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Jan 14, 2008 - Operativa di Audiologia, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena IRCCS, Milan, Italy. Our purpose was to ...

Bone Marrow Transplantation (2008) 41, 797–804 & 2008 Nature Publishing Group All rights reserved 0268-3369/08 $30.00


Prevalence of metabolic syndrome in long-term survivors of hematopoietic stem cell transplantation C Annaloro1, P Usardi1, L Airaghi2, V Giunta2, S Forti3, A Orsatti2, M Baldini2, A Delle Volpe1 and G Lambertenghi Deliliers1 1 Ematologia I e Centro Trapianti di Midollo, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena IRCCS and Universita` degli Studi, Milan, Italy; 2Medicina Interna I, Dipartimento di Medicina Interna, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena IRCCS and Universita` degli Studi, Milan, Italy and 3Servizio di Epidemiologia, Unita` Operativa di Audiologia, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena IRCCS, Milan, Italy

Our purpose was to determine the prevalence and features of metabolic syndrome (MS) in a series of long-term hematopoietic stem cell transplantation (HSCT) survivors. We assessed the clinical, metabolic and endocrinological data, and plasma TNF, leptin, resistin and adiponectin levels relating to 85 HSCT recipients. MS was diagnosed on the basis of the National Cholesterol Education Program-Adult Treatment Panel III criteria. Its prevalence was compared with that observed in an Italian population, and its relationship with the clinical and laboratory parameters was assessed univariately and multivariately. Twenty-nine HSCT recipients had MS instead of the 12.8 expected (Po0.0001), with hypertriglyceridemia being the most common feature. Univariate analysis indicated that high insulin and leptin levels, low-adiponectin levels and hypogonadism were significantly related to a diagnosis of MS; multivariate analysis indicated plasma leptin, insulin resistance, age and hypogonadism. We conclude that HSCT recipients are at increased risk of a form of MS that has particular clinical features. Plasma leptin levels are independently related to MS, thus suggesting that leptin resistance may play a role as a pathogenetic clue, as in other conditions in which MS occurs as a secondary phenomenon. MS deserves consideration as a life-threatening complication in patients who are probably cured of their underlying disease. Bone Marrow Transplantation (2008) 41, 797–804; doi:10.1038/sj.bmt.1705972; published online 14 January 2008 Keywords: hematopoietic stem cell transplantation; metabolic syndrome; insulin resistance; hypogonadism

Correspondence: Dr C Annaloro, Ematologia I e Centro Trapianti di Midollo, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena IRCCS, Via Francesco Sforza 35, Milan 20112, Italy. E-mail: [email protected] Received 4 May 2007; revised 12 November 2007; accepted 26 November 2007; published online 14 January 2008

Introduction The clustering of cardiovascular risk factors (obesity, hypertension, hyperglycemia and dyslipidemia) that was long known as ‘X syndrome’ has more recently been renamed ‘metabolic syndrome’ (MS).1,2 Although the concept of MS is quite intuitive, there is still some debate as to how best to define and diagnose it.3 The preferred diagnostic systems are from the revised 2001 National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII)4,5 and the World Health Organisation (WHO).6 According to NCEP-ATPIII, any three of the following abnormal parameters allows a diagnosis of MS: (1) trunk obesity, defined as an abdominal circumference of X102 cm in men and X88 cm in women; (2) serum triglycerides X150 mg/100 ml (1.7 mmol/l); (3) HDL cholesterolo40 mg/100 ml (1.0 mmol/l) in men and o50 mg/ 100 ml (1.3 mmol/l) in women; (4) arterial hypertension, defined as systolic blood pressure (BP) 4130 mm Hg and diastolic BP 485 mm Hg and (5) fasting plasma glucose (FPG) X100 mg/100 ml (5.6 mmol/l). According to the WHO, its diagnosis always requires the presence of hyperinsulinemia (defined as the upper quartile of insulin resistance in the nondiabetic population) or FPG X110 mg/ 100 ml (6.1 mmol/l) or plasma glucose X200 mg/100 ml (11.1 mmol/l) 2 h after an oral glucose tolerance test, plus at least two of the following: (1) abdominal obesity defined as a waist-to-hip ratio of 40.90, a body mass index (BMI) of X30 kg/m2 or a waist girth of X94 cm; (2) dyslipidemia, defined as serum triglycerides X150 mg/100 ml (1.7 mmol/l) or HDL cholesterol o35 mg/100 ml (0.9 mmol/l) and (3) BP X140/90 mm Hg. These systems reflect differences in pathogenetic concepts as the WHO is clearly based on insulin resistance, and NCEP-ATPIII on obesity. An increasing number of extravascular manifestations have been recognized as belonging to the clinical spectrum of MS, including nonalcoholic fatty liver disease, polycystic ovary syndrome, sleep apnea and chronic renal impairment.2 Moreover, some abnormal laboratory findings are regarded as common flanking conditions, including hyperuricemia,7 a proinflammatory state indicated by increased

Metabolic syndrome after HSCT C Annaloro et al


C-reactive protein and interleukin (IL)-6 levels,8 and impaired fibrinolysis due to an increase in plasminogen activator inhibitor.9 Furthermore, chronic inflammation and thrombophilia may lead to insulin resistance and increase the risk of developing cardiovascular diseases.2 Clinical and laboratory findings reminiscent of MS have been observed in long-term survivors of HIV infection10,11 and solid organ transplant recipients,12–14 and the incomplete overlap between these and the clinical pattern of spontaneous MS suggests that the MS in these patients may have its own pathogenetic characteristics. The features of MS have also been reported in series of pediatric survivors after hematopoietic stem cell transplantation (HSCT),15,16 and similar findings have been more sporadically reported in adult recipients.17–19 The aim of this study was to evaluate a series of adult long-term HSCT survivors to determine the prevalence and characteristics of MS, and seek possible differences from spontaneously occurring MS.

Patients and methods Patient selection The study involved patients who had received autologous or allogeneic hematopoietic stem cells of peripheral blood or bone marrow origin and whose first continuous complete remission (CCR) had lasted at least 5 years, with the exception of those who were still on immunosuppressive therapy (including corticosteroids) or affected by overt diabetes mellitus or untreated hypothyroidism. All of the HSCT recipients fulfilling the inclusion criteria who attended follow-up examinations at our Bone Marrow Transplantation Unit between March 2005 and March 2006 were invited to participate, and those willing to adhere to the program signed an informed consent form.

A total of 194 HSCT recipients were initially considered eligible as they had all experienced a post transplant CCR lasting 5 years or more. However, eight had died (five of cardiovascular disease, two of infection and one of a secondary neoplasm), and five (three males and two females, two allogeneic and three autologous HSCT recipients) could not be included because of a diagnosis of overt diabetes mellitus; all of them had MS according to the NCEP-ATPIII criteria. A further 51 patients were not included in the study because they had not been scheduled for follow-up examinations during the chosen time interval, and another 29 (including four pediatric patients who underwent HSCT before 1992) could not be considered because they were undergoing follow-up in the referring center. Finally, 13 patients were excluded because they still were on immunosuppressive therapy. The main data concerning the patients belonging to the principal exclusion groups are summarized in Table 1. Eighty-eight patients were therefore enrolled in the study, but three (one male and two females, all autologous HSCT recipients and two with MS) did not undergo the planned investigations (two for private reasons and one who refused consent). The data concerning the patients included in the analysis are given in the Results section.

Evaluation program A record was made of each patient’s gender; age at HSCT and at the time of the study; family history of diabetes, hypertension and coronary heart disease; personal clinical history; alcohol intake, smoking habits and physical activity; estrogen/progestin therapy in the case of postmenopausal women; underlying disease leading to HSCT; type of HSCT and conditioning regimen and history of acute or chronic GVHD. They all underwent a physical examination, including the measurement of height (m), weight (kg), abdominal circumference (cm) and the

Table 1 Main data concerning the patients experiencing continuous complete remission for more than 5 years who were not included in the study, by exclusion criterion Deceased patients

Patients not on follow-up

Patients on follow-up at the referring Center

Patients still on immunosuppression

8 46 (30–58) 7/1 7 (87.5) 1 (12.5) 8 (100) 8 (100) 6 (5–10) 40 (24–50)

51 47 (22–65) 26/25 23 (45.1) 28 (54.9) 36 (70.6) 45 (88.2) 9 (5–23) 37 (16–57)

29 38 (27–64) 17/12 11 (37.9) 18 (72.1) 23 (79.3) 28 (96.5) 13 (5–22) 22 (9–55)

13 49 (30–62) 7/6 13 0 6 (46.1) 9 (69.2) 8 (5–16) 37 (20–53)

Baseline diagnosis Acute leukemia Lymphoma Chronic myelogenous leukemia

4 2 2

23 23 5

16 8 5

5 6 2

Metabolic syndrome





Number of patients (%) Median age (range) Gender, M/F Allogeneic HSCT (%) Autologous HSCT (%) Total body irradiation (%) High-dose CTX (%) Median follow-up after HSCT Median age at transplantation (range)

Abbreviations: CTX ¼ cyclophosphamide; F ¼ Female; HSCT ¼ hematopoietic stem cell transplantation; M ¼ Male. Tha data concerning five diabetic and three refusing patients are reported in the text. The metabolic syndrome data were collected at the time of the study. (*) Only follow-up data are available. Bone Marrow Transplantation

Metabolic syndrome after HSCT C Annaloro et al


calculation of their BMI. Sitting arterial BP was measured after at least a 30-min rest in an outpatient examination room. Routine laboratory investigations included FPG, HbA1c, triglycerides, total and HDL-cholesterol (LDL-cholesterol was calculated using Friedwald’s formula), uric acid, C-reactive protein, fibrinogen, 24-h microalbuminuria, complete hemometry, coagulation parameters and renal and hepatic function tests. The endocrine assessment included fasting insulinemia, thyroid function, and gonadotropin, total testosterone and 17-b estradiol levels; gonadal insufficiency was considered in the case of men whose total serum testosterone level was below the reference range (o231 ng/100 ml), and women whose plasma 17-b estradiol levels were below the reference range (o20 pg/ml) and/or follicle-stimulating hormone levels above the reference range (440 mIU/ml), regardless of whether they were on hormone replacement therapy or not. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using the formula ((fasting insulin (mU/ml)  FPG (mmol/l))/22.5), and insulin resistance was defined as a HOMA-IR value of 44.65 or a BMI of 427.5 kg/m2 plus HOMA-IR 43.60.20 The patients underwent an oral glucose loading test with 75 g of water-diluted glucose, and their glucose and insulin levels were determined 2 h after they had taken the glucose loading dose. Blood samples were taken and immediately centrifuged, and the serum was stored at 20 1C for the determination of fasting serum levels of leptin (RIA, Linco Research, St Charles, MO, USA; sensitivity 0.5 ng/ml), tumor necrosis factor-a (TNF-a) (Diagnostic Products Corporation, Los Angeles, CA, USA; sensitivity 1.7 pg/ml), adiponectin (RIA, Linco Research, St. Charles, MO, USA; sensitivity 1 ng/ml) and resistin (ELISA, Bio Vendor Laboratory Medicine Inc., Brno, Czech Republic; sensitivity 0.1 ng/ml). MS was diagnosed on the basis of the NCEP-ATPIII criteria,4,5 and its prevalence was compared with that observed by Miccoli et al.21 in a sample of 2100 adult subjects randomly drawn from the general population of Lucca, a medium-sized Italian city. This population was divided into 10-year cohorts, and the prevalence of MS was calculated for each cohort. To compare the number of patients with MS observed in our series of 85 HSCT recipients with that expected on the basis of the findings of the prevalence study,21 they were divided into the same 10-year age cohorts and the number of expected MS cases in each cohort was calculated by multiplying the number of subjects at risk with the corresponding prevalence observed by Miccoli et al.21 in the same cohort. The total number of expected cases was obtained by adding together the number of cases expected in each age cohort.

Statistical analysis All of the results are expressed as mean values±s.e. The data were statistically analyzed using the SigmaStat software package (Jandel Corporation, San Rafael, CA, USA). The variables considered as possible predictors of the development of MS were age and gender; the diagnosed underlying disease; the type of transplant (allogeneic or autologous); plasma insulin levels; HOMA score; the serum

levels of leptin, TNF-a, resistin and adiponectin; hypogonadism; a positive family history of diabetes mellitus or atherosclerotic cardiovascular disease; GVHD; smoking and hypothyroidism. Reciprocal correlations were determined between the variables that proved to be predictive at univariate analysis, and possible whole series relationships were sought between the above variables and the individual features of MS. The hypothesis of normality was evaluated using the Shapiro–Wilk test and, on the basis of the results, betweengroup differences at univariate analysis were assessed using the t-test for normally distributed variables and the Mann–Whitney test for nonparametric variables. The relationship between the analyzed variables and a diagnosis of MS were determined using Fisher’s exact test. The relationship between MS and the dichotomous variables was evaluated by means of Pearson’s and Spearman’s correlations, and the OR confidence limits for 2  2 tables. After obtaining a dichotomous response (affected or not affected), logistic regression was used to investigate the relationship between MS and a set of possibly explanatory continuous variables in a binary logit model optimized on the basis of Fisher’s scoring. Significance was set at 0.05.

Results Cohort description The main clinical and metabolic data concerning the 85 HSCT recipients who fulfilled the inclusion criteria are summarized in Table 2. GVHD prophylaxis in the 39 allogeneic HSCT recipients included cyclosporin (CYA) for 1 year in combination with standard dose methotrexate in all but one patient, who received combined CYA/mycophenolate; 10 patients required prolonged additional immunosuppression because of GVHD. Diagnosis of MS A total of 30 of the 85 patients (20 males and 10 females; 11 autologous and 19 allogeneic HSCT recipients) showed overt insulin resistance, and 29 (15 females and 14 males; 17 autologous and 12 allogeneic HSCT recipients; median age 52 years, range 32–61) were diagnosed as having MS on the basis of the NCEP-ATPIII criteria: 13 satisfied three, 15 four and 1 five diagnostic criteria. All of the male patients with MS were insulin resistant and all of the female patients with insulin resistance had MS; there were therefore six male patients with insulin resistance but without MS, and five female patients with MS but without insulin resistance. A further 18 patients without MS satisfied one criterion and 10 satisfied two. Hypertriglyceridemia was the most common single finding, being found in 24 of the 29 patients with MS; abdominal obesity and hyperglycemia were both observed in 21 patients, arterial hypertension in 19 patients and low HDL-cholesterol levels in 18 patients. Fourteen patients had double dyslipidemia (hypertriglyceridemia and low-HDL cholesterol levels), which was also found in five patients without MS (Figure 1). Bone Marrow Transplantation

Metabolic syndrome after HSCT C Annaloro et al

800 Main clinical and metabolic data of the HSCT recipients

Table 2

Number of patients (%) Median age (range) Allogeneic HSCT (%) Autologous HSCT (%) Total body irradiation (%) High-dose CTX (%) Median time between HSCT and patient selection (range) Median age at transplant (range) Baseline diagnosis Acute myelogenous leukemia Acute lymphoblastic leukemia Non-Hodgkin’s lymphoma Hodgkin’s disease Multiple myeloma Chronic myelogenous leukemia Myelodysplastic syndrome BMI (kg/m2) Waist circumference (cm) Gonadal failure (%) Current cigarette smoker (%) Arterial hypertension (%) Fasting glucose (mg/100 ml) Fasting insulinemia (mcU/ml) HOMA-IR HbA1c (% of Hb A1) TSH (mUI/ml) fT4 (ng/100 ml) Total cholesterol (mg/100 ml) LDL cholesterol (mg/100 ml) HDL cholesterol (mg/100 ml) Triglycerides (mg/100 ml) Serum urate (mg/100 ml) Fibrinogen (mg/100 ml)


All patients

Female patients

Male patients

85 46 (26–63) 39 (45.9) 46 (54.1) 66 (77.6) 69 (81.2) 9 (6–21)

38 (44.7) 48 (28–63) 19 (50) 19 (47.3) 27 (71) 34 (89.5) 9 (6–22)

47 (55.3) 45 (26–61) 20 (42.5) 27 (59.5) 39 (82.9) 35 (74.5) 9 (6–18)

0.220 0.218 0.641 0.366 0.294 0.139 0.788

37 (16–55)

38 (18–55)

36 (16–53)


24 9 28 5 3 13 3

14 4 9 4 1 5 1

10 5 19 1 2 8 2

0.179 1.000 0.161 0.168 1.000 0.850 1.000

24.9±0.4 92±1.3 46 (56.1) 14 (16.5) 38 (48.7) 93.6±1.4 18±1.3 4±0.4 5.5±0.1 2±0.2 1.2±0 212.8±4.1 125.3±6 62.4±2.1 136.2±8.5 5.3±0.1 399.9±7.9

24.1±0.6 88.5±2.1 33 (86.8) 3 (7.9) 17 (47.2) 90.5±1.8 16.4±1.9 3.8±0.6 5.5±0.1 2.4±0.3 1.2±0 224.6±6.4 124.1±3.7 73.3±3.2 129.6±12.7 5.0±0.2 417.9±12.2

25.5±0.5 94.8±1.6 13 (29.5) 11 (23.4) 21 (50.0) 96.1±2.1 19.3±1.7 4.1±0.5 5.5±0.1 1.7±0.1 1.2±0 203.3±5 123±4.7 53.5±2.1 141.6±11.5 5.5±0.169 385±9.8

0.036 0.030 o0.001 0.105 0.830 0.074 0.325 0.651 0.847 0.067 0.593 0.009 0.758 o0.001 0.374 0.063 0.037

Abbreviations: BMI ¼ Body Mass Index; CTX ¼ cyclophosphamide; fT4 ¼ free thyroxine; HDL ¼ high-density lipoprotein; HOMA-IR ¼ homeostasis model assessment of insulin resistance; HSCT ¼ hematopoietic stem cell transplantation; LDL ¼ low-density lipoprotein; TSH ¼ thyroid-stimulating hormone. Mean values±s.e. or proportions. a Female vs male patients. 15


No. of patients








8 7


Women (38) Men (47)

7 6

6 4

2 1



0 0

1 2 3 4 No. of features of MS


Figure 1

Distribution of metabolic syndrome (MS) diagnostic criteria among the hematopoietic stem cell transplantation (HSCT) recipients with and without MS. The number of patients for each diagnostic criterion is shown at the bottom of the columns. Comparison of the recipients with and without MS revealed significant differences (Po0.001) in each criterion.

Instead of the 12.8 MS cases expected on the basis of the age cohort prevalence reported by Miccoli et al.21 there were actually 29 cases (Po0.0001). Bone Marrow Transplantation

Risk factors for MS The HSCT patients with MS had significantly higher plasma insulin (26.5±2.9 vs 13.7±0.9 mU/ml; Po0.0001) and leptin levels (35.6±5.2 vs 13.8±1.8 ng/ml; Po0.0001) than those without MS; their HOMA-IR score was also higher (6.7±0.8 vs 3.1±0.2; Po0.0001). The patients with MS were younger (median age 43.5 vs 52 years). Although age was not a statistically significant predictor of MS when considered as a continuous variable, the patients aged 45 years or more had an almost three times higher risk of developing MS than younger patients (odds ratio (OR) 2.936; CI 1.153–7.478). There were no significant differences in TNF-a and resistin, but adiponectin levels were significantly lower in the patients with MS (15.5±1.3 vs 22.6±1.7 mg/ml; Po0.001). C-reactive protein levels were below the upper reference value in all but seven cases, six of whom had values of 1.1–1.4 mg/100 ml, and one 4.3 mg/100 ml; there was no significant difference between the patients with or without MS. Table 3 shows plasma adipohormone levels in all of the patient subgroups, that is, HSCT patients with or without MS, and with or without insulin resistance.

Metabolic syndrome after HSCT C Annaloro et al

801 Table 3 resistance

Plasma adipohormone levels in the HSCT patient subgroups with or without metabolic syndrome, and with or without insulin

Plasma adipohormones Adiponectin (mg/ml) Resistin (ng/ml) TNF-a (pg/ml) Leptin (ng/ml)

Patients with MS

Patients without MS


Patients with IR

Patients without IR


15.5±1.3 7.0±1.2 11.5±1.0 35.6±5.2

22.6±1.7 6.4±0.4 11.1±0.7 13.8±1.8

o0.001 0.99 0.44 o0.0001

15.8±1.8 7.5±1.1 12.2±0.9 28±4.7

22.8±1.6 6.1±0.4 10.6±0.8 17.1±2.5

0.004 0.90 0.035 0.004

Abbreviations: HSCT ¼ hematopoietic stem cell transplantation; IR ¼ insulin resistance; MS ¼ metabolic syndrome; TNF-a ¼ tumor necrosis factor-a. Mean values±s.e. a Comparison of patient subgroups.

The only other considered variable that showed a statistically significant relationship with the development of MS at univariate analysis was hypogonadism (P ¼ 0.018).

Relationship between risk factors and features of MS There were statistically significant differences between the patients with and without insulin resistance in terms of fasting glucose levels (101.4±2.9 vs 88.8±1.1 mg/ 100 ml; Po0.001), abdominal circumference (99.9±2.5 vs 87.3±1.2 cm; Po0.001) and HDL cholesterol (54.4±2.9 vs 66.8±2.8 mg/100 ml; P ¼ 0.005) and triglyceride levels (113.1±9.1 vs 75.7±15.4 mg/100 ml; Po0.001). The insulinresistant patients also had significantly higher plasma leptin (28±4.7 vs 17.1±2.5 ng/ml; P ¼ 0.004) and TNF-a levels (12.2±0.9 vs 10.6±0.8 pg/ml; P ¼ 0.035), and significantly lower adiponectin levels (15.8±1.8 vs 22.8±1.6 mg/ml; P ¼ 0.004). Finally, there was no significant relationship between their plasma leptin levels and BMI, unlike in the patients without insulin resistance (P ¼ 0.38). Among the other variables linked to the development of MS at univariate analysis, hypogonadism and leptin levels significantly related only with triglycerides (Po0.001). There was no significant relationship between insulin resistance and a positive family history of diabetes or atherosclerotic cardiovascular diseases, hypogonadism or the development of GVHD (in the subset of allogeneic HSCT recipients). At multivariate analysis, age (Wald’s w2: 6.001; P ¼ 0.014), insulin resistance (Wald’s w2: 4.325; P ¼ 0.038), hypogonadism (Wald’s w2: 8.255; P ¼ 0.004) and leptin levels (Wald’s w2: 6.215; P ¼ 0.013) were all significantly associated with the development of MS.

Discussion It has been widely reported that HSCT has long-term effects on endocrine function but, apart from two pediatric series15,16 and some reports in adult patients,17,18 less is known about the prevalence of MS. The distinction between pediatric and adult patients is not trivial because factors, such as growth hormone replacement therapy, cranial radiotherapy and a high prevalence of acute lymphoblastic leukemia are peculiar to the former and have no clear-cut counterpart in the latter.

Moreover, most published reports only consider allogeneic HSCT, thus overlooking the possible contribution of myeloablative conditioning per se in the pathogenesis of MS. The possibility that chemotherapy alone may be responsible for long-term metabolic effects has been repeatedly suggested in testicular cancer survivors;22,23 however, testicular cancer may not be the best example because primary, surgical or chemotherapy-induced hypogonadism may play a primary role.24 Transplant procedures can theoretically affect glucose and lipid metabolism, and other MS flanking conditions.12,25,26 Baseline disease, supramaximal radiochemotherapy, immune reconstitution and infectious complications all induce altered cytokine release, a chronic inflammatory state and impaired fibrinolysis, which may in turn be responsible for adipohormone disequilibrium and insulin resistance, and thus lead to the development of MS-like features; furthermore, the drugs taken to prevent or treat GVHD (particularly, calcineurin inhibitors and corticosteroids) may further interfere with metabolic homeostasis.26,27 We therefore included in our study only possibly cured HSCT recipients who were unaffected by drug interference or active complications, and so it can be assumed that our findings are truly late effects of HSCT. The same cannot be said of other studies in which the time interval between HSCT and the metabolic evaluation ranges from one to more than 18 years, and some occasional patients were still on immunosuppressive therapy.15–17 The prevalence of MS in our series was significantly higher than that observed in a cohort study of an Italian population,21 and the difference would have been even greater if the patients with overt diabetes mellitus had been taken into account. The fact that a substantial proportion of patients without MS fulfilled two of the diagnostic criteria (frequently double dyslipidemia) also supports the hypothesis that the HSCT recipient population as a whole is at high risk of MS. The most frequent finding in ‘spontaneous’ MS is obesity, and it is still debated as to whether it plays a major pathogenetic role by increasing insulin resistance, or is actually an effect of insulin resistance viewed as the primary event. The NHANES III study showed that more than 80% of MS patients were at least overweight,28 and an Italian population survey found that abdominal obesity and arterial hypertension were the most common features of MS.21 Conversely, hypertriglyceridemia was the most Bone Marrow Transplantation

Metabolic syndrome after HSCT C Annaloro et al


common single finding in our post-HSCT MS patients, and was frequently associated with low-HDL cholesterol levels (double dyslipidemia). Obesity was less frequent than in spontaneous MS, and was more common in females, as has also been reported in other studies of MS in populations of different ancestries.29–32 MS may of course develop in accordance with the commonly observed pathogenetic sequence in some HSCT recipients, but our data raise the question as to whether others may develop it through alternative pathways. The fact that many possible risk factors (such as a positive family history of diabetes or atherosclerotic cardiovascular diseases) were not associated with the development of MS in our HSCT recipients underlines the prevalence of acquired over genetic factors. C-reactive protein levels, which are commonly regarded as a marker of an obesity-associated chronic inflammatory state,33,34 were almost invariably normal in our patients. It is also worth mentioning that GVHD was not a predictor of MS in the subset of allogeneic HSCT recipients, and allogeneic HSCT was not associated with a higher risk of MS than autologous HSCT, thus emphasizing the overlooked role of myeloablative conditioning as a possible pathogenetic factor. The multivariate analysis finding of a relationship between MS and insulin resistance was obviously expected because primary or obesity-induced insulin resistance is known to play a key role in MS. Furthermore, insulin resistance is the only variable significantly related to all of the phenotypical features of MS. However, multivariate analysis did not identify low-adiponectin levels as a predictor of MS, which is in line with the relatively low percentage of obese patients in our and others’ HSCT series. This suggests that the obesity–adiponectin–insulin resistance pathway may not play a role in a substantial proportion of HSCT recipients with MS. Conversely, leptin was an independent variable predicting the development of MS after HSCT. Leptin levels have been rarely reported after HSCT, although it has been occasionally claimed that hormonal and transplant-related variables can affect leptin levels in HSCT recipients.35 Taskinen et al.15 found slightly increased values in their pediatric HSCT series, and interpreted this as a result of hyperinsulinemia, but the relationship between leptin and hyperinsulinemia is complex and somewhat contradictory. Leptin is traditionally seen as an effector of insulin resistance, thus leading to the development of MS features and some flanking conditions, such as hyperuricemia,36,37 and it has more recently been shown that it can autonomously induce insulin resistance and may thus act earlier in the pathogenetic sequence of MS.38 Leptin production is regulated by a range of proinflammatory cytokines and, in its turn, leptin regulates the secretion of other cytokines such as g-interferon, TNF-a and IL-4.39 Therefore, some kind of leptin resistance can be hypothesized as a result of immunological, infectious or toxic events. High-leptin levels are encountered in patients undergoing solid organ transplants, in whom MS develops via somewhat different pathways.40,41 Post-HSCT MS bears some resemblance to such conditions of ‘secondary MS’. Bone Marrow Transplantation

Hypogonadism, another factor inducing insulin resistance,42–44 was found in almost all of our female HSCT recipients and was independently linked to MS at multivariate analysis; therefore, it mainly explains the development of MS in male patients. There is a substantial overlap between these results and the pediatric series accounting for most of the reported cases of post-HSCT MS;15,16 the same is also true of the series of MS cases among long-term testicular cancer.24 Age positively related to the development of MS in our series, whereas another study found a relationship between the prevalence of MS and the duration of the post transplant time interval.15 Our data support the obvious view that the prevalence of MS increases with age. Conversely, especially in younger patients, prolonged follow-up minimizes the role of transplant-related causative agents of MS. Cyclosporin A, corticosteroids and other immunosuppressants induce dyslipidemia and hypertension, but most of the effects do not last more than 6 months after discontinuation.27 Furthermore, it can be assumed that a long follow-up weakens the effects of ill-defined conditions, such as immunological impairment and infectious complications, which affect leptin production and insulin resistance. In any case, these elements support our choice of selecting only off-therapy and longterm CCR patients. The sometimes overemphasized improvement in the oncological outcome of HSCT recipients has gradually shifted interest to other questions, such as late effects and the quality of life of survivors, and a multicenter survey has recently focused on the prevalence of cardiovascular risk factors (including some MS features) and cardiovascular diseases after HSCT.19 On the basis of the data discussed above, MS is a common finding after both autologous and allogeneic HSCT and seems to be a true late effect. Post-HSCT MS differs from spontaneously occurring MS on clinical and laboratory grounds. It can be suggested that leptin resistance plays a role, as in the case of the MS complicating autoimmune diseases and solid organ transplantation, and it may even account for the observed excess prevalence of MS. In our experience, cardiovascular etiologies are more frequent than the other possible causes of nonrelapse mortality in long-term and probably cured CCR survivors, and so any attempts to prevent the development of such life-threatening complications would seem to be warranted.

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