Post-Transplant Events

High incidence of fatty liver and insulin resistance in long-term adult survivors of childhood SCT

Abstract

Overweight/obesity among adult survivors of childhood SCT has been considered to be predictive of eventual development of metabolic abnormalities. Fatty liver is increasingly recognized as a major cause of liver-related morbidity and mortality in the general population. However, the real incidence of fatty liver in adult survivors of SCT has not been fully elucidated. We determined whether adult survivors are at risk for overweight/obesity, metabolic abnormalities and fatty liver and whether these risks are associated with cranial radiotherapy (CRT) before SCT. Among the 51 patients (30 males), only two male patients were overweight/obese at the last evaluation. On the other hand, 9 male (30%) and 15 female (71%) patients were underweight. Fatty liver was diagnosed in 11 male (37%) and 10 female (48%) patients during the follow-up period, although patients who had fatty liver did not tend to be overweight/obese. Significantly more patients who received CRT before SCT developed fatty liver with insulin resistance than those who did not (P<0.05). Even patients who are not overweight/obese may develop fatty liver and metabolic abnormalities. We recommend that healthcare professionals recognize these risks and give life-long attention to detecting, preventing and treating late complications after SCT.

Introduction

The number of long-term surviving SCT recipients has increased steadily and attention is now extended to the late endocrine complications of this procedure.1 Overweight/obesity has been identified as a potential late effect of therapy in survivors of acute lymphoblastic leukemia (ALL) treated with conventional therapy,2 and cranial radiotherapy (CRT) during ALL treatment has been implicated as a potential cause of excess weight gain among these survivors. Although the mechanism by which CRT leads to overweight/obesity is unknown, hypothalamic damage leading to GH deficiency and/or leptin insensitivity has been suggested.3, 4 Overweight/obesity in childhood, adolescence and young adulthood after SCT treatment is an important predictor of eventual development of hyperinsulinism and its attendant metabolic syndrome.5 Specifically, excessive accumulation of visceral fat within the abdomen is strongly and independently associated with metabolic syndrome,6, 7 and the storage of fat in non-adipose tissue such as the liver is known to cause insulin resistance in mouse models.8

Fatty liver is increasingly recognized as a major cause of liver-related morbidity and mortality9 because of its potential to progress to cirrhosis and liver failure.10 This disease is often associated with metabolic abnormalities characterized by obesity,11 type II diabetes mellitus,12 dyslipidemia,13 and hypertension,14 and, finally, each of these abnormalities also carries a cardiovascular disease risk. Whether the risk for these metabolic abnormalities is increased in adult survivors of childhood SCT recipients has, however, not been fully elucidated. There is a possibility that identification of the risk factors for development of fatty liver in survivors is, therefore, critical for the development of strategies for prevention of and intervention in cardiovascular disease.

Although overweight/obesity in adult survivors of childhood ALL has been well evaluated, no longitudinal study that investigated metabolic abnormalities in survivors of childhood SCT has been reported,15, 16 and the mechanism of these conditions has not been completely understood. A longitudinal retrospective study of a cohort of adult survivors of childhood SCT was performed to determine whether adult survivors are at risk for overweight/obesity, metabolic abnormalities and fatty liver and whether this risk is associated with CRT or other factors used in the treatment of SCT.

Materials and methods

Patients

We reviewed the clinical records of 215 patients who received allogeneic SCT at Tokai University Hospital between 1982 and 1997. Inclusion criteria of this study were survival at least 10 years after SCT, age 18 years or greater at the time of the last evaluation and no history of liver dysfunction, endocrinological and metabolic abnormalities before SCT and of treatments that affect fatty liver after SCT. Fifty-one surviving patients (30 male and 21 female patients) fulfilled these criteria. The median age of the 51 patients at SCT was 10.5 years (range, 0.9–15.9 years), the median age at the last evaluation was 26.6 years (range, 19.4–34.3 years) and the median follow-up duration after SCT was 17.4 years (range, 10.9–25.8 years).

A written informed consent was obtained from the patients and/or their parents. Patient characteristics are summarized in Table 1.

Table 1 Patient characteristics

Transplantation procedure

In addition to conventional chemotherapy, nine patients who had ALL and one patient who had non-Hodgkin's lymphoma received prophylactic CRT (1, 12 Gy; 1, 15 Gy; 7, 18 Gy and 1, 24 Gy) before SCT. Conditioning regimens for 46 patients consisted of irradiation combined with/without CY and/or other drugs; 6–12 Gy of TBI for the malignant disease group was given in 3–6 fractions, and 3–10 Gy of thoraco-abdominal irradiation (TAI) for the non-malignant disease group in 1–5 fractions. The remaining five patients received conditioning without irradiation. Prophylaxis against GVHD varied during the time period; methotrexate, CYA or a combination of both drugs were used. Because no differences were observed in the main outcome between those who received TAI and chemotherapy only, the study population was categorized into three groups according to the conditioning protocol they had received: CRT+TBI, TBI and TAI+Chemo groups.

Anthropometric measures of body composition

All patients had achieved their final height at the last evaluation. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2). Patients were classified as overweight/obese if their BMI was 25 kg/m2 or greater and as underweight if their BMI was 18.5 kg/m2 or less according to the World Health Organization definition of obesity.17 Waist circumference (WC) was measured at the level of the superior iliac crest. Abdominal adiposity was defined as a waist-to-height ratio greater than 0.5.18, 19, 20 Bioelectronical impedance analysis was performed for measurement of body fat by InnerScan (TANITA, Tokyo, Japan).

Evaluation of metabolic syndrome

Metabolic syndrome was defined according to criteria of a committee for the establishment of the definition and diagnostic criteria of metabolic syndrome in Japanese:21 Central obesity (WC 85 cm in male or 90 cm in female patients) and the presence of at least two of the following factors: (1) triglyceride (TG) levels 150 mg/dL and/or high-density lipoprotein cholesterol (HDL-C) <40 mg/dL; (2) systolic blood pressure 130 mm Hg and/or diastolic blood pressure 85 mm Hg; and (3) fasting plasma glucose 110 mg/dL.

Evaluation of fatty liver and steatohepatitis

Fatty liver was evaluated by 460 longitudinal ultrasounds among the 51 patients during the follow-up period. The Hitachi EUB340 (Hitachi, Tokyo, Japan), Yokogawa RT2800 (GE Yokogawa Medical System, Tokyo, Japan) and Yokogawa RT3000 were used as ultrasound equipment until 1994 for evaluation of fatty liver. The Aloka SSD 650CL (Aloka, Tokyo, Japan) was used after 1995. Of the four criteria used for the diagnosis of fatty liver (hepatorenal echo contrast (HR), liver brightness (LB), deep attenuation and vascular blurring), the first two were used as definitive criteria and the last two were taken into account as needed.22 Degree of fatty liver was classified as follows: Severe, both HR and LB were positive; Moderate, either HR or LB was positive and/or either deep attenuation or vascular blurring was positive; and Mild, neither HR, LB, deep attenuation or vascular blurring was positive. In all cases, two specialists in gastroenterology separately confirmed the diagnosis.

Abdominal computed tomography was performed in 38 patients (23 male and 15 female patients) for coordination with fatty liver diagnosed by ultrasound. Fatty liver was determined using the ratio of liver to spleen, as described in detail elsewhere.23 The criterion for fatty liver was below 0.9 of the hepatosplenic Hounsfield Units ratio.

Liver biopsy was performed in three allografted patients who received CRT+TBI (2 male; 1 female) and in one autografted female patient who received TBI, for coordination with fatty liver diagnosed by ultrasound and histological evaluation. Markers of hepatic fibrosis was evaluated by serum Procollage III peptide (normal range, 0.3–0.8 U/mL), serum type IV collagen (<150 ng/mL) and serum hyaluronic acid concentrations (<50 ng/mL).

Evaluation of glucose and lipid metabolism profiles

An overnight fasting blood sample was obtained in all patients for the measurement of plasma glucose, plasma insulin, plasma glycosylated hemoglobin, serum TG, serum total cholesterol, serum HDL-C, serum low-density lipoprotein cholesterol, serum-free fatty acid, plasma leptin and serum adiponectin. Hypertriglyceridemia was defined as a serum TG level above 150 mg/dL and low HDL-cholesterolemia was defined as a serum HDL-C level below 40 mg/dL. The normal ranges for plasma leptin were 1.0–11.5 ng/mL in male and 2.0–20.6 ng/mL in female patients, and those for serum adiponectin were 3.8–16.6 μg/mL in male and 4.1–18.9 μg/mL in female patients.

Oral glucose tolerance test (OGTT) was performed in 48 patients (28 male and 20 female patients) for evaluation of glucose metabolism. Patients were given glucose at 1.75 g/kg (maximum 75 g) after a 12-h overnight fast, and samples for measurement of plasma glucose and plasma insulin were drawn at baseline every 30 min until 120 min. Hyperinsulinemia was defined as a fasting plasma insulin value of 20 mU/L or greater or a peak plasma insulin during OGTT of 150 mU/L or greater. Definitions of diabetes mellitus and impaired glucose tolerance were according to the Japan Diabetes Society criteria. The presence of either type I or type II diabetes was diagnosed if fasting plasma glucose was 126 mg/dL or greater and/or if plasma glucose 2 h after glucose load was 200 mg/dL or greater. A random plasma glucose value higher than 200 mg/dL was also regarded as indicating diabetes. Results were considered normal if fasting plasma glucose was below 110 mg/dL and the 2-h plasma glucose was below 140 mg/dL. Impaired glucose tolerance was diagnosed in those who had values that were neither normal or that indicated diabetes mellitus.

The capacity of insulin secretion was evaluated by the insulinogenic index (II) using OGTT: (plasma insulin at 30 min—plasma insulin at baseline)/(plasma glucose at 30 min—plasma glucose at baseline) with a result of 0.4 or less indicated dysfunction of insulin secretion. Insulin resistance was further estimated by the homeostasis model assessment-insulin resistance: fasting plasma insulin (mU/L) × plasma glucose (mg/dL)/405 with a result of 2.5 or greater indicated IR.

Evaluation of endocrine function

Growth hormone (GH) secretion was repeatedly assessed by the insulin tolerance test and IGF-I before and annually after SCT as described in detail elsewhere.24 GH deficiency was defined as a GH level of <10 ng/mL in response to stimulation with regular insulin.

Thyroid function was evaluated before and annually after SCT by serial measurement of basal serum thyroid-stimulating hormone (TSH) levels, serum-free triiodothyronine (FT3) levels and free thyroxine (FT4) levels. Normal values in our institute were: TSH 0.30–4.00 U/mL, FT3 2.50–4.50 pg/mL and FT4 0.75–1.75 ng/dL. Subclinical compensated hypothyroidism was defined as elevated TSH levels (4–10 U/mL) with normal FT4 levels with no clinical symptoms.

In male patients, onset of puberty was defined by a testicular volume of 4 mL.25 Testicular volume was determined using an orchidometer, as described by Prader.26 Testicular Leydig cell function and germinal epithelium damage were evaluated with basal serum luteinizing hormone (LH) levels, basal serum follicle-stimulating hormone (FSH) levels and serum testosterone levels. Normal basal serum LH and FSH levels at our institute were <5 mIU/mL and <9 mIU/mL, respectively. Partial Leydig cell dysfunction and partial germinal epithelium damage were defined by increased basal LH levels or basal FSH levels with normal testosterone levels. In female patients, the time of menarche and the recurrence of menstruation after SCT were recorded. Ovarian function was evaluated with basal serum LH levels, basal serum FSH levels and serum estradiol (E2) levels after SCT. Primary ovarian failure was defined by increased basal FSH levels. Endocrine tests were undertaken in a morning fasting state to avoid diurnal variation of hormones. Our definition of partial testicular or ovarian insufficiency is as follows; Testes; basal FSH 15 IU/mL, basal LH 20 IU/mL and normal testosterone. Ovary; we defined the partial ovarian failure when E2 was within normal range and when FSH was >10 IU/mL in adulthood. And we defined the primary ovarian failure when FSH was >40 IU/mL or the menarche did not appear spontaneously.

Statistical analysis

As the data had a skewed distribution, median and range are presented throughout the text, tables and figures. Fisher's exact probability and the χ2 test were used to assess the association either between or among groups. Differences in anthropometric and laboratory variables among groups were analyzed by the Kruskal–Wallis test with Dunn's multiple comparison test. All statistical analyses were performed with the statistical package GraphPad Prism for Windows (Ver. 4.03 Prism). A P-value of less than 0.05 was considered statistically significant.

Results

Anthropometrics

Patients in the CRT+TBI groups were significantly older than those in either the TBI groups or TAI+Chemo groups (P<0.05, Table 2). Among the 51 patients, two male patients had a greater than 25 kg/m2 BMI (25.6 and 26.2, respectively) at the last evaluation, whereas none of the female patients were overweight/obese (Figure 1). On the other hand, 9 male (30%) and 15 female (71%) patients had a BMI less than 18.5 kg/m2 (Figure 1). No patient satisfied the criteria for metabolic syndrome, although three male patients had a WC greater than 85 cm (91.2 cm in CRT+TBI group and 87.2 and 92.2 cm in TAI+Chemo group, Figure 1). CRT was significantly associated with an increased BMI, waist-to-height ratio and body fat in both male and female CRT+TBI groups compared with either the male TBI group or female TAI+Chemo group (P<0.05, respectively), although the average BMI in the three groups did not indicate overweight/obesity (Table 2).

Table 2 Anthropometrics, fatty liver, lipid and glucose metabolism and endocrine function in adult survivors of childhood stem cell transplant
Figure 1
figure1

Body mass index (a, b) and waist circumference (c, d) in male and female adult survivors of childhood SCT recipients. The gray zones on Figure 1 were normal range of BMI and abdominal circumstance. Only two of the patients were BMI above 25 kg/m2, and the abdominal circumstance was above normal range only in three patients.

Fatty liver

Among the 51 patients, their liver function test was within normal range during follow-up period, although HCV–RNA test was positive in two patients (one in TBI group and another in TAI+Chemo group). Information on daily alcohol consumption was obtained from all patients by the self-report. Overall, most patients were non-drinkers or drank only minimally. Abdominal computed tomography was performed in 38 patients to confirm the diagnosis of fatty liver made through ultrasound. As a strong correlation was identified between ultrasound and abdominal computed tomography (P<0.001), ultrasound findings were used to evaluate the presence of fatty liver in this study. Fatty liver was diagnosed in 11 male (37%) and 10 female (48%) patients by ultrasound during the follow-up period. Moreover, fatty liver was histologically confirmed by biopsy in four patients. However, patients who had fatty liver did not tend to be overweight/obese (Figure 2). The mean BMIs in male and female patients who had fatty liver were 22.6 and 19.2 kg/m2, respectively, at the last evaluation. No relationships between the onset of fatty liver and gender of patients, age at SCT, primary disease and GVHD were observed. In all, 205 ultrasound examinations were performed to evaluate the presence of fatty liver during the follow-up period. Concerning the mode of irradiation, a significantly greater number of patients who received CRT+TBI developed fatty liver compared with either TBI group or TAI+Chem group (P<0.005, Figure 2). Fatty liver in four patients (two males, two females) in the TBI group and two males in the TAI+Chemo group improved with exercise and dietary regimens by physicians and dieticians during the follow-up period. However, fatty liver did not improve in any of those with this condition in the CRT+TBI group with exercise and dietary treatments (Figure 2).

Figure 2
figure2

Changes in fatty liver in adult survivors of childhood SCT. UPN, unique patient number; Degree of fatty liver classified as follows: □, absence; , mild; , moderate; ▪, severe; +, existence; + → −, improved; , SCT.

Evaluation of lipid and glucose metabolism

Studies of lipid and glucose metabolism were performed to investigate the mechanism of development of fatty liver in patients who received SCT. CRT was significantly associated with increased plasma leptin levels in the CRT+TBI group compared with either the male TBI group or with the female TAI+Chemo group (P<0.01 and P<0.05, respectively, Table 2). Moreover, serum adiponectin levels in the CRT+TBI group decreased compared with either the TBI or TAI+Chemo group, although the difference among groups was not statistically significant.

Homeostasis model assessment-insulin resistance in the male and female CRT+TBI groups increased compared with either the TBI or TAI+Chemo groups, although no statistically significant difference was recognized among groups. (Table 2). CRT was, however, significantly associated with increased insulin resistance in the CRT+TBI groups compared either with TBI or TAI+Chemo groups (P<0.05 in male and female patients, Table 2). None of the patients had a decreased insulinogenic index at evaluation. Plasma glucose levels in the 75 g OGTT did not differ among groups and were within normal range at each time point.

Evaluation of endocrine function

Ten patients experienced poor GH secretion (5, CRT+TBI; 4, TBI; 1, TAI+Chemo) at least twice, although a permanent GH deficiency was not observed. CRT was significantly associated with transiently poor GH secretion in the CRT+TBI group compared with either the TBI or TAI+Chemo group (P<0.05, respectively). Serum IGF-I levels remained in the lower half of the normal range for age throughout the follow-up period, although in male patients decreased serum IGF-I levels in the CRT+TBI group were significantly more frequent than in the TAI+Chemo group (P<0.05, Table 2).

Thyroid function in all but one subject was within normal range at the last evaluation, although 12 patients experienced transient subclinical compensated hypothyroidism (4, CRT+TBI; 5, TBI; 3, TAI+Chemo) during the follow-up period.

All patients had developed adult genitalia (Tanner stage V) at the last evaluation. In male patients, puberty started spontaneously in all patients according to increases in testicular volume increase (4 mL). Serum testosterone levels in all patients reached the adult level at some time point from adolescence to adulthood after SCT. CRT was, however, associated with decreased serum testosterone levels in the CRT+TBI group compared with either the TBI or TAI+Chemo group, although statistically significant differences were not recognized among groups (Table 2). All patients experienced raised basal LH and FSH levels with normal serum testosterone levels while approaching adolescence, indicating the presence of partial Leydig cell dysfunction and partial damage of the testicular germinal epithelium at some time during the follow-up period.

In female patients who received SCT before the age of 10 years, 9 of 11 patients who had not manifested menarche before SCT entered puberty spontaneously after SCT and subsequently had menarche at a median age of 13.3 years (range, 12.3–15.3 years), which was an appropriate age for healthy Japanese girls. These patients who received SCT before the age of 10 had normal E2 levels during the pubertal period without hormone replacement therapy (data not shown), although partial ovarian failure was observed in these patients. On the other hand, 3 of 10 patients who received SCT after the age of 10 had manifested menarche after SCT spontaneously. The remaining seven patients were diagnosed as having primary gonadal dysfunction after SCT, and six patients were administered hormone replacement therapy.

Discussion

This is the first report on adult survivors of childhood SCT to indicate longitudinal changes in fatty liver after SCT. The novel findings are that significantly more patients who received CRT before SCT developed fatty liver than those who did not, independent of sex, age at SCT, primary disease and GVHD. In addition, the difficulty of improving fatty liver in patients who received CRT even with appropriate exercise and dietetic treatment was revealed. Furthermore, the incidence of fatty liver was not associated with overweight/obesity in these patients who received SCT. These results underscore the increased health risk among adult survivors treated with CRT.

Reports on long-term survivors of childhood ALL have claimed that overweight/obesity, using the definition of WHO of a BMI>25 kg/m2, is common. Sklar et al.2 reported that leukemia survivors treated with CRT were more likely to be overweight/obese at attainment of final height than those treated with chemotherapy only. Although the mechanism by which ALL survivors become overweight/obese remains unclear, several explanations have been proposed including GH insufficiency, use of corticosteroids and reduced energy expenditure.27, 28, 29 One proposed mechanism to explain the association between CRT and overweight/obesity in survivors of childhood ALL is leptin insensitivity. Leptin is an adipocyte-derived hormone that binds to the biologically active long form of its receptor in the hypothalamus.30 It has been speculated that radiation-induced damage to the pituitary–hypothalamus axis may result in a disruption of leptin signal, which eventually results in obesity.4

Ross et al.31 also reported that leptin insensitivity may influence obesity in survivors of childhood ALL, particularly those exposed to cranial radiation and leptin polymorphism. In this study, CRT was significantly associated with an increased plasma leptin level in the CRT+TBI groups compared with either the male TBI group or female TAI+Chemo group. Our data provide support that CRT affects the pituitary–hypothalamus, causing leptin receptor insensitivity. However, it is surprising that the average BMI in all three groups did not show a shift toward overweight/obesity. The National Health and Nutrition Survey of Japan in 2004 reported that the frequency of BMI less than 18.5 kg/m2 in the general Japanese male and female population in their 20s and 30s were 6.1 and 18.5%, respectively.32 In this study, 9 males (30%) and 15 females (71%) had a BMI less than 18.5 kg/m2, and they did not manifest chronic GVHD and a nutritional disorder during the follow-up period. Therefore, these patients were almost 4 to 5 times as likely to be underweight as the general Japanese population even though they had received CRT before SCT and their plasma leptin levels increased during the follow-up period. It is difficult to explain a change in body composition after SCT only by a leptin increase and to adopt the concept of the metabolic syndrome for these patients after SCT.

An in vivo mouse experiment performed by Ablamunits et al.33 clarified the relationship between SCT including TBI and body composition. Leptin-deficient ob/ob mice were exposed to TBI followed by SCT to rescue hematopoiesis and their body composition was monitored. TBI/SCT completely arrested body weight gain as early as 2 months after irradiation. Body composition measurements showed that body weight arrest was because of both retardation of lean mass accumulation and the inability to accumulate fat mass. Bingham et al.34 also created ventromedial hypothalamic nucleus leptin receptor knockout (Lepr KOVMH) mice to evaluate the relationship between leptin level and body composition. Lepr KOVMH mice on normal mouse chow showed a twofold increase in plasma leptin and insulin levels relative to wild-type littermates. However, Lepr KOVMH mice did not show a significant weight increase over their wild-type littermates. Nuclear magnetic resonance analysis demonstrated that the increased weight in Lepr KOVMH mice entirely reflects increased adiposity and histological evidence also supported the nuclear magnetic resonance body composition data. Examination of white adipose tissue from Lepr KOVMH mice revealed a marked cellular hypertrophy, whereas examination of brown adipose tissue showed a significant increase in the size of cellular vacuoles. Thus, despite comparable body weights, Lepr KOVMH mice showed increased lipid accumulation in adipocytes relative to wild-type littermates.

According to the results of these experiments and our current study, changes in body weight after SCT may be influenced not only by increased leptin levels caused by radiation-induced damage to the pituitary–hypothalamus axis but also by direct exposure of adipocytes to radiation. Although visceral fat was not quantified by abdominal CT in this study, the WC as an indication of abdominal adiposity in these patients did not indicate a significant increase in visceral fat. Therefore, direct exposure of abdominal adipocytes to radiation may participate in the mechanism of the arrested body weight in survivors of SCT.

Fatty liver is increasingly recognized as a major cause of liver-related morbidity and mortality, because of its potential to progress to cirrhosis and liver failure. We have investigated the prevalence of fatty liver in Japan over the past 12 years.22 The subjects of the previous study were 39 151 individuals who visited the Tokai University Hospital Health Checkup Center for the first time during the 12-year period from 1989 to 2000. In all cases, the diagnosis of fatty liver was based on abdominal ultrasonography with the same ultrasound equipment and diagnostic criteria as used in this study. Prevalence of fatty liver in subjects in their 20s and 30s was 18–27% and 4–7% in male and female patients, respectively. In contrast, the current study reports an incidence of fatty liver, that is, in 37% of male and in 48% of female adult survivors who were not overweight/obese during the follow-up period, respectively. These results indicated that SCT may affect the prevalence of fatty liver in adult survivors and that they were more likely to develop fatty liver compared with the general Japanese population. It was impossible or very difficult for us to collect sufficient information on all drugs, which were used before SCT, because most patients were referred from many hospitals with a summary of treatment, which did not contain the exact total doses of all drugs. We tried to collect data on steroids, which were used pre-SCT and post-SCT periods, and analyzed if there was relation between steroid and development of fatty liver. We could not find any significant relation between steroid use or dosage and fatty liver.

We performed liver biopsy in four patients in whom diagnosis of severe fatty liver was made by echography. Atypical non-alcoholic steatohepatitis was suspected in one of these patients, and fatty liver was diagnosed histological in all patients. As the computed tomography also supported the echographical diagnosis of fatty liver in all patients including these four patients, and taking the risk of liver biopsy into consideration, we decided to evaluate and to follow up these patients mainly by echography.

Insulin normally inhibits the production of glucose and very low-density lipoprotein in the liver.35 Fat accumulation in the liver is known to cause insulin resistance in mouse models that have neither s.c. nor visceral fat8 and is observed in insulin-resistant mice33 and human subjects with lipoatrophy.36 Therefore, insulin resistance is a key player in the pathogenesis of fatty liver. Kotronen et al.37 showed that liver fat accumulation was 4-fold higher in subjects with than without metabolic syndrome and the best correlate of liver fat was the fasting serum insulin level. This strong association may be explained by the decrease in hepatic insulin clearance in subjects with increased hepatic fat content.38 Indeed, a 51% decrease in liver fat achieved by rosiglitazone therapy has been shown to increase insulin clearance by 20%.39 Bingham et al.34 demonstrated that Lepr KOVMH mice showed significantly increased insulin resistance, hyperleptinemia, adipose mass and fatty liver on a low-fat diet. By 20 weeks of age, the livers of Lepr KOVMH mice fed normal mouse chow weighted approximately 50% more than wild-type littermates and contained approximately 50% more triacylglycerol. In this study, CRT was significantly associated with increased insulin resistance. Therefore, insulin resistance may be one possible explanation of the relationship between adult survivors without overweight/obesity and high prevalence of fatty liver. However, clinical investigations and further studies in animal models should elucidate the underlying mechanism.

In conclusion, we found that significantly more patients who received CRT before SCT developed fatty liver and insulin resistance than those who did not and that improvement in fatty liver in patients with increased leptin levels was difficult with appropriate treatments. Even patients who do not tend to be overweight/obese may develop metabolic abnormalities and fatty liver after SCT so in the future we must think about treatment of these conditions, including application of medical therapy. We, therefore, recommend that healthcare professionals recognize these risks and pay life-long attention to detecting, preventing and treating the late complications after SCT.

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Acknowledgements

We thank Laurie E. Cohen for advice and critical review of the article. We also thank all the medical staff at Tokai University Hospital for patient care. This work was supported in part by a Research Grant (H20-015) on allergic disease and immunology from the Ministry of Health, Labor and Welfare of Japan.

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Correspondence to H Ishiguro.

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Tomita, Y., Ishiguro, H., Yasuda, Y. et al. High incidence of fatty liver and insulin resistance in long-term adult survivors of childhood SCT. Bone Marrow Transplant 46, 416–425 (2011). https://doi.org/10.1038/bmt.2010.144

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Keywords

  • fatty liver
  • insulin resistance
  • childhood cancer survivors
  • irradiation

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