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Sajadi Hezaveh Z, Hadidi M, Shidfar F. The Splenectomy Effects on Lipid Profile and Glucose Metabolism in the Major Thalassemia Patients. JNFS 2021; 6 (1) :58-64
URL: http://jnfs.ssu.ac.ir/article-1-320-en.html
URL: http://jnfs.ssu.ac.ir/article-1-320-en.html
Department of Human Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
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Zohreh Sajadi Hezaveh; MSc1, Mahsa Hadidi; MSc1 & Farzad Shidfar; PhD*2
1 Student Research Committee, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
2 Department of Human Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
Introduction
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The Splenectomy Effects on Lipid Profile and Glucose Metabolism in the Major Thalassemia Patients
Zohreh Sajadi Hezaveh; MSc1, Mahsa Hadidi; MSc1 & Farzad Shidfar; PhD*2
1 Student Research Committee, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
2 Department of Human Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
| ARTICLE INFO | ABSTRACT | |
| ORIGINAL ARTICLE | Background: Splenectomy is a common treatment for beta thalassemia. It not only eliminates many complications by reducing the need for blood transfusion, but also causes new complications that threaten the patients' health. The aim of this study was to determine if splenectomy could alter the lipid profile and glucose metabolism in beta thalassemia major patients. Methods: In this case-control study, 41 splenectomized and 42 non-splenectomized eligible beta thalassemia patients were selected from Zafar Thalassemia Clinic, Tehran, Iran. Anthropometric, demographic, and biochemical data were collected using standard methods. Physical activity and food intake were measured using International Physical Activity Questionnaire (IPAQ) and food frequency questionnaires (FFQ), respectively. Results: Demographic characteristics and dietary intake were not significantly different between the two groups. However, triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios were significantly higher, but HDL-C was significantly lower in splenectomized patients (P < 0.05). Furthermore, fasting blood glucose (P < 0.39) and oral glucose tolerance test (P < 0.53) did not significantly differ between the two groups. Conclusions: Reduced activity of the reticuloendothelial system and reduced removal of cholesterol might be the reason for higher plasma lipid profile and greater risk of cardiovascular diseases in splenectomized patients. On the other hand, glucose metabolism was not affected by splenectomy in adult patients. To clarify this relationship, prospective studies are suggested. Keywords: Thalassemia; Splenectomy; Lipid profile; Glucose |
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| Article history: Received: 6 May 2020 Revised: 21 Jun 2020 Accepted: 6 Jun 2020 |
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| *Corresponding author: Shidfar.f@iums.ac.ir Department of Human Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran. Postal code: 14496-14535 Tel: +98 9123082922 |
Introduction
Thalassemia, as the most common hemoglobinopathy worldwide, has higher prevalence in the Mediterranean area, the Middle East, and Southern Asia (Wehr et al., 2010). Beta thalassemia major is a sever hemolytic anemia, which causes a defective hematopoiesis and necessitates frequent blood transfusion (Muncie Jr and Campbell, 2009). Given that spleen performs vital hematologic activity and filters the defected blood cells, its activity is increased in this disease. This hyperactivity causes splenomegaly, so that the patient has to be splenectomized due to the discomfort, abdominal pain, and false satiety (Crary and Buchanan, 2009, Nishi et al., 2010). Partial or complete removal of the spleen reduces the need for the blood transfusion, which reduces the iron overload consequently. However, it induces new complications such as increased pulmonary arterial pressure, sepsis, thrombosis, reduced response to encapsulated bacteria, and increased susceptibility to infection (Bhatia and Cairo, 2009, Cappellini et al., 2014, Piga et al., 2011).
Altered lipid profile seems to be another complication emerging after the splenectomy. Animal studies reported increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and decreased high-density lipoprotein cholesterol (HDL-C) in asplenic patients. This effect was stronger in animals fed with high-fat diets (Fatouros et al., 1995, Kanichi et al., 1988). Caligiuri et al. demonstrated that splenectomy accelerated atherosclerosis in mice (Caligiuri et al., 2002). As the most frequent cause of death in thalassemia is cardiopathy (69%) (Ceci et al., 2006), investigating the changes in lipid profile after the splenectomy is of high importance.
Splenectomy can indirectly affect the glucose metabolism as well (Rosa et al., 2015). Observations suggest that serum lipopolysaccharide levels are increased in splenectomized patients (Feleder et al., 2003, Yoshida et al., 1995).The spleen is an important bacteria debugger and the absence of this lymphoid organ causes the liver’s Kupffer cells to assume the role of clearing Lipopolysaccharides (LPS) (Ge et al., 1997, Sivitz et al., 1997). In turn, Kupffer cells increase the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, interfering with insulin signaling and glucose transport (Feleder et al., 2003, Sivitz et al., 1997), which increases fasting blood glucose (FBG). Children with severe thalassemia who required splenectomy were noted to develop insulin resistance due to the interaction of spleen and pancreas (Lee et al., 1985). We suspect that splenectomy might play a role in the high prevalence of diabetes mellitus in thalassemia patients.
Since splenectomy is prevalent among beta thalassemia major patients, we decided to find out the effect of splenectomy on these patients' health through glucose and lipid metabolism alteration.
Materials and Methods
Study population: This case-control study was conducted in Zafar Thalassemia Clinic, Tehran, Iran from January to February 2019. This clinic is a referral center for thalassemia patients to receive governmental and free health services. Forty one splenectomized and forty two non-splenectomized patients were recruited to participate in this study through convenient sampling method. Participants aged 18-30 years who had a history of using standard iron-chelating drugs, were non-alcoholic, non-smoker, and did not have any metabolic or infectious diseases were selected to participate in this research. Splenectomized patients had undergone the surgery at least a year before the study. All participants received multivitamin-mineral supplement during the past six months. Measurements: The participants’ height was measured to the nearest 0.01 cm while they were wearing no shoes. Their weight was also measured in light clothes without shoes and with a digital scale to the nearest 100 g. Body mass index (BMI) was calculated using weight (kg) divided by squared height (m). All measurements were performed using standardized procedures. Other information including age, gender, iron chelator drug, and blood transfusion intervals of the patients were obtained from their medical records.
To control the effect of confounders, dietary intake and physical activity were measured using reliable and validated questionnaires. Dietary data was collected using food frequency questionnaire (FFQ) (168-item), which represented the food intake throughout the last year. The information was collected using a face-to-face interview by a trained interviewer.
Information on physical activity was obtained using the International Physical Activity Questionnaire (IPAQ) (Moghaddam et al., 2012).
Blood samples were collected at least 10 days after the last blood transfusion and were obtained after 12 hours of fasting overnight. Samples were analyzed for FBG, oral glucose tolerance test (OGTT), TG, TC, HDL-C, LDL-C, TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratio using ELISA method (Ebioscience, USA). Hemoglobin (Hb), ferritin, white blood cells (WBC), and platelet were also measured as confounders.
Ethical considerations: All participants signed a written informed consent to enter the study. The protocol of this study was approved by the Ethics Committee of Iran University of Medical Sciences (IR.IUMS.REC 1397.97-04-207-31244).
Data analysis: The Kolmogorov-Smirnov test was run to test normality. The data for quantitative variables were reported in the form of mean ± Standard Deviation (SD). Independent t-test was applied to compare the mean of quantitative outcomes between the two groups. The ANCOVA analysis was used to examine the association between splenectomy, serum lipid, and glucose indices by adjusting the confounding variables. P- value < 0.05 was considered statistically significant. All analyses were performed using Statistical Package for Social Sciences (version 21.0, SPSS Inc,Chicago, IL).
Results
Comparison of the clinical and biochemical characteristics between splenectomized and non-splenectomized participants (Table 1) showed that 66.1% of them used desferrioxamine, 17.7% used deferiprone, and 16.1% used both drugs as iron chelator. Furthermore, 48.9% of the participants were male and 51.1% were female. No significant difference was observed between the two groups in clinical characteristics and physical activity. Splenectomy reduced the need for blood transfusion in splenectomized patients (P = 0.001) significantly. The WBC (P = 0.001) and platelet (P = 0.02) were significantly higher in splenectomized participants.
As observed in Table 2, no significant differences were found between the two groups regarding energy and macronutrients’ intake.
The correlation of splenectomy with glucose and lipid profile of the participants is represented in Table 3. According to ANCOVA analysis, after adjusting for blood transfusion intervals, WBC, and Platelet, splenectomy had no significant association with FBG or OGTT, but HDL-C was significantly lower. Moreover, the TG, TC, LDL-C, VLDL-C, TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios were significantly higher in asplenic participants (P ˂ 0.05).
Altered lipid profile seems to be another complication emerging after the splenectomy. Animal studies reported increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and decreased high-density lipoprotein cholesterol (HDL-C) in asplenic patients. This effect was stronger in animals fed with high-fat diets (Fatouros et al., 1995, Kanichi et al., 1988). Caligiuri et al. demonstrated that splenectomy accelerated atherosclerosis in mice (Caligiuri et al., 2002). As the most frequent cause of death in thalassemia is cardiopathy (69%) (Ceci et al., 2006), investigating the changes in lipid profile after the splenectomy is of high importance.
Splenectomy can indirectly affect the glucose metabolism as well (Rosa et al., 2015). Observations suggest that serum lipopolysaccharide levels are increased in splenectomized patients (Feleder et al., 2003, Yoshida et al., 1995).The spleen is an important bacteria debugger and the absence of this lymphoid organ causes the liver’s Kupffer cells to assume the role of clearing Lipopolysaccharides (LPS) (Ge et al., 1997, Sivitz et al., 1997). In turn, Kupffer cells increase the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, interfering with insulin signaling and glucose transport (Feleder et al., 2003, Sivitz et al., 1997), which increases fasting blood glucose (FBG). Children with severe thalassemia who required splenectomy were noted to develop insulin resistance due to the interaction of spleen and pancreas (Lee et al., 1985). We suspect that splenectomy might play a role in the high prevalence of diabetes mellitus in thalassemia patients.
Since splenectomy is prevalent among beta thalassemia major patients, we decided to find out the effect of splenectomy on these patients' health through glucose and lipid metabolism alteration.
Materials and Methods
Study population: This case-control study was conducted in Zafar Thalassemia Clinic, Tehran, Iran from January to February 2019. This clinic is a referral center for thalassemia patients to receive governmental and free health services. Forty one splenectomized and forty two non-splenectomized patients were recruited to participate in this study through convenient sampling method. Participants aged 18-30 years who had a history of using standard iron-chelating drugs, were non-alcoholic, non-smoker, and did not have any metabolic or infectious diseases were selected to participate in this research. Splenectomized patients had undergone the surgery at least a year before the study. All participants received multivitamin-mineral supplement during the past six months. Measurements: The participants’ height was measured to the nearest 0.01 cm while they were wearing no shoes. Their weight was also measured in light clothes without shoes and with a digital scale to the nearest 100 g. Body mass index (BMI) was calculated using weight (kg) divided by squared height (m). All measurements were performed using standardized procedures. Other information including age, gender, iron chelator drug, and blood transfusion intervals of the patients were obtained from their medical records.
To control the effect of confounders, dietary intake and physical activity were measured using reliable and validated questionnaires. Dietary data was collected using food frequency questionnaire (FFQ) (168-item), which represented the food intake throughout the last year. The information was collected using a face-to-face interview by a trained interviewer.
Information on physical activity was obtained using the International Physical Activity Questionnaire (IPAQ) (Moghaddam et al., 2012).
Blood samples were collected at least 10 days after the last blood transfusion and were obtained after 12 hours of fasting overnight. Samples were analyzed for FBG, oral glucose tolerance test (OGTT), TG, TC, HDL-C, LDL-C, TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratio using ELISA method (Ebioscience, USA). Hemoglobin (Hb), ferritin, white blood cells (WBC), and platelet were also measured as confounders.
Ethical considerations: All participants signed a written informed consent to enter the study. The protocol of this study was approved by the Ethics Committee of Iran University of Medical Sciences (IR.IUMS.REC 1397.97-04-207-31244).
Data analysis: The Kolmogorov-Smirnov test was run to test normality. The data for quantitative variables were reported in the form of mean ± Standard Deviation (SD). Independent t-test was applied to compare the mean of quantitative outcomes between the two groups. The ANCOVA analysis was used to examine the association between splenectomy, serum lipid, and glucose indices by adjusting the confounding variables. P- value < 0.05 was considered statistically significant. All analyses were performed using Statistical Package for Social Sciences (version 21.0, SPSS Inc,Chicago, IL).
Results
Comparison of the clinical and biochemical characteristics between splenectomized and non-splenectomized participants (Table 1) showed that 66.1% of them used desferrioxamine, 17.7% used deferiprone, and 16.1% used both drugs as iron chelator. Furthermore, 48.9% of the participants were male and 51.1% were female. No significant difference was observed between the two groups in clinical characteristics and physical activity. Splenectomy reduced the need for blood transfusion in splenectomized patients (P = 0.001) significantly. The WBC (P = 0.001) and platelet (P = 0.02) were significantly higher in splenectomized participants.
As observed in Table 2, no significant differences were found between the two groups regarding energy and macronutrients’ intake.
The correlation of splenectomy with glucose and lipid profile of the participants is represented in Table 3. According to ANCOVA analysis, after adjusting for blood transfusion intervals, WBC, and Platelet, splenectomy had no significant association with FBG or OGTT, but HDL-C was significantly lower. Moreover, the TG, TC, LDL-C, VLDL-C, TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios were significantly higher in asplenic participants (P ˂ 0.05).
| Table 1. Comparison of mean ± SD of anthropometric, physical activity score and laboratyry variables between splenectomized and non-splenectomized patients. | |||
| Variables | Splenectomized (n=41) | Non-splenectomized (n=42) | P-valuea |
| Age (y) | 28.59 ± 6.33 | 29.79 ± 6.55 | 0.92 |
| Weight (kg) | 58.31 ± 6.08 | 57.15 ± 6.36 | 0.69 |
| Height (cm) | 157.44 ± 4.89 | 159.44 ± 4.81 | 0.63 |
| Body mass index (kg/m2) | 23.51 ± 2.11 | 22.47 ± 2.21 | 0.44 |
| Blood transfusion intervals (day) | 93.21 ± 8.01 | 16.90 ± 3.49 | < 0.001 |
| Hemoglobin (g/dl) | 9.80 ± 1.03 | 9.72 ± 0.92 | 0.79 |
| Ferritin (ng/mL) | 1249.87 ± 576.27 | 1385.56 ± 652.14 | 0.14 |
| Wight blood cell (×109 cells/l) | 27.95 ± 4.29 | 5.87 ± 0.89 | < 0.001 |
| Platelet (×10 9cells/l) | 528.70 ± 146.74 | 284.21 ± 21 | 0.003 |
| Physical activity score | 447.96 ± 393.74 | 376.6 ± 338.61 | 0.25 |
| a: Student t-test | |||
| Table 2. Comparison of mean ± SD of daily dietary nutrients intake between splenectomized and non-splenectomized patients. | |||
| Nutrients | Splenectomized (n=41) | Non-splenectomized (n=42) | P-valuea |
| Energy (kcal) | 1541.45 ± 518.86 | 1412 ± 401.52 | 0.21 |
| Protein (g) | 51.02 ± 13.48 | 54.30 ± 13.73 | 0.81 |
| Carbohydrate (g) | 236.35 ± 26.17 | 203.29 ± 24.02 | 0.34 |
| Fat (g) | 56.14 ± 13.19 | 51.25 ± 13.11 | 0.48 |
| Cholesterol (g) | 270.33 ± 118.45 | 224.38 ± 102.28 | 0.10 |
| Fiber (g) | 6.52 ± 3.10 | 5.63 ± 3.07 | 0.48 |
| a: Student t-test | |||
| Table 3. Comparison of mean ± SD of biochemical characteristics between splenectomized and non-splenectomized patients. | |||
| Variables | Splenectomized (n=41) | Non-splenectomized (n=42) | P-valuea |
| FBG (mg/dl) | 79.54 ± 6.42 | 83.43 ± 6.96 | 0.39 |
| OGTT (mg/dl) | 138.70 ± 12.40 | 127.56 ± 14.37 | 0.53 |
| TG (mg/dl) | 2.59 ± 0.26 | 1.61 ± 0.26 | 0.01 |
| TC (mg/dl) | 3.73 ± 0.46 | 3.10 ± 0.44 | 0.04 |
| HDL-C (mg/dl) | 0.87 ± 0.25 | 1.47 ± 0.18 | 0.001 |
| LDL-C (mg/dl) | 2.72 ± 0.44 | 1.52 ± 0.34 | 0.001 |
| VLDL-C (mg/dl) | 0.54 ± 0.07 | 0.37 ± 0.05 | 0.02 |
| TC/HDL-C ratio | 4.64 ± 1.55 | 2.13 ± 0.42 | 0.001 |
| LDL-C/TG ratio | 1.10 ± 0.21 | 0.97 ± 0.30 | 0.04 |
| LDL-C/HDL-C ratio | 3.34 ± 1.10 | 1.03 ± 0.23 | 0.001 |
| a: ANCOVA test, FBG: fasting blood glucose, OGTT: oral glucose tolerance test, TG: triglycerides, TC: total cholesterol, HDL-C: high density lipoprotein cholesterol, VLDL-C: very low density lipoprotein cholesterol, LDL-C: low density lipoprotein cholestero, |
|||
Discussion
According to our findings, splenectomy could not affect FBG and OGTT, but it significantly decreased HDL and increased TG, TC, LDL-C, VLDL-C, TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios in beta thalassemia major patients.
In the 1970s, Robinette and Fraumeni Jr. observed a high mortality rate due to the cardiovascular diseases along with reduction in the serum lipids in soldiers who were splenectomized during the World War II. (Dennis Robinette and Fraumeni, 1977). In addition, other researchers investigated the relationship between splenectomy and serum lipid profile in human and animal studies, most of which noted the same results. Asai K. et al. found that splenectomized rabits ended up with atherosclerosis due to higher TG, TC, LDL, and lower HDL in comparison with the non-splenectomized rabits (Asai, 1988). Petroianu A. et al. observed higher TC and LDL and lower HDL in splenectomized female rats but no differences were observed between the two groups in VLDL and TG. They also reported that partial splenectomy would not induce such metabolic alterations that represent the important role of spleen in the lipid metabolism (Petroianu et al., 2006).
Our study also suggests a possible role for the spleen in lipid metabolism. A mechanism to explain the regulation of plasma lipids by the spleen can be the decreased activity of the reticuloendothelial system in the absence of the spleen. Under normal circumstances, macrophages absorb LDL and VLDL lipids via phagositisis, which transfers them to the spleen that is responsible for most of the LDL and VLDL catabolism. According to M. Aviram et al., this mechanism is responsible for the altered cholesterol metabolism in patients with myeloproliferative Disorder who have undergone splenectomy (Aviram et al., 1986).
A. Petroianu et al. suggested that changes in serum lipidograms observed after splenectomy may be due to the catabolic effect of surgical trauma on the organism, not the absence of spleen itself (Petroianu et al., 2008). However, this seems not to be the case in this study considering our inclusion criteria.
Higher TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios in asplenic patients suggest that splenectomized patients are in greater cardiovascular risk than non-splenectomized ones. Bordbar M. et al. proclaimed that LDL-C/TG ratio, which predicts LDL-C oxidation, is higher in young thalassemia patients than the healthy members of the control group (Bordbar et al., 2012). Boudrahem-Addour N. et al. noted that splenectomy constitutes an additional high risk factor for cardiac complications regarding TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios in thalassemia patients (Boudrahem-Addour et al., 2015). Splenectomy not only causes intravascular thrombosis and pulmonary hypertension, but also enhances the risk of coronary heart disease in thalassemia patients who are already at risk due to their heart's iron overload.
According to our findings, no significant differences were observed between splenectomized and non-splenectomized patients regarding FBG and OGTT. Findings suggest that spleen plays an important supportive role in the endocrine function of the pancreas and adjustment of blood glucose level in children (Ley et al., 2012). This can be caused by the unique population of cells located in the splenic capsule capable of differentiation into pancreatic islets (Kodama et al., 2003, Ley et al., 2012). However, according to our participants' age, the glucose metabolism can be affected by factors other than splenectomy such as iron deposition in pancreas and inflammation caused by iron overload, which indirectly affect insuline signaling and blood glucose level (Mowla et al., 2004, Zuppinger et al., 1979). A review study suggested that serum ferritin levels and iron content of endocrine glands, especially liver, Thyroide, and kidney were important factors in predicting glucose intolerance in thalassemia patients (De Sanctis et al., 2016). We could not assess the iron deposition in endocrine glands using the magnetic resonance imaging (MRI) method in our study due to the financial limitations. However, since the ferritin level of our participants was less than 2000 ng/ml, we could guess that the iron overload in the
mentioned tissues has not been enough to cause dysfunction.
We faced some limitations in this study. First, the patients’ diet was assessed using FFQ, which is based on self-reported dietary intake. Therefore, information bias might have occurred. Second, although we controlled many confounders, some other confounders might have been missed including the level of measured indices before the splenectomy in splenectomized patients. Retrospective design of this study was another defect because splenectomy could alter glucose metabolism in a longer period of time among older patients. Finally, lack of a direct and precise measurement of the amount of tissue's iron deposition confused us since we could not determine whether this finding was the effect of splenectomy or iron overload. The strengths of this study include adjusting for various confounders, using validated and reliable measurements, and sampling in a referral clinic.
Conclusion
According to our observation, splenectomy may affect the plasma lipid profile and the risk of cardiovascular disease, but not the glucose metabolism in adult beta thalassemia major patients. Further prospective studies are required with larger number of patients, longer follow up periods, and stronger analysis to better reveal the possible association between splenectomy and metabolic health of these patients.
Acknowledgement
We would like to thank the participants of this study and the staff of Zafar Thalassemia Clinic for their cooperation. The Vice Chancellor of Research of Iran University of Medical Sciences provided funding for this research under the grant number 31244.
Conflict of interest
None
Author’s contributions
All authors were involved in designing, developing, and drafting this manuscript. Sajedi-Hezaveh Z and Hadidi M cooperated in data collection and data analysis. Shidfar F was involved in interpretation of the results and critical revision. All authors approved the final draft of manuscript.
References
According to our findings, splenectomy could not affect FBG and OGTT, but it significantly decreased HDL and increased TG, TC, LDL-C, VLDL-C, TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios in beta thalassemia major patients.
In the 1970s, Robinette and Fraumeni Jr. observed a high mortality rate due to the cardiovascular diseases along with reduction in the serum lipids in soldiers who were splenectomized during the World War II. (Dennis Robinette and Fraumeni, 1977). In addition, other researchers investigated the relationship between splenectomy and serum lipid profile in human and animal studies, most of which noted the same results. Asai K. et al. found that splenectomized rabits ended up with atherosclerosis due to higher TG, TC, LDL, and lower HDL in comparison with the non-splenectomized rabits (Asai, 1988). Petroianu A. et al. observed higher TC and LDL and lower HDL in splenectomized female rats but no differences were observed between the two groups in VLDL and TG. They also reported that partial splenectomy would not induce such metabolic alterations that represent the important role of spleen in the lipid metabolism (Petroianu et al., 2006).
Our study also suggests a possible role for the spleen in lipid metabolism. A mechanism to explain the regulation of plasma lipids by the spleen can be the decreased activity of the reticuloendothelial system in the absence of the spleen. Under normal circumstances, macrophages absorb LDL and VLDL lipids via phagositisis, which transfers them to the spleen that is responsible for most of the LDL and VLDL catabolism. According to M. Aviram et al., this mechanism is responsible for the altered cholesterol metabolism in patients with myeloproliferative Disorder who have undergone splenectomy (Aviram et al., 1986).
A. Petroianu et al. suggested that changes in serum lipidograms observed after splenectomy may be due to the catabolic effect of surgical trauma on the organism, not the absence of spleen itself (Petroianu et al., 2008). However, this seems not to be the case in this study considering our inclusion criteria.
Higher TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios in asplenic patients suggest that splenectomized patients are in greater cardiovascular risk than non-splenectomized ones. Bordbar M. et al. proclaimed that LDL-C/TG ratio, which predicts LDL-C oxidation, is higher in young thalassemia patients than the healthy members of the control group (Bordbar et al., 2012). Boudrahem-Addour N. et al. noted that splenectomy constitutes an additional high risk factor for cardiac complications regarding TC/HDL-C, LDL-C/TG, and LDL-C/HDL-C ratios in thalassemia patients (Boudrahem-Addour et al., 2015). Splenectomy not only causes intravascular thrombosis and pulmonary hypertension, but also enhances the risk of coronary heart disease in thalassemia patients who are already at risk due to their heart's iron overload.
According to our findings, no significant differences were observed between splenectomized and non-splenectomized patients regarding FBG and OGTT. Findings suggest that spleen plays an important supportive role in the endocrine function of the pancreas and adjustment of blood glucose level in children (Ley et al., 2012). This can be caused by the unique population of cells located in the splenic capsule capable of differentiation into pancreatic islets (Kodama et al., 2003, Ley et al., 2012). However, according to our participants' age, the glucose metabolism can be affected by factors other than splenectomy such as iron deposition in pancreas and inflammation caused by iron overload, which indirectly affect insuline signaling and blood glucose level (Mowla et al., 2004, Zuppinger et al., 1979). A review study suggested that serum ferritin levels and iron content of endocrine glands, especially liver, Thyroide, and kidney were important factors in predicting glucose intolerance in thalassemia patients (De Sanctis et al., 2016). We could not assess the iron deposition in endocrine glands using the magnetic resonance imaging (MRI) method in our study due to the financial limitations. However, since the ferritin level of our participants was less than 2000 ng/ml, we could guess that the iron overload in the
mentioned tissues has not been enough to cause dysfunction.
We faced some limitations in this study. First, the patients’ diet was assessed using FFQ, which is based on self-reported dietary intake. Therefore, information bias might have occurred. Second, although we controlled many confounders, some other confounders might have been missed including the level of measured indices before the splenectomy in splenectomized patients. Retrospective design of this study was another defect because splenectomy could alter glucose metabolism in a longer period of time among older patients. Finally, lack of a direct and precise measurement of the amount of tissue's iron deposition confused us since we could not determine whether this finding was the effect of splenectomy or iron overload. The strengths of this study include adjusting for various confounders, using validated and reliable measurements, and sampling in a referral clinic.
Conclusion
According to our observation, splenectomy may affect the plasma lipid profile and the risk of cardiovascular disease, but not the glucose metabolism in adult beta thalassemia major patients. Further prospective studies are required with larger number of patients, longer follow up periods, and stronger analysis to better reveal the possible association between splenectomy and metabolic health of these patients.
Acknowledgement
We would like to thank the participants of this study and the staff of Zafar Thalassemia Clinic for their cooperation. The Vice Chancellor of Research of Iran University of Medical Sciences provided funding for this research under the grant number 31244.
Conflict of interest
None
Author’s contributions
All authors were involved in designing, developing, and drafting this manuscript. Sajedi-Hezaveh Z and Hadidi M cooperated in data collection and data analysis. Shidfar F was involved in interpretation of the results and critical revision. All authors approved the final draft of manuscript.
References
Asai K 1988. Effects of splenectomy on serum lipids and experimental atherosclerosis. Angiology. 39 (6): 497-504.
Aviram M, Brook J, Tatarsky I, Levy Y & Carter A 1986. Increased Low-Density Lipoprotein Levels After Splenectomy: A Role for the Spleen in Cholesterol Metabolism in Myeloproliferative Disorders. American Journal of the Medical Sciences. 291 (1): 25-28.
Bhatia M & Cairo M 2009. Splenectomy or no splenectomy prior to allogeneic stem-cell transplantation in patients with severe thalassemia: this is the question. Pediatric transplantation. 13 (2): 143-145.
Bordbar M, Haghpanah S, Afrasiabi A, Dehbozorgian J & Karimi M 2012. Genotype-phenotype correlation related to lipid profile in beta-thalassemia major and intermedia in southern Iran. Journal of clinical lipidology. 6 (2): 108-113.
Boudrahem-Addour N, et al. 2015. Oxidative status and plasma lipid profile in beta-thalassemia patients. Hemoglobin. 39 (1):36-41.
Caligiuri G, Nicoletti A, Poirier B & Hansson GK 2002. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. Journal of Clinical Investigation. 109 (6): 745-753.
Cappellini MD, Cohen A, Porter J, Taher A & Viprakasit V 2014. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). Nicosia, Cyprus: Thalassaemia International Federation.
Ceci A, et al. 2006. Risk factors for death in patients with beta-thalassemia major: results of a case-control study. Haematologica. 91 (10): 1420-1421.
Crary SE & Buchanan GR 2009. Vascular complications after splenectomy for hematologic disorders. Blood. 114 (14): 2861-2868.
De Sanctis V, et al. 2016. Diabetes and Glucose Metabolism in Thalassemia Major: An Update. Expert Review of Hematology. 9 (4): 401-408.
Dennis Robinette C & Fraumeni J 1977. Splenectomy and subsequent mortality in veterans of the 1939-45 war. Lancet. 310 (8029): 127-129.
Fatouros M, et al. 1995. Role of the spleen in lipid metabolism. British Journal of Surgery. 82 (12): 1675-1677.
Feleder C, Li Z, Perlik V, Evans A & Blatteis CM 2003. The spleen modulates the febrile response of guinea pigs to LPS. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 284 (6 53-6): R1466-R1476.
Ge Y, et al. 1997. Relationship of Tissue and Cellular Interleukin-1 and Lipopolysaccharide after Endotoxemia and Bacteremia. Journal of Infectious Diseases. 176 (5): 1313-1321.
Kanichi A, Masafumi K, Michitaka N, Chiaki F & Fumio K 1988. Effects of Splenectomy on Serum Lipids and Experimental Atherosclerosis. Angiology. 39 (6): 497-504.
Kodama S, Kuhtreiber W, Fujimura S, Dale EA & Faustman D 2003. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science (New York, N.Y.). 302 (5648): 1223-1227.
Lee B, et al. 1985. Glucose tolerance test and insulin levels in children with transfusion-dependent thalassaemia. Annals of tropical paediatrics. 5 (4): 215-218.
Ley E, et al. 2012. Long-term effect of trauma splenectomy on blood glucose. Journal of Surgical Research. 177 (1): 152-156.
Moghaddam MB, et al. 2012. The Iranian Version of International Physical Activity Questionnaire (IPAQ) in Iran: content and construct validity, factor structure, internal consistency and stability. World Applied Sciences Journal. 18 (8): 1073-1080.
Mowla A, Karimi M, Afrasiabi A & De Sanctis V 2004. Prevalence of diabetes mellitus and impaired glucose tolerance in beta-thalassemia patients with and without hepatitis C virus infection. Pediatric Endocrinology Reviews. 2 Suppl 2: 282-284.
Muncie Jr HL & Campbell JS 2009. Alpha and beta thalassemia. . American Family Physician. 80 (4): 339-344.
Nishi M, Satendra S, Sood SK, Roshan C & Bhatia HM 2010. Frequency of β-thalassemia trait and other hemoglobinopathies in northern and western India. Indian Journal of Human Genetics. 16 (1): 16-25.
Petroianu A, Veloso D, Alberti L & de Souza Vasconcellos L 2008. Plasma lipid alterations after total splenectomy, subtotal splenectomy and splenic auto-implants in rats. Journal of gastroenterology and hepatology. 23 (7 Pt 2): e221-224.
Petroianu A, Veloso DF, Costa GR & Alberti LR 2006. [Effects of splenic surgeries on lipidogram of rats]. Revista da Associacao Medica Brasileira (1992). 52 (1): 56-59.
Piga A, et al. 2011. Changing patterns of splenectomy in transfusion-dependent thalassemia patients. American journal of hematology. 86 (9): 808-810.
Rosa T, et al. 2015. Role of leptin in body temperature regulation and lipid metabolism following splenectomy. Neuropeptides. 54: 67-72.
Sivitz W, Walsh S, Morgan D, Thomas M & Haynes W 1997. Effects of leptin on insulin sensitivity in normal rats. Endocrinology. 138 (8): 3395-3401.
Wehr E, Pilz S, Boehm BO, März W & Obermayer‐Pietsch B 2010. Association of vitamin D status with serum androgen levels in men. Clinical endocrinology. 73 (2): 243-248.
Yoshida M, Roth RI & Levin J 1995. The effect of cell-free hemoglobin on intravascular clearance and cellular, plasma, and organ distribution of bacterial endotoxin in rabbits. Journal of Laboratory and Clinical Medicine. 126 (2): 151-160.
Zuppinger K, et al. 1979. Increased risk of diabetes mellitus in beta- thalassemia major due to iron overload. Helvetica paediatrica acta. 34 (3): 197-207.
Aviram M, Brook J, Tatarsky I, Levy Y & Carter A 1986. Increased Low-Density Lipoprotein Levels After Splenectomy: A Role for the Spleen in Cholesterol Metabolism in Myeloproliferative Disorders. American Journal of the Medical Sciences. 291 (1): 25-28.
Bhatia M & Cairo M 2009. Splenectomy or no splenectomy prior to allogeneic stem-cell transplantation in patients with severe thalassemia: this is the question. Pediatric transplantation. 13 (2): 143-145.
Bordbar M, Haghpanah S, Afrasiabi A, Dehbozorgian J & Karimi M 2012. Genotype-phenotype correlation related to lipid profile in beta-thalassemia major and intermedia in southern Iran. Journal of clinical lipidology. 6 (2): 108-113.
Boudrahem-Addour N, et al. 2015. Oxidative status and plasma lipid profile in beta-thalassemia patients. Hemoglobin. 39 (1):36-41.
Caligiuri G, Nicoletti A, Poirier B & Hansson GK 2002. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. Journal of Clinical Investigation. 109 (6): 745-753.
Cappellini MD, Cohen A, Porter J, Taher A & Viprakasit V 2014. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). Nicosia, Cyprus: Thalassaemia International Federation.
Ceci A, et al. 2006. Risk factors for death in patients with beta-thalassemia major: results of a case-control study. Haematologica. 91 (10): 1420-1421.
Crary SE & Buchanan GR 2009. Vascular complications after splenectomy for hematologic disorders. Blood. 114 (14): 2861-2868.
De Sanctis V, et al. 2016. Diabetes and Glucose Metabolism in Thalassemia Major: An Update. Expert Review of Hematology. 9 (4): 401-408.
Dennis Robinette C & Fraumeni J 1977. Splenectomy and subsequent mortality in veterans of the 1939-45 war. Lancet. 310 (8029): 127-129.
Fatouros M, et al. 1995. Role of the spleen in lipid metabolism. British Journal of Surgery. 82 (12): 1675-1677.
Feleder C, Li Z, Perlik V, Evans A & Blatteis CM 2003. The spleen modulates the febrile response of guinea pigs to LPS. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 284 (6 53-6): R1466-R1476.
Ge Y, et al. 1997. Relationship of Tissue and Cellular Interleukin-1 and Lipopolysaccharide after Endotoxemia and Bacteremia. Journal of Infectious Diseases. 176 (5): 1313-1321.
Kanichi A, Masafumi K, Michitaka N, Chiaki F & Fumio K 1988. Effects of Splenectomy on Serum Lipids and Experimental Atherosclerosis. Angiology. 39 (6): 497-504.
Kodama S, Kuhtreiber W, Fujimura S, Dale EA & Faustman D 2003. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science (New York, N.Y.). 302 (5648): 1223-1227.
Lee B, et al. 1985. Glucose tolerance test and insulin levels in children with transfusion-dependent thalassaemia. Annals of tropical paediatrics. 5 (4): 215-218.
Ley E, et al. 2012. Long-term effect of trauma splenectomy on blood glucose. Journal of Surgical Research. 177 (1): 152-156.
Moghaddam MB, et al. 2012. The Iranian Version of International Physical Activity Questionnaire (IPAQ) in Iran: content and construct validity, factor structure, internal consistency and stability. World Applied Sciences Journal. 18 (8): 1073-1080.
Mowla A, Karimi M, Afrasiabi A & De Sanctis V 2004. Prevalence of diabetes mellitus and impaired glucose tolerance in beta-thalassemia patients with and without hepatitis C virus infection. Pediatric Endocrinology Reviews. 2 Suppl 2: 282-284.
Muncie Jr HL & Campbell JS 2009. Alpha and beta thalassemia. . American Family Physician. 80 (4): 339-344.
Nishi M, Satendra S, Sood SK, Roshan C & Bhatia HM 2010. Frequency of β-thalassemia trait and other hemoglobinopathies in northern and western India. Indian Journal of Human Genetics. 16 (1): 16-25.
Petroianu A, Veloso D, Alberti L & de Souza Vasconcellos L 2008. Plasma lipid alterations after total splenectomy, subtotal splenectomy and splenic auto-implants in rats. Journal of gastroenterology and hepatology. 23 (7 Pt 2): e221-224.
Petroianu A, Veloso DF, Costa GR & Alberti LR 2006. [Effects of splenic surgeries on lipidogram of rats]. Revista da Associacao Medica Brasileira (1992). 52 (1): 56-59.
Piga A, et al. 2011. Changing patterns of splenectomy in transfusion-dependent thalassemia patients. American journal of hematology. 86 (9): 808-810.
Rosa T, et al. 2015. Role of leptin in body temperature regulation and lipid metabolism following splenectomy. Neuropeptides. 54: 67-72.
Sivitz W, Walsh S, Morgan D, Thomas M & Haynes W 1997. Effects of leptin on insulin sensitivity in normal rats. Endocrinology. 138 (8): 3395-3401.
Wehr E, Pilz S, Boehm BO, März W & Obermayer‐Pietsch B 2010. Association of vitamin D status with serum androgen levels in men. Clinical endocrinology. 73 (2): 243-248.
Yoshida M, Roth RI & Levin J 1995. The effect of cell-free hemoglobin on intravascular clearance and cellular, plasma, and organ distribution of bacterial endotoxin in rabbits. Journal of Laboratory and Clinical Medicine. 126 (2): 151-160.
Zuppinger K, et al. 1979. Increased risk of diabetes mellitus in beta- thalassemia major due to iron overload. Helvetica paediatrica acta. 34 (3): 197-207.
Type of article: orginal article |
Subject:
public specific
Received: 2020/05/6 | Published: 2017/11/15 | ePublished: 2017/11/15
Received: 2020/05/6 | Published: 2017/11/15 | ePublished: 2017/11/15
References
1. Asai K 1988. Effects of splenectomy on serum lipids and experimental atherosclerosis. Angiology. 39 (6): 497-504.
2. Aviram M, Brook J, Tatarsky I, Levy Y & Carter A 1986. Increased Low-Density Lipoprotein Levels After Splenectomy: A Role for the Spleen in Cholesterol Metabolism in Myeloproliferative Disorders. American Journal of the Medical Sciences. 291 (1): 25-28.
3. Bhatia M & Cairo M 2009. Splenectomy or no splenectomy prior to allogeneic stem-cell transplantation in patients with severe thalassemia: this is the question. Pediatric transplantation. 13 (2): 143-145.
4. Bordbar M, Haghpanah S, Afrasiabi A, Dehbozorgian J & Karimi M 2012. Genotype-phenotype correlation related to lipid profile in beta-thalassemia major and intermedia in southern Iran. Journal of clinical lipidology. 6 (2): 108-113.
5. Boudrahem-Addour N, et al. 2015. Oxidative status and plasma lipid profile in beta-thalassemia patients. Hemoglobin. 39 (1): 36-41.
7. Caligiuri G, Nicoletti A, Poirier B & Hansson GK 2002. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. Journal of Clinical Investigation. 109 (6): 745-753.
8. Cappellini MD, Cohen A, Porter J, Taher A & Viprakasit V 2014. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). Nicosia, Cyprus: Thalassaemia International Federation.
9. Ceci A, et al. 2006. Risk factors for death in patients with beta-thalassemia major: results of a case-control study. Haematologica. 91 (10): 1420-1421.
10. Crary SE & Buchanan GR 2009. Vascular complications after splenectomy for hematologic disorders. Blood. 114 (14): 2861-2868.
11. De Sanctis V, et al. 2016. Diabetes and Glucose Metabolism in Thalassemia Major: An Update. Expert Review of Hematology. 9 (4): 401-408.
12. Dennis Robinette C & Fraumeni J 1977. Splenectomy and subsequent mortality in veterans of the 1939-45 war. Lancet. 310 (8029): 127-129.
13. Fatouros M, et al. 1995. Role of the spleen in lipid metabolism. British Journal of Surgery. 82 (12): 1675-1677.
14. Feleder C, Li Z, Perlik V, Evans A & Blatteis CM 2003. The spleen modulates the febrile response of guinea pigs to LPS. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 284 (6 53-6): R1466-R1476.
15. Ge Y, et al. 1997. Relationship of Tissue and Cellular Interleukin-1 and Lipopolysaccharide after Endotoxemia and Bacteremia. Journal of Infectious Diseases. 176 (5): 1313-1321.
16. Kanichi A, Masafumi K, Michitaka N, Chiaki F & Fumio K 1988. Effects of Splenectomy on Serum Lipids and Experimental Atherosclerosis. Angiology. 39 (6): 497-504.
17. Kodama S, Kuhtreiber W, Fujimura S, Dale EA & Faustman D 2003. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science (New York, N.Y.). 302 (5648): 1223-1227.
18. Lee B, et al. 1985. Glucose tolerance test and insulin levels in children with transfusion-dependent thalassaemia. Annals of tropical paediatrics. 5 (4): 215-218.
19. Ley E, et al. 2012. Long-term effect of trauma splenectomy on blood glucose. Journal of Surgical Research. 177 (1): 152-156.
20. Moghaddam MB, et al. 2012. The Iranian Version of International Physical Activity Questionnaire (IPAQ) in Iran: content and construct validity, factor structure, internal consistency and stability. World Applied Sciences Journal. 18 (8): 1073-1080.
21. Mowla A, Karimi M, Afrasiabi A & De Sanctis V 2004. Prevalence of diabetes mellitus and impaired glucose tolerance in beta-thalassemia patients with and without hepatitis C virus infection. Pediatric Endocrinology Reviews. 2 Suppl 2: 282-284.
22. Muncie Jr HL & Campbell JS 2009. Alpha and beta thalassemia. . American Family Physician. 80 (4): 339-344.
23. Nishi M, Satendra S, Sood SK, Roshan C & Bhatia HM 2010. Frequency of β-thalassemia trait and other hemoglobinopathies in northern and western India. Indian Journal of Human Genetics. 16 (1): 16-25.
24. Petroianu A, Veloso D, Alberti L & de Souza Vasconcellos L 2008. Plasma lipid alterations after total splenectomy, subtotal splenectomy and splenic auto-implants in rats. Journal of gastroenterology and hepatology. 23 (7 Pt 2): e221-224.
25. Petroianu A, Veloso DF, Costa GR & Alberti LR 2006. [Effects of splenic surgeries on lipidogram of rats]. Revista da Associacao Medica Brasileira (1992). 52 (1): 56-59.
26. Piga A, et al. 2011. Changing patterns of splenectomy in transfusion-dependent thalassemia patients. American journal of hematology. 86 (9): 808-810.
27. Rosa T, et al. 2015. Role of leptin in body temperature regulation and lipid metabolism following splenectomy. Neuropeptides. 54: 67-72.
28. Sivitz W, Walsh S, Morgan D, Thomas M & Haynes W 1997. Effects of leptin on insulin sensitivity in normal rats. Endocrinology. 138 (8): 3395-3401.
29. Wehr E, Pilz S, Boehm BO, März W & Obermayer‐Pietsch B 2010. Association of vitamin D status with serum androgen levels in men. Clinical endocrinology. 73 (2): 243-248.
30. Yoshida M, Roth RI & Levin J 1995. The effect of cell-free hemoglobin on intravascular clearance and cellular, plasma, and organ distribution of bacterial endotoxin in rabbits. Journal of Laboratory and Clinical Medicine. 126 (2): 151-160.
31. Zuppinger K, et al. 1979. Increased risk of diabetes mellitus in beta- thalassemia major due to iron overload. Helvetica paediatrica acta. 34 (3): 197-207.
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