 patients with HCV infection [16], a high-risk condition for MS [4,8]. There are several potential explanations for the apparently lower prevalence of MS in our study. Firstly, although PTMS is an early phenomenon, its prevalence might further increase in longer follow-up periods. This is supported by a trend towards an increased prevalence of PTMA in longer follow-up periods, as observed in the retrospective studies mentioned above [9,14–16]. However, a preliminary report showed that MS prevalence at 12 months was only slightly lower than that at 6 years (39% vs. 46%) [17]. Secondly, the prospective design of our study, specifically focused on MS, may have favoured a reduced occurrence of this condition. In fact, our patients underwent a strict follow-up and nutritional counselling during the study period, which could have reduced post-OLT weight gain and its metabolic consequences. This interpretation is consistent with the finding that, while prevalence of diabetes, hypertension and dyslipidaemia in our cohort were similar, obesity, but not central obesity, was present in a much lower percentage of patients (7–15% vs. 27.5%, respectively), than in previous reports [9,14,15], including a study with a short followup [16]. Further follow-up of our patients will answer this question. Finally, another factor might be the low pre-OLT MS frequency (16.6%). MS prevalence in patients with cirrhosis is not well established and may vary with aetiology, with higher rates observed in cryptogenic cirrhosis (29%) than in other liver disorders (6%) [18]. However, low prevalence rates are consistent with malnutrition and the haemodynamic and metabolic changes characterizing liver cirrhosis, which reduce the frequency of hypertension and dyslipidaemia [8] but favour the occurrence of “hepatogenous” diabetes, as shown by a case control study [19]. Multiple regression analysis of pre-operative risk factors showed, in contrast to a previous report [9], that aetiology of liver disease was not an independent predictor of PTMS in our cohort. In contrast, we found that family history of diabetes, pre-OLT diabetes and excess weight were independently associated with the development of PTMS, consistently with previous studies [9,14,15]. Among the post-OLT risk factors, the overall prevalence of diabetes and obesity did not significantly change after OLT. However, there was a trend towards an increase of central obesity from 3 to 12 months. Additionally HbA1c , BMI, and waist circumference were significantly higher in subjects who developed PTMS than those who did not. This is consistent with previous reports showing that the greatest relative weight gain occurs during the first year [7,20]. In contrast to the prevalence of diabetes and obesity,
Table 3 Baseline and 3-, 6- and 12-month characteristics of patients who did (n = 32) and did not (n = 35) develop post-transplantation metabolic syndrome. Pre-OLT Non-PTMS
PTMS
P
Non-PTMS
PTMS
50.5 ± 11 9 (26) 26 (74) 13 (37) 96 ± 37 4.7 ± 1.2 77 ± 40 138 ± 51 57.6 ± 22 73 ± 44.5 111 ± 15 69 ± 11 24 ± 2.6 90.7 ± 8.5 16 ± 5.1 52.4 ± 9.2 4.3 ± 1.7 0.85 ± 0.23 0 (0) 5 (14) 5 (14) 7 (20) 2 (5.7) 5 (14) 5 (14)
56 ± 7 16 (50) 25 (78) 19 (54) 107 ± 27 5.4 ± 1.2 84.5 ± 27.5 129 ± 31.4 54 ± 15.3 60 ± 29 116 ± 11 73 ± 8 27.2 ± 4 98.8 ± 10.5 23.5 ± 7.0 54.0 ± 9.0 4.9 ± 1.3 0.9 ± 0.3 5 (15.5) 18 (56) 5 (15.5) 17 (53) 0 (0) 4 (12.5) 2 (6.2)
0.028 0.036 0.469 0.057 0.159 0.061 0.421 0.394 0.581 0.252 0.102 0.083 0.001 0.001 0.001 0.452 0.092 0.414 0.021 0.001 0.220 0.005 0.269 0.559 0.220
– – – – 96.6 ± 27 5.0 ± 0.7 99 ± 27 170.5 ± 40 61.0 ± 21.5 90.7 ± 27 126 ± 14 78 ± 9 23 ± 2.3 90.0 ± 8.1 15.3 ± 5.4 51 ± 9.5 5.3 ± 1.8 0.98 ± 0.3 0 (0) 6 (17) 4 (11.4) 5 (14) 1 (2.8) 4 (11.5) 5 (14)
– – – – 111.5 ± 34 6.0 ± 0.9 145.3 ± 55 188 ± 45 50.5 ± 17 114 ± 33 131 ± 11 80 ± 8.5 26.4 ± 3.5 97 ± 9.3 23 ± 12.1 56.5 ± 8 6.0 ± 1.4 1.08 ± 0.3 5 (15.5) 14 (44) 3 (9.4) 20 (62.5) 13 (40.6) 11 (34.5) 18 (56)
6 months post-OLT *
P
Non-PTMS
PTMS
0.054 0.001 0.001 0.105 0.057 0.014 0.170 0.343 0.001 0.001 0.003 0.018 0.073 0.176 0.021 0.017 0.312 0.001 0.001 0.033 0.001
– – – – 94 ± 17 5.3 ± 0.7 104 ± 48.5 160 ± 40.5 54.5 ± 17 92.2 ± 35 121 ± 14.5 74 ± 6.6 24.0 ± 2.3 90 ± 7.8 15.9 ± 4.8 52.4 ± 8.9 5.6 ± 1.8 1.06 ± 0.3 0 (0) 5 (14) 4 (11.4) 5 (14) 3 (8.5) 6 (17) 8 (23)
– – – – 108 ± 23 6.0 ± 0.8 163 ± 96 171 ± 41.5 49 ± 17.5 90 ± 36 129 ± 13 79 ± 8.5 27.0 ± 3.9 98 ± 11.6 22 ± 7.8 56.1 ± 9.4 6.1 ± 1.7 1.2 ± 0.3 6 (19) 18 (56) 4 (12.5) 20 (62.5) 14 (44) 10 (31.2) 20 (62.5)
12 months post-OLT *
P
Non-PTMS
PTMS
P*
0.078 0.001 0.002 0.292 0.244 0.904 0.019 0.023 0.001 0.003 0.002 0.132 0.200 0.084 0.010 0.001 0.177 0.001 0.001 0.164 0.001
– – – – 96.6 ± 19.4 5.2 ± 0.7 92 ± 38 162.7 ± 40 51 ± 14 93 ± 24 122 ± 15 77 ± 9 24 ± 2.8 90 ± 9.8 15.5 ± 5.8 53.2 ± 10 5.6 ± 1.7 1.08 ± 0.2 0 (0) 7 (20) 5 (14) 6 (17) 3 (8.5) 9 (25.7) 13 (37)
– – – – 108 ± 17 5.8 ± 0.7 148 ± 62 172.6 ± 41 46 ± 17 98 ± 33.2 131.5 ± 12 80 ± 6.5 28 ± 4 102 ± 9.6 22.3 ± 6.2 58 ± 9.8 6.6 ± 1.4 1.07 ± 0.2 10 (31) 20 (62.5) 5 (15.5) 20 (62.5) 14 (44) 14 (44) 22 (68.7)
0.012 0.001 0.001 0.329 0.242 0.626 0.009 0.080 0.001 0.001 0.001 0.102 0.024 0.858 0.001 0.001 0.106 0.001 0.001 0.091 0.009
M.E. Lunati et al. / Digestive and Liver Disease 45 (2013) 833–839
Age (years) Family history of diabetes, n (%) Male gender, n (%) HCV positive, n (%) Fasting glucose level (mg/dL) HbA1c (%) Triglycerides (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) SBP (mmHg) DBP (mmHg) BMI (kg/mt2 ) Waist (cm) FAT (kg) FFM (kg) Uric acid (mg/dL) Serum creatinine (mg/dL) Obesity, n (%) Central obesity, n (%) IFG, n (%) Diabetes mellitus, n (%) Hypertriglyceridemia, n (%) Low HDL cholesterol, n (%) Hypertension, n (%)
3 months post-OLT *
Values are mean ± SD or n (%). PTMS: post-transplantation metabolic syndrome; OLT: orthotopic liver transplantation; HCV: hepatitis C virus; HbA1c : haemoglobin A1c ; HDL: high-density cholesterol; LDL: low-density cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; FAT: fat mass; FFM: fat free mass; IFG: impaired fasting glucose; SD: standard deviation. * Student’s t test/Mann–Whitney test for continue variables, 2 test for categorical variables.
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M.E. Lunati et al. / Digestive and Liver Disease 45 (2013) 833–839
Table 4 Total energy daily intake and macronutrients distribution pre-OLT and 3 and 6 and 12 months after OLT (n = 81). Pre-OLT Total energy (kcal/day) Carbohydrates (%) Proteins (%) Fats (%) Saturated fats (%) Cholesterol (mg) Fibres (g)
2006 57 15 28 8.3 211 18.5
± ± ± ± ± ± ±
3 months post-OLT
624 27 4.7 8.2 3.7 155 7.8
2516 49 15.5 35.5 10.8 332 21.0
± ± ± ± ± ± ±
6 months post-OLT
763 7.5 3.5 8.1 3.3 174 6.4
2069 49.5 15.5 35 10.0 248 18.9
± ± ± ± ± ± ±
P*
12 months post-OLT
466 8.3 2.9 7.4 3.5 104 7.5
2100 50 14.5 35.5 9.2 241.5 18.5
± ± ± ± ± ± ±
506 9.9 3.0 9.2 3.9 185 6.5
<0.001 0.002 0.768 <0.001 <0.001 <0.001 0.126
Values are mean ± SD. OLT: orthotopic liver transplantation; SD: standard deviation. * One-way analysis of variance for repeated measures. Table 5 Total energy daily intake and macronutrient distribution between patients with (n = 46) and without (n = 35) the metabolic syndrome, at 3, 6 and 12 months after orthotopic liver transplantation. 3 months post-OLT Non-MS Total energy (kcal/day) Carbohydrates (%) Proteins (%) Fats (%) Saturated fats (%) Cholesterol (mg) Fibres (g)
2417 50 15.2 34.5 9.9 330 21.5
± ± ± ± ± ± ±
533 7.8 3.5 7.3 2.7 179 7.4
6 months post-OLT
MS 2584 49 15.5 35.5 11.4 336 20.7
± ± ± ± ± ± ±
887 7.3 3.8 8.7 3.5 167 6.5
P*
Non-MS
0.35 0.26 0.99 0.73 0.05 0.88 0.625
1980 48.8 15.5 35 8.5 230 19.3
± ± ± ± ± ± ±
12 months post-OLT
MS
604 10.6 2.3 8.8 2.5 82 7.7
2112 48.5 16 36 10.7 257 18.2
± ± ± ± ± ± ±
389 7.2 3.9 6.7 3.7 113 7.3
P*
Non-MS
0.35 0.99 0.48 0.71 0.03 0.39 0.63
1912 50.5 14.5 34 7.7 238 24.4
± ± ± ± ± ± ±
534 5.0 3.3 7.9 2.8 193 5.2
P*
MS 2433 48.5 15.5 36 11.8 247 14.8
± ± ± ± ± ± ±
190 12 2.5 11.3 4.4 183 4.2
0.01 0.70 0.39 0.50 0.01 0.91 0.01
Values are mean ± SD. MS: metabolic syndrome; OLT: orthotopic liver transplantation; SD: standard deviation. * Student’s t test/Mann–Whitney test.
the rates of hypertriglyceridemia and hypertension increased dramatically after OLT according to previous reports [4,8,21], thus favouring the fulfilment of the criteria for MS diagnosis, especially in subjects who gained weight after OLT. These different trends in prevalence rates of MS components after OLT might be explained by the different effects that the restoration of liver function has on metabolic and haemodynamic parameters. In fact, OLT is associated with a reduction of insulin resistance due to improvement of hepatic insulin clearance. This is confirmed by the finding that, after OLT, non-diabetic patients showed reduced HOMA-IR index [20]; nevertheless, it cannot be ruled out that a toxic effect of immunosuppressive drugs may have contributed, at least in part, to the reduced insulin levels. On the other hand, a functioning liver graft favours an increase of lipid and blood pressure levels, as mentioned above. Other post-operative risk factors, i.e. immunosuppressive drugs and nutritional changes, may adversely affect all components of the MS. According to previous publications [7,14,15], despite the fact that immunosuppressive regimen was not included in the regression model, subjects on cyclosporine had a higher prevalence of MS and of some of its components than those on tacrolimus, thus suggesting the need for tailoring the immunosuppressive drugs. Moreover, tapering of corticosteroids was associated with a reduction of the number of subjects on insulin and of the daily insulin dose. Finally, the most intriguing findings of our study derive from the analysis of food diaries, which showed a modification of the nutritional habits after OLT, with higher intake of calories, saturated fat and cholesterol, despite strict nutritional surveillance and counselling. These changes were more pronounced in MS patients, who also showed a lower intake of fibres than non-MS subjects, thus supporting the concept that nutritional factors play a major role in the development of PTMS. In this view, it can be speculated that obese and/or overweight patients before transplantation are at higher risk of developing obesity and MS after OLT because they may return to their previous unbalanced diet. Multiple factors may contribute to changes in nutritional habits. First, the improvements in general health and well-being stimulate appetite and food intake. Additionally, many patients complain of constant hunger
after transplantation, which may be related to the use of prednisone or to emotional issues. Previous long-term retrospective studies showed that the risk of complications, and particularly of major CVD events, is higher in subjects developing MS after OLT. In fact, Laryea et al. reported a higher rate of CVD events in MS than in non-MS subjects (30% vs. 8%; p = 0.003) [9], and similar findings were reported by Laish et al. (15.2% vs. 4.9%; p < 0.007) [14]. A relevant finding of our study is the demonstration that this risk was already increased in the early post-OLT period in MS subjects. Strengths of this study are the prospective design, the focus on the early post-OLT period, and the strict nutritional surveillance and counselling. A possible limitation is the smaller number of subjects compared to previous reports [14,15]. Moreover, assessment of body weight and waist circumference may have been confounded by the presence of ascites and oedema in some patients with cirrhosis, thus affecting pre-OLT prevalence rate of MS. In fact, the percentage of subjects with an increased waist circumference decreased from 41.6% to 28.5% at 3 months post-OLT, when excess fluids were no longer observed. In conclusion, these data show that the development of PTMS is an early phenomenon and is related to pre-OLT diabetes and obesity and to nutritional changes after OLT. Lifestyle modifications, especially in overweight and/or obese patients, should be recommended to transplanted individuals starting in the early post-OLT period [22]. This would facilitate prevention of body weight gain and the associated abnormalities, including dyslipidaemia and hypertension, thus reducing the incidence of PTMS and the related CVD complications [23]. Conflict of interest statement None declared. Acknowledgements This work was supported by the IRCCS “Cà Granda – Ospedale Maggiore Policlinico” Foundation, Milan (MI), Italy.
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